miércoles, 6 de abril de 2016
Long working hours and cancer risk: a multi-cohort study
Short Communication
BJC Open article
British Journal of Cancer (2016) 114, 813–818. doi:10.1038/bjc.2016.9 www.bjcancer.com
Published online 18 February 2016
Long working hours and cancer risk: a multi-cohort study
Katriina Heikkila1,2, Solja T Nyberg2, Ida E H Madsen3, Ernest de Vroome4, Lars Alfredsson5,6, Jacob J Bjorner3, Marianne Borritz7, Hermann Burr8, Raimund Erbel9, Jane E Ferrie10,11, Eleonor I Fransson6,12,13, Goedele A Geuskens4, Wendela E Hooftman4, Irene L Houtman4, Karl-Heinz Jöckel14, Anders Knutsson15, Markku Koskenvuo16, Thorsten Lunau17, Martin L Nielsen18, Maria Nordin13,19, Tuula Oksanen2, Jan H Pejtersen20, Jaana Pentti2, Martin J Shipley10, Andrew Steptoe10, Sakari B Suominen21,22,23, Töres Theorell13, Jussi Vahtera2,21,24, Peter J M Westerholm25, Hugo Westerlund13, Nico Dragano17, Reiner Rugulies3,26, Ichiro Kawachi27, G David Batty10,28, Archana Singh-Manoux10,29, Marianna Virtanen2 and Mika Kivimäki2,10,30 for the IPD-Work Consortium
Correspondence: Dr K Heikkila, E-mail: katriina.heikkila@lshtm.ac.uk
Received 22 September 2015; Revised 10 December 2015; Accepted 26 December 2015
Advance online publication 18 February 2016
Abstract
Background:
Working longer than the maximum recommended hours is associated with an increased risk of cardiovascular disease, but the relationship of excess working hours with incident cancer is unclear.
Methods:
This multi-cohort study examined the association between working hours and cancer risk in 116 462 men and women who were free of cancer at baseline. Incident cancers were ascertained from national cancer, hospitalisation and death registers; weekly working hours were self-reported.
Results:
During median follow-up of 10.8 years, 4371 participants developed cancer (n colorectal cancer: 393; n lung cancer: 247; n breast cancer: 833; and n prostate cancer: 534). We found no clear evidence for an association between working hours and the overall cancer risk. Working hours were also unrelated the risk of incident colorectal, lung or prostate cancers. Working greater than or equal to55 h per week was associated with 1.60-fold (95% confidence interval 1.12–2.29) increase in female breast cancer risk independently of age, socioeconomic position, shift- and night-time work and lifestyle factors, but this observation may have been influenced by residual confounding from parity.
Conclusions:
Our findings suggest that working long hours is unrelated to the overall cancer risk or the risk of lung, colorectal or prostate cancers. The observed association with breast cancer would warrant further research.
Epidemiological research suggests that working long hours has a detrimental effect on health. Extended working hours have been reported as being associated with an increased incidence of coronary heart disease and stroke (Kang et al, 2012; Virtanen et al, 2012; Kivimaki et al, 2015a) pre-term delivery (van Melick et al, 2014) and, in manual occupations, type 2 diabetes (Kivimaki et al, 2015b), as well as a high prevalence of anxiety, depression, sleeping difficulties and accidental injuries at work. (Dembe et al, 2005; Bannai and Tamakoshi, 2014). The relationship between long working hours and cancer, however, is unclear.
Long working hours could impact on cancer risk via their association with lifestyle-related exposures. Observational evidence suggests that working longer than recommended hours is linked to many behavioural cancer risk factors, such as excessive alcohol intake (Virtanen et al, 2015) and physical inactivity (Kirk and Rhodes, 2011; Angrave et al, 2015), possibly because individuals feel that they lack time to exercise because they spend extensive time at work (Escoto et al, 2012). As far as we are aware, the association between long working hours and incident cancer has been examined in only one previous investigation, which had inconclusive findings: in that prospective cohort study the association between working 45 h or longer per week and breast cancer was imprecisely estimated (hazard ratio (HR): 0.93, 95% confidence interval (CI): 0.54, 1.58) and no other cancer outcomes were examined (Nielsen et al, 2008).
