News & Perspective > Reuters Health Information
New Study on Monsanto Weedkiller to Feed Into Crucial EU Vote
By Kate Kelland
April 14, 2017
LONDON (Reuters) - Results of a new animal study into possible health risks of the weedkiller glyphosate will be published in time to inform a key EU re-licensing vote due by the end of 2017, according to the researcher leading the trial.
A row over possible effects of glyphosate - an ingredient in Monsanto's big-selling herbicide Roundup - has prompted investigations by congressional committees in the United States and forced a delay in Europe to a decision on whether it should be banned or re-licensed for sale.
Giving details and preliminary findings of the latest study to Reuters, Italian scientist Fiorella Belpoggi said experimental rats exposed to the herbicide at levels equivalent to those allowed in humans showed no initial adverse reaction.
"Exposed animals had no evident differences from non-exposed animals," Belpoggi, who is director of the Cesare Maltoni Cancer Research Centre at the Ramazzini Institute in Italy, said in a telephone interview.
"But this tells us very little at the moment, because the examinations of key parameters that could be affected by exposure are still being done (and) we are waiting for those results," Belpoggi added.
Those parameters include any genetic changes, as well as potential toxic effects on measures related to fertility, such as sperm, embryo development and offspring growth, she said.
Argument over glyphosate centers on whether it is carcinogenic. Scientists at the International Agency for Research on Cancer (IARC) say it probably does cause cancer, putting them at odds with scientists at the European Food Safety Authority, the U.S. Environmental Protection Agency and multiple other safety and regulatory agencies around the world, who say it likely doesn't.
Congressional committees in the United States have raised questions about the work and funding of IARC, which is based in Lyon, France, and the Ramazzini Institute, based in Bologna.
IARC and Ramazzini defend the independence of their work and say their research is conducted to the highest scientific standards.
DECADES OF RESEARCH
A spokesman for Monsanto said: "There are nearly a thousand scientific studies from decades of research that are already available to every regulatory agency in the world, which have all concluded that glyphosate is safe to use."
According to data published by IARC, glyphosate was registered in more than 130 countries as of 2010 and is one of the most heavily used weedkillers in the world. Analysts have estimated Monsanto could lose out on up to $100 million of sales if glyphosate were banned in Europe.
Belpoggi said her team decided to conduct their trial to produce fresh, independent results in an effort to settle differences over glyphosate's health effect.
But she stressed that due to time constraints, the study is not able to analyze the weed killer's potential carcinogenicity, which would take several years to research properly, given the time any tumors might take to develop and grow.
"We are focused on reproductive and developmental issues, in other words, whether glyphosate . . . affects the development of embryos, fetuses and pups," she said.
Chemicals that can affect hormones and reproduction are known as endocrine disruptors and, like carcinogens, are subject to strict regulations in the European Union.
This study involves scientists working at five laboratories, Belpoggi's and one other in Italy, and three outside the country. "This was to ensure we would have the best experts analyze each end point," Belpoggi said. The study is funded by the Ramazzini Institute, a research cooperative of around 28,000 members who are its co-owners and raise funds for its work.
Using laboratory rodents known as Sprague Dawley rats, the researchers exposed them to low levels of glyphosate and its formulation Roundup in their diet, equivalent to U.S. Acceptable Daily Intake (ADI) levels permitted in humans.
The U.S. ADI for glyphosate is 1.75 milligrams per kilogram (2.2 pounds) of body weight per day while the European Union ADI for consumers is 0.5 milligrams per kilogram of body weight.
Full results should be available by June, Belpoggi said, and will be submitted in a paper for peer review and publication in a scientific journal. A draft copy of the results will be sent at the same time to the European Commission.
The Commission has said it expects to restart talks with EU member states by August on re-approving the use of glyphosate in herbicides. A decision is due before the end of 2017.
"We would like to have the results in time to help regulators have a good judgment about this chemical," Belpoggi said. "If it is negative (no effect), then I will be happy because I am also exposed. But if there is some damage, then we would like everyone to know."
miércoles, 26 de abril de 2017
FDA sends warning over 65 fraudulent cancer treatments
FDA sends warning over 65 fraudulent cancer treatments
FDAApril 25, 2017—Today, the U.S. Food and Drug Administration posted several warning letters addressed to 14 U.S.-based companies found to be illegally marketing, selling, and distributing fraudulent cancer treatment. Over 65 specific products were found to claim to prevent, diagnose, or cure various types of cancer. These products are marketed and sold without receiving FDA approval. They are marketed most commonly on websites and social media platforms, directly to individual consumers.
“Consumers should not use these or similar unproven products because they may be unsafe and could prevent a person from seeking an appropriate and potentially life-saving cancer diagnosis or treatment,” said Douglas W. Stearn, director of the Office of Enforcement and Import Operations in the FDA’s Office of Regulatory Affairs in a press release.
The Federal Food, Drug and Cosmetic Act (FD&C) makes it illegal to market and sell products that claim to prevent, diagnose, treat, mitigate, or cure diseases without first demonstrating to the FDA that they are safe and effective for their labeled uses.
The products cited in the warning letters include pills, creams, ointments, oils, and diagnostics devices, among others. Cited products made unproven claims regarding preventing, or curing cancer; killing/inhibiting cancer cells and tumors; or similarly explosive anti-cancer claims.
The FDA continues to monitor companies promoting and selling unproven treatments to reduce potential dangers to consumers and to educate about associated risks.
The FDA encourages health care professionals and consumers to report adverse reactions associated with these or similar products to the agency’s MedWatch program.
As a part of continued competency, it is important for practitioners to be aware of the dangers of illegal drugs and how best to warn their patients to avoid them. “We encourage people to remain vigilant whether online or in a store, and avoid purchasing products marketed to treat cancer without any proof they will work. Patients should consult a health care professional about proper prevention, diagnosis and treatment of cancer,” said Stearn.
FDAApril 25, 2017—Today, the U.S. Food and Drug Administration posted several warning letters addressed to 14 U.S.-based companies found to be illegally marketing, selling, and distributing fraudulent cancer treatment. Over 65 specific products were found to claim to prevent, diagnose, or cure various types of cancer. These products are marketed and sold without receiving FDA approval. They are marketed most commonly on websites and social media platforms, directly to individual consumers.
“Consumers should not use these or similar unproven products because they may be unsafe and could prevent a person from seeking an appropriate and potentially life-saving cancer diagnosis or treatment,” said Douglas W. Stearn, director of the Office of Enforcement and Import Operations in the FDA’s Office of Regulatory Affairs in a press release.
The Federal Food, Drug and Cosmetic Act (FD&C) makes it illegal to market and sell products that claim to prevent, diagnose, treat, mitigate, or cure diseases without first demonstrating to the FDA that they are safe and effective for their labeled uses.
The products cited in the warning letters include pills, creams, ointments, oils, and diagnostics devices, among others. Cited products made unproven claims regarding preventing, or curing cancer; killing/inhibiting cancer cells and tumors; or similarly explosive anti-cancer claims.
The FDA continues to monitor companies promoting and selling unproven treatments to reduce potential dangers to consumers and to educate about associated risks.
The FDA encourages health care professionals and consumers to report adverse reactions associated with these or similar products to the agency’s MedWatch program.
As a part of continued competency, it is important for practitioners to be aware of the dangers of illegal drugs and how best to warn their patients to avoid them. “We encourage people to remain vigilant whether online or in a store, and avoid purchasing products marketed to treat cancer without any proof they will work. Patients should consult a health care professional about proper prevention, diagnosis and treatment of cancer,” said Stearn.
martes, 18 de abril de 2017
Niraparib for Ovarian Cancer
FDA Approves Niraparib for Ovarian Cancer
Jason M. Broderick @jasoncology
Published Online: Monday, Mar 27, 2017
The FDA has approved the PARP inhibitor niraparib (Zejula) for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
The approval is based on the phase III NOVA trial, in which niraparib reduced the risk of progression or death by 74% compared with placebo for patients with germline BRCA-positive platinum-sensitive, recurrent ovarian cancer.1,2
The median progression-free survival (PFS) with maintenance niraparib was 21 months compared with 5.5 months for placebo in patients with germline BRCA mutations (HR, 0.26; 95% CI, 0.17-0.41; P <.0001). These findings remained consistent across subgroups of patients, including those without BRCA mutations.
“Despite high response rates to platinum-based treatment in recurrent ovarian cancer patients, the effectiveness of such chemotherapy diminishes over time. Unfortunately, progression-free survival generally gets shorter after each subsequent treatment with a platinum-based chemotherapy regimen. Therefore, a treatment like Zejula that can increase progression-free survival after platinum therapy is very meaningful to patients and their families,” Ursula Matulonis, MD, director, gynecologic oncology at Dana-Farber Cancer Institute and professor of medicine, Harvard Medical School, said in a statement.
“Until recently, there have been few treatment advances for women with recurrent ovarian cancer and even fewer options available for women who do not harbor BRCA mutations. We are excited to have the opportunity to offer appropriate patients an oral, once-daily maintenance treatment that reduces the risk of cancer progression and extends the time between courses of chemotherapy for patients who have few treatment options,” added Matulonis.
The phase III NOVA study randomized patients in a 2:1 ratio across 2 independent cohorts. In the first cohort, 201 patients with germline BRCA mutations received niraparib at 300 mg daily (n = 138) or placebo (n = 65). In the second cohort, 345 patients with non-germline BRCA-mutant tumors received the PARP Inhibitor (n = 231) or placebo (n = 114). Patients in this group were tested for homologous recombination deficiency (HRD), and could be either positive (n = 162) or negative (n = 134). Of those who tested positive, 47 had somatic BRCA mutations and 115 were wild-type.
Patient demographics were well balanced between the arms for each cohort. In the germline BRCA group, the median age was 57 years and 65.9% had an ECOG performance status (PS) of 0. In the placebo group, the median age was 58 years and 73.8% of patients had an ECOG PS of 0. Overall, 48.6% and 53.8% of patients had received ≥3 prior therapies, in the niraparib and placebo arms, respectively.
Across both cohorts, the majority of patients had stage III cancer (68.8% to 74.1%). Approximately half of patients had achieved a complete response to prior platinum-based therapy and a quarter had received prior bevacizumab. In the non-BRCA-mutant arm, 33.8% and 32.8% of patients had received ≥3 prior therapies.
In the germline BRCA mutation group, the chemotherapy-free interval was 22.8 months with niraparib compared with 9.4 months for placebo (HR, 0.26; 95% CI, 0.17-0.41; P <.001). The median time to subsequent therapy was 21 months with niraparib versus 8.4 months with placebo (HR, 0.31; 95% CI, 0.21-0.48). The median time to progression or death during the first subsequent therapy following the study (PFS2) was 25.8 months for those who received maintenance niraparib versus 19.5 months for placebo (HR, 0.48; 95% CI, 0.28-0.82; P = .006). Findings for overall survival were not yet mature (fewer than 20% of events). At the time of the analysis, niraparib had reduced the risk of death by 27% versus placebo, although this finding was not statistically significant (HR, 0.73; 95% CI, 0.480-1.125; P = .1545). In patients with HRD-positive, BRCA wild-type tumors, median PFS was 9.3 versus 3.7 months for niraparib and placebo, respectively (HR, 0.38; 95% CI, 0.23-0.63; P <.001). In those with HRD-positive, somatic BRCA-mutated tumors, the median PFS was 20.9 months with niraparib versus 11.0 months for placebo (HR, 0.27; 95% CI, 0.08-0.90; P = .02). In patients with HRD-negative, non-germline BRCA-mutated tumors, median PFS was 6.9 versus 3.8 months for niraparib and placebo, respectively (HR, 0.58; 95% CI, 0.36-0.92; P = .02). In those with non-germline BRCA mutations regardless of HRD status, the median chemotherapy-free interval was 12.7 versus 8.6 months for niraparib and placebo, respectively (HR, 0.50; 95% CI, 0.37-0.67; P <.001). The median time to subsequent therapy was 11.8 versus 7.2 months (HR, 0.55; 95% CI, 0.41-0.72; P <.001) and the median PFS2 was 18.6 and 15.6 months for the niraparib and placebo arms, respectively (HR, 0.69; 95% CI, 0.49-0.96; P = .03). Across cohorts, 14.7% of 367 niraparib-treated patients discontinued therapy due to an adverse event (AE) compared with 2.2% of the 179 patients in the placebo arm. There were no treatment-related deaths in the study. In the follow-up period, 1 patient in the niraparib arm and 2 in the placebo group died of myelodysplastic syndrome or acute myeloid leukemia. One of these deaths in each arm was deemed to be treatment related. “The approval of Zejula, the first maintenance therapy approved in the United States for recurrent ovarian cancer, is extremely encouraging for the ovarian cancer community,” Mansoor Raza Mirza, MD, ENGOT-OV16/NOVA study chair and medical director of the Nordic Society of Gynaecological Oncology (NSGO), said in a statement. “The unique design of the NOVA study, which included women both with and without germline BRCA mutations, allowed us to determine that Zejula provides significant progression-free survival improvement in a very broad patient population. Having the option of prescribing Zejula without the need for a diagnostic test could fundamentally change the way we treat this disease from ‘watch and wait’ after a response to chemotherapy, to active treatment. With the significant increase in PFS observed in NOVA, I believe that we are changing the course of disease for patients with ovarian cancer, regardless of platinum sensitivity and independent of BRCA mutation or biomarker status.”
The most common all-grade AEs for niraparib versus placebo, respectively, were nausea (73.6% vs 35.2%, respectively), thrombocytopenia (61.3% vs 5.6%), fatigue (59.4% vs 41.3%), anemia (50.1% vs 6.7%), constipation (39.8% vs 20.1%), vomiting (34.3% vs 16.2%), and neutropenia (30.2% vs 6.1%).
The most common grade 3/4 AEs in the niraparib arm were hematologic, and included thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%). The most common non-hematologic AEs were hypertension (8.2%), fatigue (8.2%), and nausea (3%). A majority of hematologic AEs were experienced in the first 3 cycles.
Tesaro, the manufacturer of niraparib, initiated a rolling submission of data from the NOVA trial for a new drug application in September 2016, after receiving a fast track designation from the FDA. In its statement today, the company reported that it anticipates that niraparib will be officially launched in the United States in late April.
“We are so gratified to bring this unique new medicine to women with ovarian cancer, and would like to thank the patients who gave selflessly to participate in this trial with the assistance of their caregivers and physicians. We consider clinical trial participants to be the most important contributors to the success of the Zejula clinical development program,” Mary Lynne Hedley, PhD, president and chief operating officer of Tesaro, said in a statement. “We would also like to express our appreciation to the FDA for its rapid and thorough assessment of the Zejula application in less than 3 months after it was accepted for review, as well as our partners at ENGOT for their diligence and care in executing the NOVA clinical trial. Tesaro is committed to supporting women bravely facing ovarian cancer and we are planning to work with patients, healthcare providers and payers to ensure access to this paradigm-changing medicine.”
Jason M. Broderick @jasoncology
Published Online: Monday, Mar 27, 2017
The FDA has approved the PARP inhibitor niraparib (Zejula) for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
The approval is based on the phase III NOVA trial, in which niraparib reduced the risk of progression or death by 74% compared with placebo for patients with germline BRCA-positive platinum-sensitive, recurrent ovarian cancer.1,2
The median progression-free survival (PFS) with maintenance niraparib was 21 months compared with 5.5 months for placebo in patients with germline BRCA mutations (HR, 0.26; 95% CI, 0.17-0.41; P <.0001). These findings remained consistent across subgroups of patients, including those without BRCA mutations.
“Despite high response rates to platinum-based treatment in recurrent ovarian cancer patients, the effectiveness of such chemotherapy diminishes over time. Unfortunately, progression-free survival generally gets shorter after each subsequent treatment with a platinum-based chemotherapy regimen. Therefore, a treatment like Zejula that can increase progression-free survival after platinum therapy is very meaningful to patients and their families,” Ursula Matulonis, MD, director, gynecologic oncology at Dana-Farber Cancer Institute and professor of medicine, Harvard Medical School, said in a statement.
“Until recently, there have been few treatment advances for women with recurrent ovarian cancer and even fewer options available for women who do not harbor BRCA mutations. We are excited to have the opportunity to offer appropriate patients an oral, once-daily maintenance treatment that reduces the risk of cancer progression and extends the time between courses of chemotherapy for patients who have few treatment options,” added Matulonis.
The phase III NOVA study randomized patients in a 2:1 ratio across 2 independent cohorts. In the first cohort, 201 patients with germline BRCA mutations received niraparib at 300 mg daily (n = 138) or placebo (n = 65). In the second cohort, 345 patients with non-germline BRCA-mutant tumors received the PARP Inhibitor (n = 231) or placebo (n = 114). Patients in this group were tested for homologous recombination deficiency (HRD), and could be either positive (n = 162) or negative (n = 134). Of those who tested positive, 47 had somatic BRCA mutations and 115 were wild-type.
Patient demographics were well balanced between the arms for each cohort. In the germline BRCA group, the median age was 57 years and 65.9% had an ECOG performance status (PS) of 0. In the placebo group, the median age was 58 years and 73.8% of patients had an ECOG PS of 0. Overall, 48.6% and 53.8% of patients had received ≥3 prior therapies, in the niraparib and placebo arms, respectively.
Across both cohorts, the majority of patients had stage III cancer (68.8% to 74.1%). Approximately half of patients had achieved a complete response to prior platinum-based therapy and a quarter had received prior bevacizumab. In the non-BRCA-mutant arm, 33.8% and 32.8% of patients had received ≥3 prior therapies.
In the germline BRCA mutation group, the chemotherapy-free interval was 22.8 months with niraparib compared with 9.4 months for placebo (HR, 0.26; 95% CI, 0.17-0.41; P <.001). The median time to subsequent therapy was 21 months with niraparib versus 8.4 months with placebo (HR, 0.31; 95% CI, 0.21-0.48). The median time to progression or death during the first subsequent therapy following the study (PFS2) was 25.8 months for those who received maintenance niraparib versus 19.5 months for placebo (HR, 0.48; 95% CI, 0.28-0.82; P = .006). Findings for overall survival were not yet mature (fewer than 20% of events). At the time of the analysis, niraparib had reduced the risk of death by 27% versus placebo, although this finding was not statistically significant (HR, 0.73; 95% CI, 0.480-1.125; P = .1545). In patients with HRD-positive, BRCA wild-type tumors, median PFS was 9.3 versus 3.7 months for niraparib and placebo, respectively (HR, 0.38; 95% CI, 0.23-0.63; P <.001). In those with HRD-positive, somatic BRCA-mutated tumors, the median PFS was 20.9 months with niraparib versus 11.0 months for placebo (HR, 0.27; 95% CI, 0.08-0.90; P = .02). In patients with HRD-negative, non-germline BRCA-mutated tumors, median PFS was 6.9 versus 3.8 months for niraparib and placebo, respectively (HR, 0.58; 95% CI, 0.36-0.92; P = .02). In those with non-germline BRCA mutations regardless of HRD status, the median chemotherapy-free interval was 12.7 versus 8.6 months for niraparib and placebo, respectively (HR, 0.50; 95% CI, 0.37-0.67; P <.001). The median time to subsequent therapy was 11.8 versus 7.2 months (HR, 0.55; 95% CI, 0.41-0.72; P <.001) and the median PFS2 was 18.6 and 15.6 months for the niraparib and placebo arms, respectively (HR, 0.69; 95% CI, 0.49-0.96; P = .03). Across cohorts, 14.7% of 367 niraparib-treated patients discontinued therapy due to an adverse event (AE) compared with 2.2% of the 179 patients in the placebo arm. There were no treatment-related deaths in the study. In the follow-up period, 1 patient in the niraparib arm and 2 in the placebo group died of myelodysplastic syndrome or acute myeloid leukemia. One of these deaths in each arm was deemed to be treatment related. “The approval of Zejula, the first maintenance therapy approved in the United States for recurrent ovarian cancer, is extremely encouraging for the ovarian cancer community,” Mansoor Raza Mirza, MD, ENGOT-OV16/NOVA study chair and medical director of the Nordic Society of Gynaecological Oncology (NSGO), said in a statement. “The unique design of the NOVA study, which included women both with and without germline BRCA mutations, allowed us to determine that Zejula provides significant progression-free survival improvement in a very broad patient population. Having the option of prescribing Zejula without the need for a diagnostic test could fundamentally change the way we treat this disease from ‘watch and wait’ after a response to chemotherapy, to active treatment. With the significant increase in PFS observed in NOVA, I believe that we are changing the course of disease for patients with ovarian cancer, regardless of platinum sensitivity and independent of BRCA mutation or biomarker status.”
The most common all-grade AEs for niraparib versus placebo, respectively, were nausea (73.6% vs 35.2%, respectively), thrombocytopenia (61.3% vs 5.6%), fatigue (59.4% vs 41.3%), anemia (50.1% vs 6.7%), constipation (39.8% vs 20.1%), vomiting (34.3% vs 16.2%), and neutropenia (30.2% vs 6.1%).
The most common grade 3/4 AEs in the niraparib arm were hematologic, and included thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%). The most common non-hematologic AEs were hypertension (8.2%), fatigue (8.2%), and nausea (3%). A majority of hematologic AEs were experienced in the first 3 cycles.
Tesaro, the manufacturer of niraparib, initiated a rolling submission of data from the NOVA trial for a new drug application in September 2016, after receiving a fast track designation from the FDA. In its statement today, the company reported that it anticipates that niraparib will be officially launched in the United States in late April.
“We are so gratified to bring this unique new medicine to women with ovarian cancer, and would like to thank the patients who gave selflessly to participate in this trial with the assistance of their caregivers and physicians. We consider clinical trial participants to be the most important contributors to the success of the Zejula clinical development program,” Mary Lynne Hedley, PhD, president and chief operating officer of Tesaro, said in a statement. “We would also like to express our appreciation to the FDA for its rapid and thorough assessment of the Zejula application in less than 3 months after it was accepted for review, as well as our partners at ENGOT for their diligence and care in executing the NOVA clinical trial. Tesaro is committed to supporting women bravely facing ovarian cancer and we are planning to work with patients, healthcare providers and payers to ensure access to this paradigm-changing medicine.”
jueves, 13 de abril de 2017
VISTA Is a Novel Broad-Spectrum Negative Checkpoint Regulator for Cancer Immunotherapy
VISTA Is a Novel Broad-Spectrum Negative Checkpoint Regulator for Cancer Immunotherapy
J. Louise Lines,1,2 Lorenzo F. Sempere,3 Thomas Broughton,4,5 Li Wang,7 and Randolph Noelle1,2,4,5,6
Author information ► Copyright and License information ►
The publisher's final edited version of this article is available free at Cancer Immunol Res
Abstract
In the past few years, the field of cancer immunotherapy has made great progress and is finally starting to change the way cancer is treated. We are now learning that multiple negative checkpoint regulators (NCR) restrict the ability of T-cell responses to effectively attack tumors. Releasing these brakes through antibody blockade, first with anti-CTLA4 and now followed by anti-PD1 and anti-PDL1, has emerged as an exciting strategy for cancer treatment.
More recently, a new NCR has surfaced called V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation (VISTA). This NCR is predominantly expressed on hematopoietic cells, and in multiple murine cancer models is found at particularly high levels on myeloid cells that infiltrated the tumors.
Preclinical studies with VISTA blockade have shown promising improvement in antitumor T-cell responses, leading to impeded tumor growth and improved survival.
Clinical trials support combined anti-PD1 and anti-CTLA4 as safe and effective against late-stage melanoma. In the future, treatment may involve combination therapy to target the multiple cell types and stages at which NCRs, including VISTA, act during adaptive immune responses.
Introduction
The concept of immunosurveillance for cancer was proposed by Burnet (1), who posited that transformed cells continually arise in the body as a result of mutation and are usually detected and then deleted by the immune system. Cognizant of this theory, decades have been spent attempting, and largely failing to improve the immunosurveillance against malignancies that have escaped eradication, although the concept of immunoediting has gained broad acceptance. The editors of Science chose cancer immunotherapy as Breakthrough of the Year for 2013 (2), and the journal Nature has devoted the entire 2013 year-end Outlook supplement to cancer immunotherapy (3), both of which are reflective of some of the revolutionary clinical responses being observed by agents that relieve immune suppression and allow immunosurveillance to eradicate cancer.
Negative Checkpoint Regulators, New and Old
Molecules that promote or interfere with the mounting of protective antitumor immunity are under intensive study. Many of these molecules are members of the B7 family, and they act as rheostats that control the threshold for whether a given T-cell receptor (TCR) interaction leads to activation and/or anergy. CD28 is one such molecule, as when it binds to its ligands, CD80 or CD86, it facilitates fulminant T-cell activation (4, 5).
Clinical experience with an agonistic antibody to CD28 in 6 healthy volunteers has shown that unimpeded signaling through CD28 results in a massive cytokine storm with a litany of immune-related toxicities (irT; ref. 6). Negative checkpoint regulators (NCR) are molecules that temper T-cell activation and render cell-mediated immune responses within constraints that are safe to the host. The prototypical NCR is cytotoxic T lymphocyte (CTL)–associated antigen 4 (CTLA4), which interacts with CD80 and CD86 (Fig. 1).