To address this evidence gap, we examined the relationship between weekly working hours and the overall incident cancer as well as incident colorectal, lung, breast and prostate cancers using individual participant data from 116 000 men and women from 12 prospective cohort studies from six European countries.
Materials and Methods
The 12 studies in our analyses were conducted between 1992 and 2004 in Denmark, Finland, Germany, Sweden, The Netherlands and UK. All were a part of the Individual-Participant-Data Meta-analysis of Working Populations (IPD-Work) Consortium, a collaborative research effort to investigate the health impact of work-related exposures (Kivimaki et al, 2012). Details of each study’s design, recruitment of participants, data collection and ethics committee approval are provided in Supplementary eAppendix 1.
Participants
Our analyses were based on 116 462 men and women who were working and free of cancer at study baseline, whose records were linked to register-based information on incident cancers and who had complete data available on covariates (Supplementary eAppendix 1 and Supplementary Table S1).
Exposures and outcomes
Weekly working hours were ascertained from baseline self-report questions on usual weekly working hours and defined as the total number of hours in the main job and any secondary jobs (Supplementary eAppendix 2 and Supplementary Table S2).
Cancer events were identified from national cancer, hospitalisation and death registers in all studies apart from one (for details, see Supplementary eAppendix 2). The date of the cancer event was defined as the date of diagnosis or hospital admission due to cancer, whichever was earlier. Cancer cases were categorised according to the type and time of diagnosis of their first cancer. We excluded individuals whose first cancer record came from their death certificate (n=10), as the date of diagnosis for these cancers was uncertain. Codes for the incident cancer events were harmonised using ICD-10 (International Classification of Diseases, version 10) as any cancer (ICD-10 codes C00-C97), colorectal (C18-C20), lung (C34), female breast (C50) and prostate (C61) cancers.
Potential confounders and mediators
Details of the selection and ascertainment of the covariates included in our models are provided in Supplementary eAppendix 2. Briefly, potential confounders were age, sex, socioeconomic position, shift work and night-time work. Potential mediators were smoking, alcohol intake and body mass index (BMI). All covariates, measured at baseline, were harmonised across the studies as reported previously (Heikkila et al, 2012; Heikkilä et al, 2012; Nyberg et al, 2012, 2014).
Statistical analysis
Weekly working hours were analysed as a categorical exposure: <35 h, 35–40 h (reference category: standard working hours for the majority of the workforce in Europe), 41–48 h (the upper limit for the European Union Working Time Directive), 49–54 h and greater than or equal to55 h. Incident cancers (any cancer, colorectal, lung, female breast and prostate cancers) were analysed as binary outcomes. Each participant was followed-up from the date of their baseline assessment to the earliest of the following: incident cancer, death or the end of the registry follow-up. We modelled the associations between working hours and each cancer outcome in each study using Cox proportional hazards regression with the participant's age (i.e., time since birth) as the time scale in the model. Study-specific results were combined using random effects meta-analyses. All statistical analyses were conducted using Stata MP 13 (Stata Corporation, College Station, TX, USA) bar the study-specific analyses in the Danish studies, which were conducted using SAS 9.3 (SAS Institute Inc., Cary, NC, USA) and POLS, which were conducted using SPSS 20.0 (SPSS Inc., Chicago, IL, USA). Results
The characteristics of the 116 462 participants are summarised in Table 1. Overall, these men and women were aged 15–73 at baseline and the majority worked a standard 35–40 h per week, with the study-specific proportions varying from 31 to 71%. During a follow-up ranging from 4 to 22 years (median of study-specific medians: 10.8), 4371 individuals were diagnosed with cancer. Of these, 393 men and women had colorectal cancer and 247 had lung cancer; 833 women developed breast cancer and 534 men prostate cancer.
lunes, 28 de marzo de 2016
CAR T-cells as Cancer Therapies
OncLive.