This T-cell membrane protein plays a central role as an NCR critical in tempering irT that would result in its absence. Mice that are genetically deficient in CTLA4 develop fatal systemic lymphoproliferative disease with multiorgan lymphocytic infiltration and damage by 3 to 4 weeks of age (7).
The importance of tempering CD28 signaling can be seen readily when negative regulators are genetically deleted or blocked (anti-CTLA4). These and other studies underscored the importance of NCRs in tempering immunity, and have offered the prospects of amplifying immune responses at will when the clinical need arises.
Negative checkpoint regulators in the TME. The major NCRs in the Ig superfamily are shown in CTL and interacting cell type (e.g., tumor cell, myeloid cell, etc.). Blocking antibodies toward these targets is showing great promise in immunotherapy.
The complex nature of the NCR pathways that control the magnitude of T cell–mediated inflammation is only now being appreciated. Many receptors and ligands have multiple binding partners (Fig. 1).
Furthermore, many of the interactions are bidirectional with regard to signaling, rendering the assignment of ligand and receptor ambiguous or irrelevant. As such, many of the so-called ligands transduce signals themselves. For the purpose and context of this Crossroads overview, “receptor” refers to the surface protein on CTLs and “ligand” is the surface protein on all other cell types that interact with CTLs. In addition to engaging CD28 and CTLA4, CD80 binds to the ligand PDL1, which then transduces a negative signal (Fig. 1; ref. 8). B-lymphocyte and T-lymphocyte attenuator (BTLA) signals negatively following interaction with herpesvirus entry mediator (HVEM; ref. 9), whereas HVEM itself has positive activity (10).
Assignment of all family members within the super immunoglobulin (Ig) family has even been breached, as HVEM, a ligand for BTLA, is in the tumor necrosis factor receptor superfamily (TNFRSF).
A further cross-family interaction occurs between B7-H6 and natural killer (NK) cell p30-related protein (NKp30; ref. 11). The complexity of NCRs of the CD28-B7 family must be considered when targeting one or more of its members for therapy.
CTLA4
CTLA4 competes with CD28 for interaction with CD80 and CD86 (Fig. 1). Early after T-cell activation, CTLA4 expression on the cell surface is increased as a result of both increased mRNA expression and release from intracellular depots. CTLA4 can bind CD80 and CD86 at higher affinity than CD28. This acts centrally to limit the extent of T-cell activation by competing with CD28 engagement and interrupting TCR signaling.
The first anti-CTLA4 human monoclonal antibody (mAb), ipilimumab, was approved in 2011 by the FDA for use in metastatic melanoma (12). Following activity in phase II clinical trials, success for ipilimumab was reported in a large phase III clinical trial involving treatment of 676 patients with metastatic melanoma, who had undergone previous failed treatment (13).
Patients received 3 mg/kg of ipilimumab with or without a vaccine derived from the melanosomal protein glycoprotein 100 (gp100), or were treated with gp100 alone as an active control.
Median overall survival was 10.0 months in the combination group (P < 0.001), and 10.1 months with ipilimumab alone (P = 0.003), as compared with 6.4 months in the control group. Furthermore, the 1- and 2-year survival rates increased from 25% and 14% in the controls to 46% and 24% with ipilimumab. It is of note that some patients exhibited delayed responses, sometimes with tumor progression before tumor regression. Although ipilimumab is generally believed to act by releasing the brakes on antitumor T-cell responses (14), we speculate that a major therapeutic mechanism of action may be ablation of regulatory T cells (Treg) within the tumor microenvironment (TME). These results broke new ground as the first immunotherapeutic strategy showing improved survival in metastatic melanoma in a phase III trial. A subsequent phase III study compared a higher dose of ipilimumab (10 mg/kg) plus dacarbazine to dacarbazine alone in 502 patients with previously untreated metastatic melanoma (15). The results mirrored the first phase III trial, achieving longer survival times (11.2 vs. 9.1 months) and higher survival rates at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%). With the efficacy of CTLA4 blockade established, clinical trials are currently addressing ways to build on these results. As discussed below, combination therapies will likely improve the efficacy of immunomodulatory approaches and will be a driving concept of future studies in this field. PD1 is a critical NCR, which mitigates inflammation to maintain peripheral tolerance (Fig. 1). Upon activation, T cells and B cells upregulate the NCR PD1, which becomes detectable from the cell surface by 24 hours (16, 17). PD1 then forms negative costimulatory microclusters associated with phosphatase SHP2 (Src homology 2 domain–containing tyrosine phosphatase 2) and TCRs, leading to the dephosphorylation of TCRs and suppression of T-cell functions (18). One of the PD1 ligands, PDL2, can be induced on dendritic cells (DC), monocytes, and macrophages (19).
In contrast, the other PD1 ligand, PDL1, is broadly and constitutively expressed on immune cells and throughout the body (Fig. 1; ref. 19). PDL1 expression can be increased by stimulation with type I or II interferons (IFN) on T cells, macrophages, and tumors (20, 21). Peripheral PDL1 is thought to be important in dampening T cells to prevent autoimmune or bystander damage in tissues, but it is also implicated in T-cell exhaustion and immune-cell evasion by tumors.
Many studies have described the correlation of PDL1 with invasiveness, metastasis, and poor prognosis. It appears well established that high PDL1 is generally associated with a poor outcome (22, 23).
PDL1 expression is upregulated by IFNγ, as a defense against collateral damage. It has been suggested that IFNγ produced by tumor-infiltrating lymphocytes (TIL) may be inducing PDL1 expression, which in turn suppresses TIL activity, or leads to T-cell anergy or exhaustion (24). Thus, PDL1 expression may be a result of TIL infiltration, or even an indicator of tumors for which useful antitumor responses may be generated.
Early clinical trials targeting the PD1 pathway with anti-PD1 or anti-PDL1 have generated much excitement. In phase I trials, compelling rates of objective responses have been achieved. Of particular note are three large phase I trials, which assessed Bristol-Myers Squibb’s anti-PD1 (BMS-936558, nivolumab) and anti-PDL1 (BMS-936559), and Merck’s anti-PD1 mAb (MK-3475, lambrolizumab).
In the first trial, 296 patients with advanced melanoma, non–small-cell lung cancer (NSCLC), castration-resistant prostate cancer, renal cell cancer, or colorectal cancer received anti-PD1 over multiple escalation doses. Long-term durable responses were achieved in 18% to 28% in NSCLC, melanoma, and renal cell cancer (25). Interestingly, there was evidence of improved efficacy in patients whose tumors expressed PDL1 (objective responses in 0 of 17 PDL1− tumors and 9 of 25 PDL1+ tumors). A similar finding was observed with patients treated concurrently with ipilimumab and nivolumab (26).
If this correlation holds true, it remains to be seen whether PDL1 expression is a general marker of tumors with immune interaction that are sensitive to immunotherapy by any NCR, or whether this is a specific requirement for PD1 blockade. The concurrent dose-escalating phase I trial for blockade of PDL1 (BMS-936559) induced durable tumor regression at rates of 6% to 17% in NSCLC, melanoma, and renal cell cancer (27). A recent clinical trial tested another anti-PD1 formulation (lambrolizumab) in 135 patients with advanced melanoma at 10 mg/kg achieving a response rate of over 50% (28).
B7-H3
B7-H3 is another B7 family member that has been implicated as a regulator of tumor immunosurveillance (Fig. 1). Expression of B7-H3 mRNA is broad, detectable in most body tissues and some tumor cell lines (29), but protein expression is detected at relatively low levels. Peripheral blood leukocytes do not express B7-H3, but it can be induced on monocytes, DCs, and T cells by stimulation (30). Like PD1, the activities of B7-H3 have faced controversy. Both in mice and humans, there are reports that show B7-H3 acts as either a costimulatory molecule (29, 31) or a NCR (30, 32, 33). Contributing to the dilemma is the inability to credibly identify the receptor for B7-H3, a feature problematic to a number of members of the NCR family. However, there are data suggesting that the receptor for B7-H3 is expressed on activated T cells and NK cells (29). A receptor called triggering receptor expressed on myeloid cells (TREM)-like transcript 2 (TLT-2) has been proposed (34), as antibodies against either TLT-2 or B7-H3 inhibited contact hypersensitivity. However, a subsequent study did not find evidence of this interaction (33). The basis for these different findings is not clear; it is possible that different isoforms of B7-H3 may interact with more than one receptor.
As might be expected from both stimulatory and inhibitory activities being detected for B7-H3, this molecule has been reported to have either immune-enhancing or immune-inhibitory impact in murine cancer models. Murine tumor cell lines transfected with B7-H3 result in increased CD8 responses, and therefore grow poorly in vivo or are rejected (35, 36). However, a large number of studies have shown that B7-H3 has detrimental effects in cancer, as it promotes tumor progression and metastasis, and reduces host survival (37). In humans, B7-H3 expression has been observed on many tumor types at varying frequencies (37). In gastric and pancreatic cancer, B7-H3 had a positive effect on survival and infiltration by CTL (38, 39). Interestingly, in clear cell renal cancer, B7-H3 expression was observed on the vasculature in 95% of specimens, but only 17% showed tumor-cell expression (40). Both vasculature and tumor-cell expression were associated with poor outcome. In NSCLC, the soluble form of B7-H3 was found to be a particularly useful biomarker for poor prognosis—better than even more traditional biomarkers such as carcinoembryonic antigen (CEA; ref. 41). As argued by Loos and colleagues (37), given the understanding that the level of expression of costimulatory molecules may influence their functional effect (42), both the intensity of staining, and the cell type involved should be taken into account in these kinds of studies.
B7-H4
Another promising NCR for cancer immunotherapy is B7-H4 (Fig. 1), whose binding partner remains unknown. B7-H4 is also known as B7x, B7 superfamily member 1 (B7-S1), and V-set domain–containing T-cell activation inhibitor 1 (vtcn1). B7-H4 is expressed on B cells and other antigen-presenting cells (APC). IL6 and IL10 increase its expression, while granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL4 reduce its expression (43). In murine models, B7-H4 has been shown to inhibit T-cell activation and cytokine production in vitro and in vivo, by antibody blockade, Fc fusion protein, and/or transfection on APCs (44–46). A role for B7-H4 on innate cells has been elucidated, as B7-H4 knockout mice are more resistant to Listeria monocytogenes infection, even in the absence of T cells in double knockout mice with recombination-activating gene-1 deficiency. The resistance to infection seems to be related to the elevated neutrophil numbers due to increased proliferation of neutrophil progenitors (47).
B7-H4 is an Ig protein with a well-established role as a biomarker for progression in cancers. B7-H4 is detected on a variety of tumors, including melanoma, NSCLC, prostate, ovary, stomach, pancreas, breast, esophagus, and kidney cancers, with expression on infiltrating myeloid cells, vasculature, and tumor cells (Fig. 1; refs. 43, 48). Most studies show a potential prognostic role correlating B7-H4 expression with tumor-stage grade biologic behavior, recurrence, and survival rate. The biologic activity, nonoverlapping expression pattern, and correlation with cancer progression are rationale for the development of B7-H4 as a new target for immunotherapy.
In addition to the CD28-B7 family of proteins, other Ig superfamily proteins may be targets for tumor immunotherapy. Two promising candidates are lymphocyte-activated gene-3 (LAG-3) and T-cell Ig- and mucin-domain–containing molecule-3 (TIM-3). LAG-3 is induced upon T-cell activation and binds major histocompatibility complex (MHC) class II molecules, leading to inhibition of TCR-induced calcium fluxes (49, 50). TIM-3 is expressed on activated T-helper 1 (Th1) cell subsets and interacts with Galectin-9, leading to suppression of macrophages and apoptosis of T cells (51, 52). Importantly, these molecules are expressed on exhausted T cells, and there is evidence that the activity of LAG-3 and TIM-3 may be synergistic with PD1 in this context (53–55).
VISTA—A New Immunomodulatory Target with Broad-Spectrum Activities
A new target for cancer immunotherapy is the Ig superfamily member V-domain Ig-containing suppressor of T-cell activation (VISTA, Entrez: 64115), also known as C10orf54, differentiation of ESC-1 (Dies1), platelet receptor Gi24 precursor, or PD1 homolog (PD1H). The extracellular domain of VISTA is most similar to that of PDL1; however, VISTA possesses some unusual structural features. VISTA does not cluster with the CD28-B7 family at standard confidence limits, and therefore is rather weakly associated with the rest of the group (56). Although studies using Fc fusion proteins clearly show that VISTA has ligand activity (56, 57), receptor-like signaling activity has also been described (58). Indeed, the extracellular domain consists of a single IgV (variable region) domain, like the receptors in the family. Additionally, a recent study utilizing VISTA knockout mice demonstrated that endogenous VISTA has inhibitory effects both as a ligand on APCs and as a receptor on T cells (58). The binding partner(s) of VISTA responsible for these activities is currently unknown (Fig. 1).
In both mice (56) and humans (57), VISTA is expressed predominantly on hematopoietic cells with the greatest densities on myeloid and granulocytic cells, and weaker expression on T cells. Similar to some members of the B7-CD28 family (e.g., PDL1; ref. 8), T cells both express and respond to VISTA. VISTA–Fc fusion protein and cellular overexpression of VISTA are suppressive to T-cell activation, proliferation, and cytokine production (56, 57). In vivo blockade of VISTA was found to enhance the T-cell response to OVA, and to exacerbate the development of experimental autoimmune encephalomyelitis (EAE; ref. 56). Interestingly, in a separate study, blockade with anti-VISTA and VISTA–Fc fusion protein was found to inhibit acute graft-versus-host disease (59). This immunosuppressive effect of VISTA may be due to the ability of specific anti-VISTA antibodies to deplete VISTA-bearing cells.
Both naïve and antigen-experienced cells are sensitive to VISTA-induced suppression (56, 57), which suggests that in addition to constitutive expression of VISTA, the receptor may be constitutively expressed on resting T cells. Therefore, we speculate that VISTA may act as a rheostat to prevent promiscuous resting T-cell responses to self-antigens. In support of this notion, findings from Flies and colleagues (58) and our own studies show that mice lacking VISTA expression have elevated frequencies of activated T cells with a systemic proinflammatory phenotype.
VISTA in Cancer
The potential of VISTA to act as an NCR in the setting of cancer was first demonstrated by Wang and colleagues in a murine model of methylcholanthrene 105 (MCA105)–induced fibrosarcoma (56). MCA105 tumor cells engineered to overexpress VISTA-RFP were shown to grow in animals with immunity protective against the growth of control MCA105 cells. More recently, Le Mercier and colleagues described elevated VISTA expression on leukocytes within the TME and tumor-draining lymph nodes in murine cancer models (60). They also examined the use of an anti-VISTA mAb for intervention and found that VISTA blockade impaired tumor growth, with particularly dramatic results when used in combination with a tumor vaccine (60). Within the TME, a shift was generated toward antitumor immunity with elevated infiltration, proliferation, and T-cell effector function.
As compared with the activity of anti-CTLA4, anti-PD1, and anti-PDL1 in preclinical studies, the VISTA blockade data appear compelling (61–63). Similar to the findings of Wang and colleagues (56), Sorensen and colleagues reported melanoma regression and long-term survival rates of 30% to 40% in a study of CTLA4 blockade in combination with CD40 stimulation and the administration of an adenoviral vaccine (62).
Following the promising studies of VISTA in murine models of cancer, we initiated studies to evaluate VISTA expression in human cancers. As anticipated, we did not detect VISTA expression in a commercially available panel of cDNAs isolated from human nonhematopoietic tumor cell lines (data not shown; Human Cell Line MTC Panel; Clontech). The mouse data suggest that VISTA is exclusively expressed on leukocytes infiltrating the tumor. Therefore, VISTA expression was examined on colon and lung cancer lesions by fluorescence-based multiplex immunohistochemistry (IHC) as previously described using the GG8 clone of anti-human VISTA (57). When present, VISTA expression was confined predominantly to the infiltrating CD11b+ cells in the TME of colon cancer lesions, whereas infiltrating VISTA+ cells in some cases, but not others, expressed CD11b in lung cancer cells (Fig. 2).
In all examined cases, we did not observe coexpression of VISTA and CD8 in infiltrating cells. However, lower VISTA expression levels on CD8+ T cells may be below the detection limits of this antibody by IHC staining. As the composition of the immune-cell infiltrates varies between tumors within the same cancer site, and in tumors of different cancer types (Fig. 2), we would predict that a frank myeloid infiltrate in tumor lesions would express high levels of VISTA. Future studies in larger cohorts of patients will be needed to identify tumor characteristics that may be associated with VISTA expression in the TME.
Understanding TME composition for personalized combination of immunotherapeutic agents. Left, expression of VISTA, CD8, and CD11b was codetected in formalin-fixed paraffin-embedded tissue sections of colon and lung cancer tumor lesions. In these merged ...
Two particularly interesting points for VISTA immunotherapy from observations in the mouse models are that VISTA blockade was effective without any detectable expression of VISTA on the tumor cells, and that VISTA blockade works even in the presence of high PDL1 expression (60). The lack of requirement for VISTA expression on the tumor suggests that VISTA blockade may have broad clinical applicability, and is potentially an advantage over PD1 or PDL1 blockade, which may require expression on the target tumor (25). Although PDL1 may shield tumor cells from immunosurveillance, VISTA blockade is still sufficient to allow antitumor activity to develop within the TME. These data suggest that VISTA activity in the TME is important for antitumor immunity, and that VISTA blockade may be a promising immunotherapy strategy. Because the VISTA and PD1 checkpoint pathways are independent, there may be potential synergy when they are targeted in combination.
Personalizing Anti-VISTA Approaches in Cancer Immunotherapy
Strategies for the use of specific NCR-based immunotherapy will be guided by the signature of NCRs that are observed within the TME (Fig. 2). This would involve screening of individual patients for markers that allow tailored blockade to their specific tumor—for example PD1 blockade for patients with tumors that are PDL1 rich. Likewise, greater efficacy may be achieved by introducing NCR blockade into a treatment regimen both within the period for the best therapeutic window—before tumors have undergone extensive immunoediting and lost immunogenicity—and to achieve the best interactions with conventional treatments. By their nature of targeting proliferating cells, standard cancer treatments are often immunosuppressive—however, locally, these effects can be immunostimulatory (64, 65). Release of antigen and damage-associated molecular patterns (DAMP) may recruit and activate TILs in the TME. In addition, homeostatic proliferation of leukocytes after depletion by chemotherapy may boost immune reactions stimulated concurrently. The timing of chemotherapy may be important for combination with immune-stimulating strategies. A recent trial combined ipilimumab with paclitaxel and carboplatin, either as a phased regimen (two doses of chemotherapy followed by four doses of chemotherapy plus ipilimumab) or concurrent (four doses of chemotherapy plus ipilimumab followed by two doses of chemotherapy; ref. 66). Interestingly, the phased regimen was effective in increasing progression-free survival, but the concurrent treatment was not.
As described above, the signaling pathways for VISTA, PD1, and CTLA4 are quite distinct. This suggests that first, failure of one blockade strategy does not necessarily mean that a patient would fail in the other strategy, and second that multiple blockade agents could be combined synergistically (Fig. 2). Two phase I trials testing either Merck’s anti-PD1 antibody lambrolizumab or the Bristol-Myers Squibb’s anti-PD1 nivolumab did not find a difference between patients who had already undergone ipilimumab therapy (anti-CTLA4) as compared with those who had not (28, 67). Combinations of PD1, CTLA4, VISTA, and/or LAG-3 blockades in preclinical studies support synergy (refs. 53, 68; Wang and colleagues; manuscript in preparation). A recent trial testing concurrent treatment of ipilimumab and nivolumab achieved a 40% overall objective response rate, and 53% at the highest dose groups (26). This indicates that the combination of antibodies for NCR blockade is both safe and clinically effective. The combination of GM-CSF with ipilimumab has shown a trend toward improved treatment tolerance and a significant improvement in survival in an ongoing phase II trial (69). One of the advantages of VISTA blockade as an immunotherapeutic strategy is that VISTA expression is not required on the tumor cells. Instead, the relevant VISTA-expressing cells seem to be the myeloid infiltrate (60). A combinatorial approach may use some permutation of the following: vaccine and ipilimumab to generate new clonal T-cell expansion, VISTA blockade to counteract some of the suppressive activity of the infiltrating myeloid cells, PD1 or PDL1 blockade to release anergic CTLs, and either B7-H4 or PD1 blockade to release the immunogenicity of the tumor (Fig. 2). As we learn more about the signature of NCR expression in the TME across human cancers, better strategies for combinatorial therapeutic intervention may be devised.
Future Directions
To improve the clinical effectiveness of NCR blockade, a clearer understanding of relevant biomarkers would be of great benefit. There is a need for markers both to predict how successful NCR blockade might be in a patient, and also to determine which NCR(s) should be targeted for tailored treatment. On the other end of the treatment process, biomarkers that indicate successful intervention are desirable. Treatment of cancers with NCR blockade can lead to delayed responses, sometimes even with tumor progression before tumor shrinkage. It has been proposed that RECIST criteria are potentially not the best criteria to use for evaluation of immunotherapeutic approaches, although the use of alternative criteria is controversial (1).
For VISTA, many questions still remain, not least being the identity of the receptor. As with B7-H3 and B7-H4, answering this question may be challenging, but would facilitate therapeutic development. Studies are under way examining how combination therapy of anti-VISTA with vaccines and/or blockade of other NCRs may be used to create synergistic responses. Although VISTA has been observed within the TME in human tumors, a comprehensive study of the correlation of VISTA expression with patient outcome in different tumor types is warranted. Antibodies targeting VISTA for cancer immunotherapy are already under development by Johnson & Johnson and VISTA may soon be a part of the immunotherapy revolution.
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Acknowledgments
Grant Support This study was supported by AICR 12-1305 (R. Noelle and J. Lines), NIH R01AI098007 (R. Noelle), Wellcome Trust, Principal Research Fellowship (R. Noelle), R01CA164225 (L. Wang), and a Hitchcock Foundation pilot grant (L.F. Sempere).
J. Louise Lines,1,2 Lorenzo F. Sempere,3 Thomas Broughton,4,5 Li Wang,7 and Randolph Noelle1,2,4,5,6
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The publisher's final edited version of this article is available free at Cancer Immunol Res
Abstract
In the past few years, the field of cancer immunotherapy has made great progress and is finally starting to change the way cancer is treated. We are now learning that multiple negative checkpoint regulators (NCR) restrict the ability of T-cell responses to effectively attack tumors. Releasing these brakes through antibody blockade, first with anti-CTLA4 and now followed by anti-PD1 and anti-PDL1, has emerged as an exciting strategy for cancer treatment.
More recently, a new NCR has surfaced called V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation (VISTA). This NCR is predominantly expressed on hematopoietic cells, and in multiple murine cancer models is found at particularly high levels on myeloid cells that infiltrated the tumors.
Preclinical studies with VISTA blockade have shown promising improvement in antitumor T-cell responses, leading to impeded tumor growth and improved survival.
Clinical trials support combined anti-PD1 and anti-CTLA4 as safe and effective against late-stage melanoma. In the future, treatment may involve combination therapy to target the multiple cell types and stages at which NCRs, including VISTA, act during adaptive immune responses.
Introduction
The concept of immunosurveillance for cancer was proposed by Burnet (1), who posited that transformed cells continually arise in the body as a result of mutation and are usually detected and then deleted by the immune system. Cognizant of this theory, decades have been spent attempting, and largely failing to improve the immunosurveillance against malignancies that have escaped eradication, although the concept of immunoediting has gained broad acceptance. The editors of Science chose cancer immunotherapy as Breakthrough of the Year for 2013 (2), and the journal Nature has devoted the entire 2013 year-end Outlook supplement to cancer immunotherapy (3), both of which are reflective of some of the revolutionary clinical responses being observed by agents that relieve immune suppression and allow immunosurveillance to eradicate cancer.
Negative Checkpoint Regulators, New and Old
Molecules that promote or interfere with the mounting of protective antitumor immunity are under intensive study. Many of these molecules are members of the B7 family, and they act as rheostats that control the threshold for whether a given T-cell receptor (TCR) interaction leads to activation and/or anergy. CD28 is one such molecule, as when it binds to its ligands, CD80 or CD86, it facilitates fulminant T-cell activation (4, 5).
Clinical experience with an agonistic antibody to CD28 in 6 healthy volunteers has shown that unimpeded signaling through CD28 results in a massive cytokine storm with a litany of immune-related toxicities (irT; ref. 6). Negative checkpoint regulators (NCR) are molecules that temper T-cell activation and render cell-mediated immune responses within constraints that are safe to the host. The prototypical NCR is cytotoxic T lymphocyte (CTL)–associated antigen 4 (CTLA4), which interacts with CD80 and CD86 (Fig. 1).
This T-cell membrane protein plays a central role as an NCR critical in tempering irT that would result in its absence. Mice that are genetically deficient in CTLA4 develop fatal systemic lymphoproliferative disease with multiorgan lymphocytic infiltration and damage by 3 to 4 weeks of age (7).