CAR T-cells Rapidly Evolving as Cancer Therapies
Silas Inman @silasinman
Published Online: Sunday, March 20, 2016
Dr Jae Park
Jae H. Park, MD
Chimeric antigen receptor (CAR)-modified T-cell therapies have demonstrated durable complete responses (CRs), the majority of which are minimal residual disease (MRD)-negative, for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). However, several questions still remain regarding their optimal use and applicability outside of ALL, according to Jae H. Park, MD, at the 2016 International Congress on Hematologic Malignancies.
“What we have learned from ALL is that they are very effective at getting to complete remissions, and the responses are very deep. Durable responses have been observe in a subset of patients who did not get subsequent allogeneic transplant,” said Park, Leukemia Service at Memorial Sloan Kettering Cancer Center. “There are a lot of questions, as we move forward, such as the role of the tumor microenvironment, and whether this can be applied outside of ALL.”
A CAR therapy consists of the binding domain from an antibody connected to the signaling domain of a T cell. The process for the therapy involves the insertion of a CAR gene subclone that recognizes a tumor antigen into a viral vector, which is transduced and expanded ex vivo in T cells and then administered to the patient. The resulting therapy has the specificity of an antibody with the killing capacity of a T cell, Park said.
At this point, clinical trials have primarily focused on CD19 and other markers on B-cell malignancies. CD19 was explored first, since it is not expressed in hematopoietic stem cells and is overexpressed in B-cell lymphoma, leukemia, and occasionally in multiple myeloma.
“With CD19, because it's not expressed on stems cells, we are only targeting mature cells. However, because the antigen is also expressed in normal B-cells, we do cause B-cell aplasia,” said Park. “We also have CARs planned for CD22 and CD20, which are other common B-cell antigens.”
CAR-modified T-cell therapies have undergone several changes since they were initially introduced, and continue to be improved and modified. They offer the advantage of having HLA-independent antigen recognition, which provides broad application across both solid and blood cancers. These therapies are also active in both CD4+ and CD8+ T cells, with a minimal risk of graft-versus-host disease.
“This is potentially a living drug. They can survive within the body and provide immunity against cancer,” said Park. “Because this is a genetic therapy, the door is open to more genetic modifications and better versions of the T-cells as the years go on. In the future, we may even be able to accomplish better results, and in solid tumors as well.”
Findings in Acute Lymphoblastic Leukemia
Historically, patients with ALL who are in their first relapsed have a 5-year overall survival (OS) of 7% to 8% and a 2-year OS of 11%. Additionally, in clinical trials studying conventional chemotherapy, the CR rates ranged between 18% and 45% for patients with relapsed/refractory ALL. These poor outcomes emphasize the need for novel therapies, said Park.
In phase I trials exploring CAR T-cell therapies, leukapheresis is conducted upfront to collect T cells for modification followed by chemotherapy, to keep the disease in check. After the T-cell production period, which takes 2 to 3 weeks, a bone marrow biopsy is conducted to assess the response to chemotherapy. After this step, the patient will receive a conditioning chemotherapy followed by an infusion of the T-cell therapy.
“The conditioning therapy, what we think it is doing, is lymphodepletion. It simply is creating a space for these T-cells to get in there and expand. In order for this T-cell therapy to be successful, you do need T-cell activation and expansion,” said Park.
As early phase results have been analyzed, a number of modifications were made to this study design. Initially, the conditioning chemotherapy was cyclophosphamide alone; however, fludarabine has now been added, Park noted. Additionally, the second infusion of the CAR T-cell therapy is customized, based on the number of blast cells present, to address toxicity concerns.
“The dosing adjustments here are counterintuitive, in a way, the more disease you have, you actually need less T-cells, since disease really means antigen load,” said Park. “The more antigen there is, the T-cells will engage and expand a lot quicker and faster, and as they do that, that is when the toxicity comes in.”