The importance of tempering CD28 signaling can be seen readily when negative regulators are genetically deleted or blocked (anti-CTLA4). These and other studies underscored the importance of NCRs in tempering immunity, and have offered the prospects of amplifying immune responses at will when the clinical need arises.
Negative checkpoint regulators in the TME. The major NCRs in the Ig superfamily are shown in CTL and interacting cell type (e.g., tumor cell, myeloid cell, etc.). Blocking antibodies toward these targets is showing great promise in immunotherapy.
The complex nature of the NCR pathways that control the magnitude of T cell–mediated inflammation is only now being appreciated. Many receptors and ligands have multiple binding partners (Fig. 1).
Assignment of all family members within the super immunoglobulin (Ig) family has even been breached, as HVEM, a ligand for BTLA, is in the tumor necrosis factor receptor superfamily (TNFRSF).
A further cross-family interaction occurs between B7-H6 and natural killer (NK) cell p30-related protein (NKp30; ref. 11). The complexity of NCRs of the CD28-B7 family must be considered when targeting one or more of its members for therapy.
CTLA4
CTLA4 competes with CD28 for interaction with CD80 and CD86 (Fig. 1). Early after T-cell activation, CTLA4 expression on the cell surface is increased as a result of both increased mRNA expression and release from intracellular depots. CTLA4 can bind CD80 and CD86 at higher affinity than CD28. This acts centrally to limit the extent of T-cell activation by competing with CD28 engagement and interrupting TCR signaling.
The first anti-CTLA4 human monoclonal antibody (mAb), ipilimumab, was approved in 2011 by the FDA for use in metastatic melanoma (12). Following activity in phase II clinical trials, success for ipilimumab was reported in a large phase III clinical trial involving treatment of 676 patients with metastatic melanoma, who had undergone previous failed treatment (13).
Patients received 3 mg/kg of ipilimumab with or without a vaccine derived from the melanosomal protein glycoprotein 100 (gp100), or were treated with gp100 alone as an active control.
Median overall survival was 10.0 months in the combination group (P < 0.001), and 10.1 months with ipilimumab alone (P = 0.003), as compared with 6.4 months in the control group. Furthermore, the 1- and 2-year survival rates increased from 25% and 14% in the controls to 46% and 24% with ipilimumab. It is of note that some patients exhibited delayed responses, sometimes with tumor progression before tumor regression. Although ipilimumab is generally believed to act by releasing the brakes on antitumor T-cell responses (14), we speculate that a major therapeutic mechanism of action may be ablation of regulatory T cells (Treg) within the tumor microenvironment (TME). These results broke new ground as the first immunotherapeutic strategy showing improved survival in metastatic melanoma in a phase III trial. A subsequent phase III study compared a higher dose of ipilimumab (10 mg/kg) plus dacarbazine to dacarbazine alone in 502 patients with previously untreated metastatic melanoma (15). The results mirrored the first phase III trial, achieving longer survival times (11.2 vs. 9.1 months) and higher survival rates at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%). With the efficacy of CTLA4 blockade established, clinical trials are currently addressing ways to build on these results. As discussed below, combination therapies will likely improve the efficacy of immunomodulatory approaches and will be a driving concept of future studies in this field. PD1 is a critical NCR, which mitigates inflammation to maintain peripheral tolerance (Fig. 1). Upon activation, T cells and B cells upregulate the NCR PD1, which becomes detectable from the cell surface by 24 hours (16, 17). PD1 then forms negative costimulatory microclusters associated with phosphatase SHP2 (Src homology 2 domain–containing tyrosine phosphatase 2) and TCRs, leading to the dephosphorylation of TCRs and suppression of T-cell functions (18). One of the PD1 ligands, PDL2, can be induced on dendritic cells (DC), monocytes, and macrophages (19).
In contrast, the other PD1 ligand, PDL1, is broadly and constitutively expressed on immune cells and throughout the body (Fig. 1; ref. 19). PDL1 expression can be increased by stimulation with type I or II interferons (IFN) on T cells, macrophages, and tumors (20, 21). Peripheral PDL1 is thought to be important in dampening T cells to prevent autoimmune or bystander damage in tissues, but it is also implicated in T-cell exhaustion and immune-cell evasion by tumors.
Many studies have described the correlation of PDL1 with invasiveness, metastasis, and poor prognosis. It appears well established that high PDL1 is generally associated with a poor outcome (22, 23).
PDL1 expression is upregulated by IFNγ, as a defense against collateral damage. It has been suggested that IFNγ produced by tumor-infiltrating lymphocytes (TIL) may be inducing PDL1 expression, which in turn suppresses TIL activity, or leads to T-cell anergy or exhaustion (24). Thus, PDL1 expression may be a result of TIL infiltration, or even an indicator of tumors for which useful antitumor responses may be generated.
Early clinical trials targeting the PD1 pathway with anti-PD1 or anti-PDL1 have generated much excitement. In phase I trials, compelling rates of objective responses have been achieved. Of particular note are three large phase I trials, which assessed Bristol-Myers Squibb’s anti-PD1 (BMS-936558, nivolumab) and anti-PDL1 (BMS-936559), and Merck’s anti-PD1 mAb (MK-3475, lambrolizumab).
In the first trial, 296 patients with advanced melanoma, non–small-cell lung cancer (NSCLC), castration-resistant prostate cancer, renal cell cancer, or colorectal cancer received anti-PD1 over multiple escalation doses. Long-term durable responses were achieved in 18% to 28% in NSCLC, melanoma, and renal cell cancer (25). Interestingly, there was evidence of improved efficacy in patients whose tumors expressed PDL1 (objective responses in 0 of 17 PDL1− tumors and 9 of 25 PDL1+ tumors). A similar finding was observed with patients treated concurrently with ipilimumab and nivolumab (26).
If this correlation holds true, it remains to be seen whether PDL1 expression is a general marker of tumors with immune interaction that are sensitive to immunotherapy by any NCR, or whether this is a specific requirement for PD1 blockade. The concurrent dose-escalating phase I trial for blockade of PDL1 (BMS-936559) induced durable tumor regression at rates of 6% to 17% in NSCLC, melanoma, and renal cell cancer (27). A recent clinical trial tested another anti-PD1 formulation (lambrolizumab) in 135 patients with advanced melanoma at 10 mg/kg achieving a response rate of over 50% (28).
B7-H3
B7-H3 is another B7 family member that has been implicated as a regulator of tumor immunosurveillance (Fig. 1). Expression of B7-H3 mRNA is broad, detectable in most body tissues and some tumor cell lines (29), but protein expression is detected at relatively low levels. Peripheral blood leukocytes do not express B7-H3, but it can be induced on monocytes, DCs, and T cells by stimulation (30). Like PD1, the activities of B7-H3 have faced controversy. Both in mice and humans, there are reports that show B7-H3 acts as either a costimulatory molecule (29, 31) or a NCR (30, 32, 33). Contributing to the dilemma is the inability to credibly identify the receptor for B7-H3, a feature problematic to a number of members of the NCR family. However, there are data suggesting that the receptor for B7-H3 is expressed on activated T cells and NK cells (29). A receptor called triggering receptor expressed on myeloid cells (TREM)-like transcript 2 (TLT-2) has been proposed (34), as antibodies against either TLT-2 or B7-H3 inhibited contact hypersensitivity. However, a subsequent study did not find evidence of this interaction (33). The basis for these different findings is not clear; it is possible that different isoforms of B7-H3 may interact with more than one receptor.
As might be expected from both stimulatory and inhibitory activities being detected for B7-H3, this molecule has been reported to have either immune-enhancing or immune-inhibitory impact in murine cancer models. Murine tumor cell lines transfected with B7-H3 result in increased CD8 responses, and therefore grow poorly in vivo or are rejected (35, 36). However, a large number of studies have shown that B7-H3 has detrimental effects in cancer, as it promotes tumor progression and metastasis, and reduces host survival (37). In humans, B7-H3 expression has been observed on many tumor types at varying frequencies (37). In gastric and pancreatic cancer, B7-H3 had a positive effect on survival and infiltration by CTL (38, 39). Interestingly, in clear cell renal cancer, B7-H3 expression was observed on the vasculature in 95% of specimens, but only 17% showed tumor-cell expression (40). Both vasculature and tumor-cell expression were associated with poor outcome. In NSCLC, the soluble form of B7-H3 was found to be a particularly useful biomarker for poor prognosis—better than even more traditional biomarkers such as carcinoembryonic antigen (CEA; ref. 41). As argued by Loos and colleagues (37), given the understanding that the level of expression of costimulatory molecules may influence their functional effect (42), both the intensity of staining, and the cell type involved should be taken into account in these kinds of studies.
B7-H4
Another promising NCR for cancer immunotherapy is B7-H4 (Fig. 1), whose binding partner remains unknown. B7-H4 is also known as B7x, B7 superfamily member 1 (B7-S1), and V-set domain–containing T-cell activation inhibitor 1 (vtcn1). B7-H4 is expressed on B cells and other antigen-presenting cells (APC). IL6 and IL10 increase its expression, while granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL4 reduce its expression (43). In murine models, B7-H4 has been shown to inhibit T-cell activation and cytokine production in vitro and in vivo, by antibody blockade, Fc fusion protein, and/or transfection on APCs (44–46). A role for B7-H4 on innate cells has been elucidated, as B7-H4 knockout mice are more resistant to Listeria monocytogenes infection, even in the absence of T cells in double knockout mice with recombination-activating gene-1 deficiency. The resistance to infection seems to be related to the elevated neutrophil numbers due to increased proliferation of neutrophil progenitors (47).
B7-H4 is an Ig protein with a well-established role as a biomarker for progression in cancers. B7-H4 is detected on a variety of tumors, including melanoma, NSCLC, prostate, ovary, stomach, pancreas, breast, esophagus, and kidney cancers, with expression on infiltrating myeloid cells, vasculature, and tumor cells (Fig. 1; refs. 43, 48). Most studies show a potential prognostic role correlating B7-H4 expression with tumor-stage grade biologic behavior, recurrence, and survival rate. The biologic activity, nonoverlapping expression pattern, and correlation with cancer progression are rationale for the development of B7-H4 as a new target for immunotherapy.
In addition to the CD28-B7 family of proteins, other Ig superfamily proteins may be targets for tumor immunotherapy. Two promising candidates are lymphocyte-activated gene-3 (LAG-3) and T-cell Ig- and mucin-domain–containing molecule-3 (TIM-3). LAG-3 is induced upon T-cell activation and binds major histocompatibility complex (MHC) class II molecules, leading to inhibition of TCR-induced calcium fluxes (49, 50). TIM-3 is expressed on activated T-helper 1 (Th1) cell subsets and interacts with Galectin-9, leading to suppression of macrophages and apoptosis of T cells (51, 52). Importantly, these molecules are expressed on exhausted T cells, and there is evidence that the activity of LAG-3 and TIM-3 may be synergistic with PD1 in this context (53–55).
VISTA—A New Immunomodulatory Target with Broad-Spectrum Activities
A new target for cancer immunotherapy is the Ig superfamily member V-domain Ig-containing suppressor of T-cell activation (VISTA, Entrez: 64115), also known as C10orf54, differentiation of ESC-1 (Dies1), platelet receptor Gi24 precursor, or PD1 homolog (PD1H). The extracellular domain of VISTA is most similar to that of PDL1; however, VISTA possesses some unusual structural features. VISTA does not cluster with the CD28-B7 family at standard confidence limits, and therefore is rather weakly associated with the rest of the group (56). Although studies using Fc fusion proteins clearly show that VISTA has ligand activity (56, 57), receptor-like signaling activity has also been described (58). Indeed, the extracellular domain consists of a single IgV (variable region) domain, like the receptors in the family. Additionally, a recent study utilizing VISTA knockout mice demonstrated that endogenous VISTA has inhibitory effects both as a ligand on APCs and as a receptor on T cells (58). The binding partner(s) of VISTA responsible for these activities is currently unknown (Fig. 1).
In both mice (56) and humans (57), VISTA is expressed predominantly on hematopoietic cells with the greatest densities on myeloid and granulocytic cells, and weaker expression on T cells. Similar to some members of the B7-CD28 family (e.g., PDL1; ref. 8), T cells both express and respond to VISTA. VISTA–Fc fusion protein and cellular overexpression of VISTA are suppressive to T-cell activation, proliferation, and cytokine production (56, 57). In vivo blockade of VISTA was found to enhance the T-cell response to OVA, and to exacerbate the development of experimental autoimmune encephalomyelitis (EAE; ref. 56). Interestingly, in a separate study, blockade with anti-VISTA and VISTA–Fc fusion protein was found to inhibit acute graft-versus-host disease (59). This immunosuppressive effect of VISTA may be due to the ability of specific anti-VISTA antibodies to deplete VISTA-bearing cells.