CAR T-cells in Action
As an example of the outcomes seen with CAR T-cell therapy, Park presented data from a 46-patient phase I study that was conducted by Memorial Sloan Kettering Cancer Center (NCT01044069). In this example, the median age of patients was 45 years and the median number of prior therapies was 3.1
In evaluable patients with CD19-positive B-cell ALL treated with the CAR T-cell therapy (n = 45), the overall CR rate was 82.2%. In those with morphologic disease (≥5% blasts; n = 24), the CR rate was 75% and for those with minimal disease (<5% blasts; n = 21) the CR rate was 90.5%. Of patients who achieved a CR, 83% were negative for MRD. The median time to a CR was 21 days. In a subgroup analysis, the response rate was higher in patients with Philadelphia chromosome (Ph)-positive ALL (n = 14), with a CR rate of 92.9%. In the Ph-negative group (n = 31), the CR rate was 77.4%. Additionally, CR rates were superior in younger patients compared with adults. In those aged 18 to 30 (n = 11), the CR rate was 90.9%. In those aged 30 to 59 years (n = 10), the CR rate was 80%. Across the full study population, the median OS was 9 months, with a 6-month OS rate of 65%. In those who achieved a CR, the median OS was 10.6 months, with a 6-month OS rate of 71%. The median OS was 10.6 months in those who did not receive a subsequent stem cell transplant and was not yet reached in those who did receive a transplant. The 6-month OS rates were similar between the two groups, at 80% and 79%, respectively. “Standard of care says they should go on to transplant. If the patient hasn't had a transplant, we do still recommend a transplant,” said Park. “These numbers are very small, so I am not suggesting that a patient shouldn't get transplant, it still seems to be uncertain in this situation.”
This experience is not unique, in regard to efficacy, Park noted. A number of clinical trials have been conducted looking at various CAR T-cell therapies for patients with relapse/refractory ALL. Across the studies looking at these agents in adult patients, the CR rate has ranged from 83% to 89%. Additionally, in studies with OS findings, the results appear consistent between trials.
In the pediatric setting, a number of promising results have also been demonstrated. In one example exploring CTL019,2 the 6-month event-free survival (EFS) was 63%, the 6-month OS was 78%, and the CR rate was 90%. In a second study exploring KTE-C19,3 the 6-month OS and EFS rates were approximately 65% and 80%, respectively. The CR rate was 70%.
“The response rates are quite excellent across all of these studies. The follow-up is relatively short for these studies; they are all fairly new. That is something to keep in mind for these results,” Park said.
Over a dozen clinical trials are currently enrolling patients with B-cell ALL looking at CD19-targeted CAR T-cell therapies, including 4 phase II investigations. The University of Pennsylvania (NCT02030847), researchers in Sweden (NCT02132624), Juno Therapeutics (NCT02535364), and Seattle Children’s Hospital (NCT02028455) are conducting these trials.
“Encouragingly there are some phase II trials going,” said Park. “All of these trials employ a similar design but there are some differences in the trials and therapies, such as the binding domain, the mode of transduction, cell source, patient population, and method of lymphodepletion.”
CAR T-cell Associated Adverse Events
The major adverse events (AEs) associated with CAR T-cell therapies are cytokine release syndrome (CRS) and neurologic changes. These occur across all of the CAR T-cell therapies, since they each have similar mechanisms of action.
“This is an infusion of T-cells, and if you have this type of event, there is really no turning the drug off or holding the drug. Once they are in, they are in,” said Park. “This is the reason we need to modify the studies to mitigate the side effects.”
A correlation exists between CRS and disease burden, which is the rationale that led to dose reductions in those with a higher disease burden. This event can be monitored using C-reactive protein levels, once detected interleuken-6 therapy can effectively treat CRS. “The IL-6 receptor inhibitor tocilizumab is highly effective at reversing the symptoms of cytokine release syndrome,” said Park.
The incidence of these toxicities has varied between clinical trials, with severe CRS occurring in as many as 92% of patients enrolled in one early study. Additionally, this event led to deaths in early studies. However, with proper management techniques now in place, severe CRS has become less common.
In addition to CRS, grade 3/4 neurotoxicity has been seen in approximately 28% of patients in some studies. At this time, the mechanism behind this event is not yet fully understood. Neurotoxicity generally consists of an altered mental state, aphasia, and seizures or seizure-like activity. “These do get better over time, and are not really prolonged in duration,” said Park.
Ongoing Studies Outside of ALL
There are a number of studies exploring CAR-modified T-cells for patients with acute myeloid leukemia (AML). These studies are all phase I, and are being conducted across several sites, including the USA, China, and Australia. These therapies have a variety of CAR targets, including CD33, CD123, CD28, and NKG2D.
At this time, a single target that appears most effective has not yet been identified for patients with AML. Additionally, the off-target toxicity of these therapies remains unclear, specifically whether they could lead to prolonged or permanent myelosuppression. At this point, there is little data supporting the impact of these agents in high volume disease and the durability of response.
A number of preclinical trials are currently in progress to assess strategies to overcome the current limitations of CAR T-cell therapies for AML or solid tumors. These include the exploration of potential "on" and "off" switches to control T-cell activation. Moreover, split receptor/dual antigen-targeting T-cells are in development along with so-called "armored" CARs.
“The armored CAR T-cells involves building in additional cytokines with T-cells to be even more potent, and to take advantage of the innate immune system,” Park said.
With the number of studies currently ongoing, and the level of competition, the field continues to evolve rapidly. Outside of acute leukemia, CAR T-cell therapies are also being explored in non-Hodgkin lymphoma, multiple myeloma, and across a variety of cancers.
- See more at: http://global.onclive.com/conference-coverage/hematology-2016/car-t-cells-rapidly-evolving-as-cancer-therapies#sthash.Jv7BofbG.dpuf
CAR T-cells Rapidly Evolving as Cancer Therapies
Silas Inman @silasinman
Published Online: Sunday, March 20, 2016
Dr Jae Park
Jae H. Park, MD
Chimeric antigen receptor (CAR)-modified T-cell therapies have demonstrated durable complete responses (CRs), the majority of which are minimal residual disease (MRD)-negative, for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). However, several questions still remain regarding their optimal use and applicability outside of ALL, according to Jae H. Park, MD, at the 2016 International Congress on Hematologic Malignancies.
“What we have learned from ALL is that they are very effective at getting to complete remissions, and the responses are very deep. Durable responses have been observe in a subset of patients who did not get subsequent allogeneic transplant,” said Park, Leukemia Service at Memorial Sloan Kettering Cancer Center. “There are a lot of questions, as we move forward, such as the role of the tumor microenvironment, and whether this can be applied outside of ALL.”
A CAR therapy consists of the binding domain from an antibody connected to the signaling domain of a T cell. The process for the therapy involves the insertion of a CAR gene subclone that recognizes a tumor antigen into a viral vector, which is transduced and expanded ex vivo in T cells and then administered to the patient. The resulting therapy has the specificity of an antibody with the killing capacity of a T cell, Park said.
At this point, clinical trials have primarily focused on CD19 and other markers on B-cell malignancies. CD19 was explored first, since it is not expressed in hematopoietic stem cells and is overexpressed in B-cell lymphoma, leukemia, and occasionally in multiple myeloma.
“With CD19, because it's not expressed on stems cells, we are only targeting mature cells. However, because the antigen is also expressed in normal B-cells, we do cause B-cell aplasia,” said Park. “We also have CARs planned for CD22 and CD20, which are other common B-cell antigens.”
CAR-modified T-cell therapies have undergone several changes since they were initially introduced, and continue to be improved and modified. They offer the advantage of having HLA-independent antigen recognition, which provides broad application across both solid and blood cancers. These therapies are also active in both CD4+ and CD8+ T cells, with a minimal risk of graft-versus-host disease.