Both naïve and antigen-experienced cells are sensitive to VISTA-induced suppression (56, 57), which suggests that in addition to constitutive expression of VISTA, the receptor may be constitutively expressed on resting T cells. Therefore, we speculate that VISTA may act as a rheostat to prevent promiscuous resting T-cell responses to self-antigens. In support of this notion, findings from Flies and colleagues (58) and our own studies show that mice lacking VISTA expression have elevated frequencies of activated T cells with a systemic proinflammatory phenotype.
VISTA in Cancer
The potential of VISTA to act as an NCR in the setting of cancer was first demonstrated by Wang and colleagues in a murine model of methylcholanthrene 105 (MCA105)–induced fibrosarcoma (56). MCA105 tumor cells engineered to overexpress VISTA-RFP were shown to grow in animals with immunity protective against the growth of control MCA105 cells. More recently, Le Mercier and colleagues described elevated VISTA expression on leukocytes within the TME and tumor-draining lymph nodes in murine cancer models (60). They also examined the use of an anti-VISTA mAb for intervention and found that VISTA blockade impaired tumor growth, with particularly dramatic results when used in combination with a tumor vaccine (60). Within the TME, a shift was generated toward antitumor immunity with elevated infiltration, proliferation, and T-cell effector function.
As compared with the activity of anti-CTLA4, anti-PD1, and anti-PDL1 in preclinical studies, the VISTA blockade data appear compelling (61–63). Similar to the findings of Wang and colleagues (56), Sorensen and colleagues reported melanoma regression and long-term survival rates of 30% to 40% in a study of CTLA4 blockade in combination with CD40 stimulation and the administration of an adenoviral vaccine (62).
Following the promising studies of VISTA in murine models of cancer, we initiated studies to evaluate VISTA expression in human cancers. As anticipated, we did not detect VISTA expression in a commercially available panel of cDNAs isolated from human nonhematopoietic tumor cell lines (data not shown; Human Cell Line MTC Panel; Clontech). The mouse data suggest that VISTA is exclusively expressed on leukocytes infiltrating the tumor. Therefore, VISTA expression was examined on colon and lung cancer lesions by fluorescence-based multiplex immunohistochemistry (IHC) as previously described using the GG8 clone of anti-human VISTA (57). When present, VISTA expression was confined predominantly to the infiltrating CD11b+ cells in the TME of colon cancer lesions, whereas infiltrating VISTA+ cells in some cases, but not others, expressed CD11b in lung cancer cells (Fig. 2).
Understanding TME composition for personalized combination of immunotherapeutic agents. Left, expression of VISTA, CD8, and CD11b was codetected in formalin-fixed paraffin-embedded tissue sections of colon and lung cancer tumor lesions. In these merged ...
Two particularly interesting points for VISTA immunotherapy from observations in the mouse models are that VISTA blockade was effective without any detectable expression of VISTA on the tumor cells, and that VISTA blockade works even in the presence of high PDL1 expression (60). The lack of requirement for VISTA expression on the tumor suggests that VISTA blockade may have broad clinical applicability, and is potentially an advantage over PD1 or PDL1 blockade, which may require expression on the target tumor (25). Although PDL1 may shield tumor cells from immunosurveillance, VISTA blockade is still sufficient to allow antitumor activity to develop within the TME. These data suggest that VISTA activity in the TME is important for antitumor immunity, and that VISTA blockade may be a promising immunotherapy strategy. Because the VISTA and PD1 checkpoint pathways are independent, there may be potential synergy when they are targeted in combination.
Personalizing Anti-VISTA Approaches in Cancer Immunotherapy
Strategies for the use of specific NCR-based immunotherapy will be guided by the signature of NCRs that are observed within the TME (Fig. 2). This would involve screening of individual patients for markers that allow tailored blockade to their specific tumor—for example PD1 blockade for patients with tumors that are PDL1 rich. Likewise, greater efficacy may be achieved by introducing NCR blockade into a treatment regimen both within the period for the best therapeutic window—before tumors have undergone extensive immunoediting and lost immunogenicity—and to achieve the best interactions with conventional treatments. By their nature of targeting proliferating cells, standard cancer treatments are often immunosuppressive—however, locally, these effects can be immunostimulatory (64, 65). Release of antigen and damage-associated molecular patterns (DAMP) may recruit and activate TILs in the TME. In addition, homeostatic proliferation of leukocytes after depletion by chemotherapy may boost immune reactions stimulated concurrently. The timing of chemotherapy may be important for combination with immune-stimulating strategies. A recent trial combined ipilimumab with paclitaxel and carboplatin, either as a phased regimen (two doses of chemotherapy followed by four doses of chemotherapy plus ipilimumab) or concurrent (four doses of chemotherapy plus ipilimumab followed by two doses of chemotherapy; ref. 66). Interestingly, the phased regimen was effective in increasing progression-free survival, but the concurrent treatment was not.
As described above, the signaling pathways for VISTA, PD1, and CTLA4 are quite distinct. This suggests that first, failure of one blockade strategy does not necessarily mean that a patient would fail in the other strategy, and second that multiple blockade agents could be combined synergistically (Fig. 2). Two phase I trials testing either Merck’s anti-PD1 antibody lambrolizumab or the Bristol-Myers Squibb’s anti-PD1 nivolumab did not find a difference between patients who had already undergone ipilimumab therapy (anti-CTLA4) as compared with those who had not (28, 67). Combinations of PD1, CTLA4, VISTA, and/or LAG-3 blockades in preclinical studies support synergy (refs. 53, 68; Wang and colleagues; manuscript in preparation). A recent trial testing concurrent treatment of ipilimumab and nivolumab achieved a 40% overall objective response rate, and 53% at the highest dose groups (26). This indicates that the combination of antibodies for NCR blockade is both safe and clinically effective. The combination of GM-CSF with ipilimumab has shown a trend toward improved treatment tolerance and a significant improvement in survival in an ongoing phase II trial (69). One of the advantages of VISTA blockade as an immunotherapeutic strategy is that VISTA expression is not required on the tumor cells. Instead, the relevant VISTA-expressing cells seem to be the myeloid infiltrate (60). A combinatorial approach may use some permutation of the following: vaccine and ipilimumab to generate new clonal T-cell expansion, VISTA blockade to counteract some of the suppressive activity of the infiltrating myeloid cells, PD1 or PDL1 blockade to release anergic CTLs, and either B7-H4 or PD1 blockade to release the immunogenicity of the tumor (Fig. 2). As we learn more about the signature of NCR expression in the TME across human cancers, better strategies for combinatorial therapeutic intervention may be devised.
Future Directions
To improve the clinical effectiveness of NCR blockade, a clearer understanding of relevant biomarkers would be of great benefit. There is a need for markers both to predict how successful NCR blockade might be in a patient, and also to determine which NCR(s) should be targeted for tailored treatment. On the other end of the treatment process, biomarkers that indicate successful intervention are desirable. Treatment of cancers with NCR blockade can lead to delayed responses, sometimes even with tumor progression before tumor shrinkage. It has been proposed that RECIST criteria are potentially not the best criteria to use for evaluation of immunotherapeutic approaches, although the use of alternative criteria is controversial (1).
For VISTA, many questions still remain, not least being the identity of the receptor. As with B7-H3 and B7-H4, answering this question may be challenging, but would facilitate therapeutic development. Studies are under way examining how combination therapy of anti-VISTA with vaccines and/or blockade of other NCRs may be used to create synergistic responses. Although VISTA has been observed within the TME in human tumors, a comprehensive study of the correlation of VISTA expression with patient outcome in different tumor types is warranted. Antibodies targeting VISTA for cancer immunotherapy are already under development by Johnson & Johnson and VISTA may soon be a part of the immunotherapy revolution.
Go to:
Acknowledgments
Grant Support This study was supported by AICR 12-1305 (R. Noelle and J. Lines), NIH R01AI098007 (R. Noelle), Wellcome Trust, Principal Research Fellowship (R. Noelle), R01CA164225 (L. Wang), and a Hitchcock Foundation pilot grant (L.F. Sempere).
martes, 4 de abril de 2017
Open-Access Data-Sharing Model
Sounding Board
Advantages of a Truly Open-Access Data-Sharing Model
Monica M. Bertagnolli, M.D., Oliver Sartor, M.D., Bruce A. Chabner, M.D., Mace L. Rothenberg, M.D., Sean Khozin, M.D., M.P.H., Charles Hugh-Jones, M.D., David M. Reese, M.D., and Martin J. Murphy, D.Med.Sc., Ph.D.
N Engl J Med 2017; 376:1178-1181March 23, 2017DOI: 10.1056/NEJMsb1702054
Multi-institutional randomized clinical trials have been a feature of oncology research in the United States since the 1950s. Since that time, cancer-treatment trials have been continuously funded by the National Cancer Institute (NCI) through a program that has evolved to become the National Clinical Trials Network (NCTN). Currently, approximately 19,000 patients with cancer participate in NCTN clinical trials each year. Approximately 70,000 additional patients with cancer are enrolled each year in treatment trials sponsored by the pharmaceutical industry.1,2
It is important to honor and reward the altruism of patients who participate in clinical trials. One way to do so is to share the data gathered in clinical trials with other researchers in a responsible and meaningful way. The cancer research community, encouraged by recommendations from the Beau Biden Cancer Moonshot, is finally moving data sharing forward from its traditional, largely unfunded, place at the end of the long list of clinical research responsibilities to center stage.
There are a number of reasons why it has it taken more than 60 years for this issue to receive the attention that it deserves. Although the incentives for doing so may differ, competitive forces lead both academic researchers and pharmaceutical companies to protect data and to use data exclusively for their purposes. This approach protects their intellectual property and also shields the primary study team and the sponsor if the release of data from a trial for analysis by others leads to conclusions or interpretations that the primary researchers deem to be misleading or erroneous. When the academic and monetary stakes are high, the chance of this situation occurring is real. Another reason for the delay is that the protection of research participants dictates that confidentiality is the highest priority, and this risk may be greater with wide sharing of the new data-dense individual data sets that are required in order to develop personalized medicine approaches. Finally, and probably most important of all, data sharing has been hampered by a lack of resources, including access to enabling data systems technology, bioinformatics expertise, and legal agreements that facilitate sharing.
The idea of data sharing is moving beyond these hurdles with a variety of models. One such model, the so-called gatekeeper model,3 uses a distinct entity to house information in a central repository, with access to specific data sets that are provided to qualified research teams on the basis of a research proposal review by an independent expert committee. Examples of this approach include ClinicalStudyDataRequest.com, a website sponsored by pharmaceutical partners, and the Vivli platform (http://vivli.org), a nonprofit corporation created to support global sharing of clinical research data. Gatekeeper models provide substantial customization and oversight for individual data requests so that contributing investigators can maintain a level of control over how their data are used. This model may appropriately address barriers to sharing for studies in which the identification of participants is a risk, such as those that involve sensitive topics, genomic data, or limited numbers of participants. This model can also offer some protection to research teams that require limitations on the use of proprietary data. A limitation of gatekeeper models is that many barriers to data use remain.
A substantial body of readily available data from clinical trials can be shared with minimal risk to patients or researchers. Examples include data sets of already published trials, particularly if the treatments that were tested are not undergoing review for regulatory approval. In addition, industry-sponsored clinical trials generally involve a comparator group for which valuable patient-level data can be shared without risk to proprietary interests. As long as the data are appropriately anonymized to protect confidentiality and there are no restrictions related to the institutional review board, the consent form, or the sponsor with regard to the patient-level data, it should be possible for the data to be freely available to the public to download, analyze, and reuse for research purposes. This approach may enable the identification of baseline characteristics of the patients or outcomes that could be identified only by means of an analysis of larger numbers of patients than would be included in an individual trial. What has been lacking, until recently, has been the infrastructure required to achieve this goal.
An example of an active open-source data-sharing model, with which some of us are affiliated, is Project Data Sphere (PDS). PDS is a free digital library-data laboratory that was launched in 2014 as an independent, nonprofit initiative of the CEO Roundtable on Cancer (www.ceoroundtableoncancer.org), which was founded in 2001 to develop and implement initiatives that reduce the risk of cancer, enable early diagnosis, facilitate access to the best available treatments, and hasten the discovery of new and more effective anticancer therapies. A Web-based platform for accessing open-source data was developed for PDS by SAS Institute. Using this website, researchers can download, share, integrate, and analyze patient-level data. Data contributors are provided access to deidentification and data-standardization protocols, as well as to templates of legal agreements, including standardized data-sharing and online-services user agreements.4-6 Users of the site have access to analytic tools developed by SAS Institute. Anyone interested in cancer research can use the website, provided that they register and agree to a responsible-use attestation. PDS is funded by the engagement of a wide range of stakeholders that together ameliorate the burden of securing adequate funding from a single organization or institution.
At present, PDS contains data from more than 41,000 research participants from 72 oncology trials, covering multiple tumor types. The data have been donated by academic, government, and industry sponsors. These numbers are increasing quickly as use of the PDS accelerates. More than 1400 unique researchers have accessed the PDS database more than 6500 times. As one interesting example, a challenge was issued in 2014 that asked respondents to use PDS to create a better prognostic model for advanced prostate cancer. A total of 549 registrants from 58 teams and 21 countries responded. Accessible data included control groups from prospective, randomized, industry-sponsored trials. Solvers had backgrounds in statistics, data modeling, data science, machine learning, bioinformatics, engineering, and other specialties. Unexpectedly, the winning entrant, a team of researchers from Finland, had never worked on prostate cancer in the past, and this team considerably outperformed the best existing model for predicting overall survival among men with advanced prostate cancer.7 Thus, the PDS Prostate Cancer DREAM Challenge confirmed that an open-access model empowers global communities of scientists from diverse backgrounds and promotes crowd-sourced solutions to important clinical problems. This level of engagement is not possible with gatekeeper models.
PDS is provided to users free of charge, but the usefulness of the PDS website is limited to the trials that it contains and the data analytics provided by the platform. Expansion of this concept to the broader research community outside the field of oncology will be time consuming and costly, and it is open to debate whether publicly funded or private concerns are the most appropriate environment to assume responsibility for data storage and sharing. The DataNet program of the National Science Foundation is one example of a public–private partnership that has been designed to achieve these goals.8
The data-sharing community is undergoing rapid development, with several potential models and approaches (Table 1Table 1Oncology Clinical and Translational Research Data Archives.). We encourage multiple models to coexist, either as a single platform with tiered access or as discrete platforms with the potential for cross-communication that includes truly open platforms. We think that as the community sees the benefits of sharing trial data, more will be shared.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Source Information
From the Dana–Farber Cancer Institute, Brigham and Women’s Hospital (M.M.B.), and Massachusetts General Hospital Cancer Center (B.A.C.), Boston; Tulane Medical School, New Orleans (O.S.); Pfizer (M.L.R.) and Carmine Research (C.H.-J.), New York; Food and Drug Administration, Silver Spring, MD (S.K.); Amgen, Thousand Oaks, CA (D.M.R.); and Project Data Sphere, Cary, NC (M.J.M.).
Advantages of a Truly Open-Access Data-Sharing Model
Monica M. Bertagnolli, M.D., Oliver Sartor, M.D., Bruce A. Chabner, M.D., Mace L. Rothenberg, M.D., Sean Khozin, M.D., M.P.H., Charles Hugh-Jones, M.D., David M. Reese, M.D., and Martin J. Murphy, D.Med.Sc., Ph.D.
N Engl J Med 2017; 376:1178-1181March 23, 2017DOI: 10.1056/NEJMsb1702054
Multi-institutional randomized clinical trials have been a feature of oncology research in the United States since the 1950s. Since that time, cancer-treatment trials have been continuously funded by the National Cancer Institute (NCI) through a program that has evolved to become the National Clinical Trials Network (NCTN). Currently, approximately 19,000 patients with cancer participate in NCTN clinical trials each year. Approximately 70,000 additional patients with cancer are enrolled each year in treatment trials sponsored by the pharmaceutical industry.1,2
It is important to honor and reward the altruism of patients who participate in clinical trials. One way to do so is to share the data gathered in clinical trials with other researchers in a responsible and meaningful way. The cancer research community, encouraged by recommendations from the Beau Biden Cancer Moonshot, is finally moving data sharing forward from its traditional, largely unfunded, place at the end of the long list of clinical research responsibilities to center stage.
There are a number of reasons why it has it taken more than 60 years for this issue to receive the attention that it deserves. Although the incentives for doing so may differ, competitive forces lead both academic researchers and pharmaceutical companies to protect data and to use data exclusively for their purposes. This approach protects their intellectual property and also shields the primary study team and the sponsor if the release of data from a trial for analysis by others leads to conclusions or interpretations that the primary researchers deem to be misleading or erroneous. When the academic and monetary stakes are high, the chance of this situation occurring is real. Another reason for the delay is that the protection of research participants dictates that confidentiality is the highest priority, and this risk may be greater with wide sharing of the new data-dense individual data sets that are required in order to develop personalized medicine approaches. Finally, and probably most important of all, data sharing has been hampered by a lack of resources, including access to enabling data systems technology, bioinformatics expertise, and legal agreements that facilitate sharing.
The idea of data sharing is moving beyond these hurdles with a variety of models. One such model, the so-called gatekeeper model,3 uses a distinct entity to house information in a central repository, with access to specific data sets that are provided to qualified research teams on the basis of a research proposal review by an independent expert committee. Examples of this approach include ClinicalStudyDataRequest.com, a website sponsored by pharmaceutical partners, and the Vivli platform (http://vivli.org), a nonprofit corporation created to support global sharing of clinical research data. Gatekeeper models provide substantial customization and oversight for individual data requests so that contributing investigators can maintain a level of control over how their data are used. This model may appropriately address barriers to sharing for studies in which the identification of participants is a risk, such as those that involve sensitive topics, genomic data, or limited numbers of participants. This model can also offer some protection to research teams that require limitations on the use of proprietary data. A limitation of gatekeeper models is that many barriers to data use remain.
A substantial body of readily available data from clinical trials can be shared with minimal risk to patients or researchers. Examples include data sets of already published trials, particularly if the treatments that were tested are not undergoing review for regulatory approval. In addition, industry-sponsored clinical trials generally involve a comparator group for which valuable patient-level data can be shared without risk to proprietary interests. As long as the data are appropriately anonymized to protect confidentiality and there are no restrictions related to the institutional review board, the consent form, or the sponsor with regard to the patient-level data, it should be possible for the data to be freely available to the public to download, analyze, and reuse for research purposes. This approach may enable the identification of baseline characteristics of the patients or outcomes that could be identified only by means of an analysis of larger numbers of patients than would be included in an individual trial. What has been lacking, until recently, has been the infrastructure required to achieve this goal.
An example of an active open-source data-sharing model, with which some of us are affiliated, is Project Data Sphere (PDS). PDS is a free digital library-data laboratory that was launched in 2014 as an independent, nonprofit initiative of the CEO Roundtable on Cancer (www.ceoroundtableoncancer.org), which was founded in 2001 to develop and implement initiatives that reduce the risk of cancer, enable early diagnosis, facilitate access to the best available treatments, and hasten the discovery of new and more effective anticancer therapies. A Web-based platform for accessing open-source data was developed for PDS by SAS Institute. Using this website, researchers can download, share, integrate, and analyze patient-level data. Data contributors are provided access to deidentification and data-standardization protocols, as well as to templates of legal agreements, including standardized data-sharing and online-services user agreements.4-6 Users of the site have access to analytic tools developed by SAS Institute. Anyone interested in cancer research can use the website, provided that they register and agree to a responsible-use attestation. PDS is funded by the engagement of a wide range of stakeholders that together ameliorate the burden of securing adequate funding from a single organization or institution.
At present, PDS contains data from more than 41,000 research participants from 72 oncology trials, covering multiple tumor types. The data have been donated by academic, government, and industry sponsors. These numbers are increasing quickly as use of the PDS accelerates. More than 1400 unique researchers have accessed the PDS database more than 6500 times. As one interesting example, a challenge was issued in 2014 that asked respondents to use PDS to create a better prognostic model for advanced prostate cancer. A total of 549 registrants from 58 teams and 21 countries responded. Accessible data included control groups from prospective, randomized, industry-sponsored trials. Solvers had backgrounds in statistics, data modeling, data science, machine learning, bioinformatics, engineering, and other specialties. Unexpectedly, the winning entrant, a team of researchers from Finland, had never worked on prostate cancer in the past, and this team considerably outperformed the best existing model for predicting overall survival among men with advanced prostate cancer.7 Thus, the PDS Prostate Cancer DREAM Challenge confirmed that an open-access model empowers global communities of scientists from diverse backgrounds and promotes crowd-sourced solutions to important clinical problems. This level of engagement is not possible with gatekeeper models.
PDS is provided to users free of charge, but the usefulness of the PDS website is limited to the trials that it contains and the data analytics provided by the platform. Expansion of this concept to the broader research community outside the field of oncology will be time consuming and costly, and it is open to debate whether publicly funded or private concerns are the most appropriate environment to assume responsibility for data storage and sharing. The DataNet program of the National Science Foundation is one example of a public–private partnership that has been designed to achieve these goals.8
The data-sharing community is undergoing rapid development, with several potential models and approaches (Table 1Table 1Oncology Clinical and Translational Research Data Archives.). We encourage multiple models to coexist, either as a single platform with tiered access or as discrete platforms with the potential for cross-communication that includes truly open platforms. We think that as the community sees the benefits of sharing trial data, more will be shared.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Source Information
From the Dana–Farber Cancer Institute, Brigham and Women’s Hospital (M.M.B.), and Massachusetts General Hospital Cancer Center (B.A.C.), Boston; Tulane Medical School, New Orleans (O.S.); Pfizer (M.L.R.) and Carmine Research (C.H.-J.), New York; Food and Drug Administration, Silver Spring, MD (S.K.); Amgen, Thousand Oaks, CA (D.M.R.); and Project Data Sphere, Cary, NC (M.J.M.).
sábado, 1 de abril de 2017
Brachytherapy for Patients With Prostate Cancer
ASCO SPECIAL ARTICLE
Brachytherapy for Patients With Prostate Cancer: American Society of Clinical Oncology/Cancer Care Ontario Joint Guideline Update
Joseph Chin, R. Bryan Rumble, Marisa Kollmeier, Elisabeth Heath, Jason Efstathiou, Tanya Dorff, Barry Berman, Andrew Feifer, Arthur Jacques†, and D. Andrew Loblaw
Joseph Chin, London Health Sciences Centre, London; Andrew Feifer, Trillium Health Partners’ Fidani Cancer Centre, University Health Network, Mississauga; Arthur Jacques, Patient Representative; D. Andrew Loblaw, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Marisa Kollmeier, Memorial Sloan Kettering Cancer Center, New York, NY; Elisabeth Heath, Karmanos Cancer Institute, Detroit, MI; Jason Efstathiou, Massachusetts General Hospital, Boston, MA; Tanya Dorff, USC Norris Cancer Center, Los Angeles, CA; and Barry Berman, Broward Health, Fort Lauderdale, FL.
Abstract
Purpose
To jointly update the Cancer Care Ontario guideline on brachytherapy for patients with prostate cancer to account for new evidence.
Methods
An Update Panel conducted a targeted systematic literature review and identified more recent randomized controlled trials comparing dose-escalated external beam radiation therapy (EBRT) with brachytherapy in men with prostate cancer.
Results
Five randomized controlled trials provided the evidence for this update.
Recommendations
For patients with low-risk prostate cancer who require or choose active treatment, low–dose rate brachytherapy (LDR) alone, EBRT alone, and/or radical prostatectomy (RP) should be offered to eligible patients. For patients with intermediate-risk prostate cancer choosing EBRT with or without androgen-deprivation therapy, brachytherapy boost (LDR or high–dose rate [HDR]) should be offered to eligible patients. For low-intermediate risk prostate cancer (Gleason 7, prostate-specific antigen < 10 ng/mL or Gleason 6, prostate-specific antigen, 10 to 20 ng/mL), LDR brachytherapy alone may be offered as monotherapy. For patients with high-risk prostate cancer receiving EBRT and androgen-deprivation therapy, brachytherapy boost (LDR or HDR) should be offered to eligible patients. Iodine-125 and palladium-103 are each reasonable isotope options for patients receiving LDR brachytherapy; no recommendation can be made for or against using cesium-131 or HDR monotherapy. Patients should be encouraged to participate in clinical trials to test novel or targeted approaches to this disease.
Additional information is available at www.asco.org/Brachytherapy-guideline and www.asco.org/guidelineswiki.
Brachytherapy for Patients With Prostate Cancer: American Society of Clinical Oncology/Cancer Care Ontario Joint Guideline Update
Joseph Chin, R. Bryan Rumble, Marisa Kollmeier, Elisabeth Heath, Jason Efstathiou, Tanya Dorff, Barry Berman, Andrew Feifer, Arthur Jacques†, and D. Andrew Loblaw
Joseph Chin, London Health Sciences Centre, London; Andrew Feifer, Trillium Health Partners’ Fidani Cancer Centre, University Health Network, Mississauga; Arthur Jacques, Patient Representative; D. Andrew Loblaw, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Marisa Kollmeier, Memorial Sloan Kettering Cancer Center, New York, NY; Elisabeth Heath, Karmanos Cancer Institute, Detroit, MI; Jason Efstathiou, Massachusetts General Hospital, Boston, MA; Tanya Dorff, USC Norris Cancer Center, Los Angeles, CA; and Barry Berman, Broward Health, Fort Lauderdale, FL.
Abstract
Purpose
To jointly update the Cancer Care Ontario guideline on brachytherapy for patients with prostate cancer to account for new evidence.
Methods
An Update Panel conducted a targeted systematic literature review and identified more recent randomized controlled trials comparing dose-escalated external beam radiation therapy (EBRT) with brachytherapy in men with prostate cancer.
Results
Five randomized controlled trials provided the evidence for this update.
Recommendations
For patients with low-risk prostate cancer who require or choose active treatment, low–dose rate brachytherapy (LDR) alone, EBRT alone, and/or radical prostatectomy (RP) should be offered to eligible patients. For patients with intermediate-risk prostate cancer choosing EBRT with or without androgen-deprivation therapy, brachytherapy boost (LDR or high–dose rate [HDR]) should be offered to eligible patients. For low-intermediate risk prostate cancer (Gleason 7, prostate-specific antigen < 10 ng/mL or Gleason 6, prostate-specific antigen, 10 to 20 ng/mL), LDR brachytherapy alone may be offered as monotherapy. For patients with high-risk prostate cancer receiving EBRT and androgen-deprivation therapy, brachytherapy boost (LDR or HDR) should be offered to eligible patients. Iodine-125 and palladium-103 are each reasonable isotope options for patients receiving LDR brachytherapy; no recommendation can be made for or against using cesium-131 or HDR monotherapy. Patients should be encouraged to participate in clinical trials to test novel or targeted approaches to this disease.
Additional information is available at www.asco.org/Brachytherapy-guideline and www.asco.org/guidelineswiki.
New US Cancer Staging System Debuts in 9 Months
Medscape Medical News > Conference News
New US Cancer Staging System Debuts in 9 Months
Nick Mulcahy
March 28, 2017
ORLANDO, Florida – Cancer staging is the "common language of cancer" and has undergone some important changes that officially debut in January 2018, said a presenter here at the National Comprehensive Cancer Network (NCCN) 22nd Annual Conference.
Staging defines the extent and prognosis of a cancer and guides treatment, said Stephen Edge, MD, of the Roswell Park Cancer Center in Buffalo New York and the American Joint Committee on Cancer (AJCC).
"The NCCN guidelines all base their recommendations on cancer stage," he observed.
Dr Edge explained that since the 1940s, cancer staging has primarily been "anatomic" and has been based on three elements: tumor (T), lymph nodes (N), and distant metastases (M).
"Anatomic staging is the aggregate information resulting from T, N, and M," but these factors are "decreasingly relevant," he said.
Technologic advances have made biologic markers such as genomic profiles and molecular targets "increasingly important" and have spawned a new classification, known as "prognostic staging," that incorporates and supercedes anatomic staging, said Dr Edge.
"Prognostic stage will be the primary stage that is recorded in cancer registries in the United States," starting in about 9 months, he told the NCCN audience.
Prognostic stage will be the primary stage that is recorded in cancer registries.
Dr Stephen Edge
In the forthcoming eighth edition the AJCC Cancer Staging Manual, which will be effective for all cases diagnosed on January 1, 2018, and onward, there will be some "dramatic" staging changes in cancers in which biologic information now informs clinical care, said Dr Edge. (But not much will change in cancers that have yet to have nonanatomic factors, such as genomic profiles, discovered and validated.)
Breast cancer is one malignancy that will undergo big changes in the new staging system. Prognostic stage will require information on T, N and M, as well as grade, HER2, estrogen-receptor, and progesterone-receptor status. When appropriate, it will include genomic profiles (such as Oncotype DX and Mammaprint results).
In the new scheme, a patient formerly designated as having a T2N0 or T1N1 HER2+ breast cancer will be classified as having a stage 1 cancer. This would not have been the case in the past, because, for example, any lymph node involvement (ie, N1) would have disqualified a case as being stage 1. "With treatment, the prognosis for those patients is truly excellent," explained Dr Edge.
With respect to breast cancer cases at diagnosis, it is estimated that with the new AJCC staging system, there will be more cases of stage I disease and fewer cases of stage IIA, IIB, and IIIA in the United States (estimated on the basis of more than 200,000 cases in the National Cancer Database).
"This will be a big culture change for all of us as we start talking to our patients," said Dr Edge.
"The new staging system is super important," said Randall Oyer, MD, medical director of the Ann Barshinger Cancer Institute at Lancaster General Health in Pennsylvania, who attended the meeting.
Dr Oyer told Medscape Medical News that he sat among a group of clinicians during Dr Edge's presentation. They all agreed the new AJCC staging system was "something we needed to understand and implement when we went back [home]."
It's the best of both worlds.
Dr Randall Oyer
"The concept of prognostic staging is terrific," he said. "It's the best of both worlds because you collate the anatomic stage and you put in the prognostic staging all in one place."
There will be some very practical benefits with the new staging system, he said.
Dr Oyer provided an example of a patient with colon cancer for whom it is unknown whether or not RAS staging was done. "You go looking in the lab section, you look in the pathology section, you look in the notes. You could always go back and find the tumor stage in the tumor registry, but you couldn't find this key piece of information. So, every time someone made a treatment decision, you had to go looking for this."
The new system solves that problem, says Dr Oyer.
The limitations of anatomic staging are obvious, he also pointed out.
"For many years, we've known that some people who had early-stage cancer didn't do well and needed better treatment, and some people who had advanced-stage cancer did well no matter what you did," he said.
Eventually, research indicated that biologic prognostic markers provided the explanation for these conundrums. "But there wasn't any clear way to incorporate that information into staging," observed Dr Oyer. Now there is, he pointed out.
There are three take-home messages, Dr Oyer summarized.
One, "the integration of prognostic markers and anatomic markers is an idea whose time has come."
Two, the new staging system provides a "central repository of case data" that is both searchable and updateable because is a digital tool. "I've been practicing medicine for more than 30 years. I've always used a paper staging manual," he said. But the utility of the paper approach has long past because of the increase in the number of prognostic tools, he said. "I would have to look at this page, that page, this page, that page."
Three, "it's going to be a lot of work to get going, but it will be worth it for our patients," he concluded.
Not Exactly a New Idea
The idea of using factors other than T, N, and M in staging is not exactly new.
For example, in 2009 in the seventh edition of the AJCC Manual, in the section on prostate cancer, prostate-specific antigen testing score and Gleason score were incorporated into staging groups.
In fact, the transition from anatomy as the ruling factor to prognostic staging has been ongoing. In the sixth and seventh editions, there has been a "marked increase" in the use of nonanatomic factors for defining stage groups, said Dr Edge.
However, he also acknowledged that many cancer types do not have validated nonanatomic factors to modify the anatomic findings and thus will not be affected by the new staging system.
Dr Edge and Dr Oyer have disclosed no relevant financial relationships.
National Comprehensive Cancer Network 22nd Annual Conference. Presented March 25, 2017.
Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick
For more from Medscape Oncology, follow us on Twitter: @MedscapeOnc
New US Cancer Staging System Debuts in 9 Months
Nick Mulcahy
March 28, 2017
ORLANDO, Florida – Cancer staging is the "common language of cancer" and has undergone some important changes that officially debut in January 2018, said a presenter here at the National Comprehensive Cancer Network (NCCN) 22nd Annual Conference.
Staging defines the extent and prognosis of a cancer and guides treatment, said Stephen Edge, MD, of the Roswell Park Cancer Center in Buffalo New York and the American Joint Committee on Cancer (AJCC).
"The NCCN guidelines all base their recommendations on cancer stage," he observed.
Dr Edge explained that since the 1940s, cancer staging has primarily been "anatomic" and has been based on three elements: tumor (T), lymph nodes (N), and distant metastases (M).
"Anatomic staging is the aggregate information resulting from T, N, and M," but these factors are "decreasingly relevant," he said.
Technologic advances have made biologic markers such as genomic profiles and molecular targets "increasingly important" and have spawned a new classification, known as "prognostic staging," that incorporates and supercedes anatomic staging, said Dr Edge.
"Prognostic stage will be the primary stage that is recorded in cancer registries in the United States," starting in about 9 months, he told the NCCN audience.
Prognostic stage will be the primary stage that is recorded in cancer registries.
Dr Stephen Edge
In the forthcoming eighth edition the AJCC Cancer Staging Manual, which will be effective for all cases diagnosed on January 1, 2018, and onward, there will be some "dramatic" staging changes in cancers in which biologic information now informs clinical care, said Dr Edge. (But not much will change in cancers that have yet to have nonanatomic factors, such as genomic profiles, discovered and validated.)
Breast cancer is one malignancy that will undergo big changes in the new staging system. Prognostic stage will require information on T, N and M, as well as grade, HER2, estrogen-receptor, and progesterone-receptor status. When appropriate, it will include genomic profiles (such as Oncotype DX and Mammaprint results).
In the new scheme, a patient formerly designated as having a T2N0 or T1N1 HER2+ breast cancer will be classified as having a stage 1 cancer. This would not have been the case in the past, because, for example, any lymph node involvement (ie, N1) would have disqualified a case as being stage 1. "With treatment, the prognosis for those patients is truly excellent," explained Dr Edge.
With respect to breast cancer cases at diagnosis, it is estimated that with the new AJCC staging system, there will be more cases of stage I disease and fewer cases of stage IIA, IIB, and IIIA in the United States (estimated on the basis of more than 200,000 cases in the National Cancer Database).
"This will be a big culture change for all of us as we start talking to our patients," said Dr Edge.
"The new staging system is super important," said Randall Oyer, MD, medical director of the Ann Barshinger Cancer Institute at Lancaster General Health in Pennsylvania, who attended the meeting.
Dr Oyer told Medscape Medical News that he sat among a group of clinicians during Dr Edge's presentation. They all agreed the new AJCC staging system was "something we needed to understand and implement when we went back [home]."
It's the best of both worlds.
Dr Randall Oyer
"The concept of prognostic staging is terrific," he said. "It's the best of both worlds because you collate the anatomic stage and you put in the prognostic staging all in one place."
There will be some very practical benefits with the new staging system, he said.
Dr Oyer provided an example of a patient with colon cancer for whom it is unknown whether or not RAS staging was done. "You go looking in the lab section, you look in the pathology section, you look in the notes. You could always go back and find the tumor stage in the tumor registry, but you couldn't find this key piece of information. So, every time someone made a treatment decision, you had to go looking for this."
The new system solves that problem, says Dr Oyer.
The limitations of anatomic staging are obvious, he also pointed out.
"For many years, we've known that some people who had early-stage cancer didn't do well and needed better treatment, and some people who had advanced-stage cancer did well no matter what you did," he said.
Eventually, research indicated that biologic prognostic markers provided the explanation for these conundrums. "But there wasn't any clear way to incorporate that information into staging," observed Dr Oyer. Now there is, he pointed out.
There are three take-home messages, Dr Oyer summarized.
One, "the integration of prognostic markers and anatomic markers is an idea whose time has come."
Two, the new staging system provides a "central repository of case data" that is both searchable and updateable because is a digital tool. "I've been practicing medicine for more than 30 years. I've always used a paper staging manual," he said. But the utility of the paper approach has long past because of the increase in the number of prognostic tools, he said. "I would have to look at this page, that page, this page, that page."
Three, "it's going to be a lot of work to get going, but it will be worth it for our patients," he concluded.
Not Exactly a New Idea
The idea of using factors other than T, N, and M in staging is not exactly new.
For example, in 2009 in the seventh edition of the AJCC Manual, in the section on prostate cancer, prostate-specific antigen testing score and Gleason score were incorporated into staging groups.
In fact, the transition from anatomy as the ruling factor to prognostic staging has been ongoing. In the sixth and seventh editions, there has been a "marked increase" in the use of nonanatomic factors for defining stage groups, said Dr Edge.
However, he also acknowledged that many cancer types do not have validated nonanatomic factors to modify the anatomic findings and thus will not be affected by the new staging system.
Dr Edge and Dr Oyer have disclosed no relevant financial relationships.
National Comprehensive Cancer Network 22nd Annual Conference. Presented March 25, 2017.
Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick
For more from Medscape Oncology, follow us on Twitter: @MedscapeOnc
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