“This is potentially a living drug. They can survive within the body and provide immunity against cancer,” said Park. “Because this is a genetic therapy, the door is open to more genetic modifications and better versions of the T-cells as the years go on. In the future, we may even be able to accomplish better results, and in solid tumors as well.”
Findings in Acute Lymphoblastic Leukemia
Historically, patients with ALL who are in their first relapsed have a 5-year overall survival (OS) of 7% to 8% and a 2-year OS of 11%. Additionally, in clinical trials studying conventional chemotherapy, the CR rates ranged between 18% and 45% for patients with relapsed/refractory ALL. These poor outcomes emphasize the need for novel therapies, said Park.
In phase I trials exploring CAR T-cell therapies, leukapheresis is conducted upfront to collect T cells for modification followed by chemotherapy, to keep the disease in check. After the T-cell production period, which takes 2 to 3 weeks, a bone marrow biopsy is conducted to assess the response to chemotherapy. After this step, the patient will receive a conditioning chemotherapy followed by an infusion of the T-cell therapy.
“The conditioning therapy, what we think it is doing, is lymphodepletion. It simply is creating a space for these T-cells to get in there and expand. In order for this T-cell therapy to be successful, you do need T-cell activation and expansion,” said Park.
As early phase results have been analyzed, a number of modifications were made to this study design. Initially, the conditioning chemotherapy was cyclophosphamide alone; however, fludarabine has now been added, Park noted. Additionally, the second infusion of the CAR T-cell therapy is customized, based on the number of blast cells present, to address toxicity concerns.
“The dosing adjustments here are counterintuitive, in a way, the more disease you have, you actually need less T-cells, since disease really means antigen load,” said Park. “The more antigen there is, the T-cells will engage and expand a lot quicker and faster, and as they do that, that is when the toxicity comes in.”
CAR T-cells in Action
As an example of the outcomes seen with CAR T-cell therapy, Park presented data from a 46-patient phase I study that was conducted by Memorial Sloan Kettering Cancer Center (NCT01044069). In this example, the median age of patients was 45 years and the median number of prior therapies was 3.1
In evaluable patients with CD19-positive B-cell ALL treated with the CAR T-cell therapy (n = 45), the overall CR rate was 82.2%. In those with morphologic disease (≥5% blasts; n = 24), the CR rate was 75% and for those with minimal disease (<5% blasts; n = 21) the CR rate was 90.5%. Of patients who achieved a CR, 83% were negative for MRD. The median time to a CR was 21 days. In a subgroup analysis, the response rate was higher in patients with Philadelphia chromosome (Ph)-positive ALL (n = 14), with a CR rate of 92.9%. In the Ph-negative group (n = 31), the CR rate was 77.4%. Additionally, CR rates were superior in younger patients compared with adults. In those aged 18 to 30 (n = 11), the CR rate was 90.9%. In those aged 30 to 59 years (n = 10), the CR rate was 80%. Across the full study population, the median OS was 9 months, with a 6-month OS rate of 65%. In those who achieved a CR, the median OS was 10.6 months, with a 6-month OS rate of 71%. The median OS was 10.6 months in those who did not receive a subsequent stem cell transplant and was not yet reached in those who did receive a transplant. The 6-month OS rates were similar between the two groups, at 80% and 79%, respectively. “Standard of care says they should go on to transplant. If the patient hasn't had a transplant, we do still recommend a transplant,” said Park. “These numbers are very small, so I am not suggesting that a patient shouldn't get transplant, it still seems to be uncertain in this situation.”
This experience is not unique, in regard to efficacy, Park noted. A number of clinical trials have been conducted looking at various CAR T-cell therapies for patients with relapse/refractory ALL. Across the studies looking at these agents in adult patients, the CR rate has ranged from 83% to 89%. Additionally, in studies with OS findings, the results appear consistent between trials.
In the pediatric setting, a number of promising results have also been demonstrated. In one example exploring CTL019,2 the 6-month event-free survival (EFS) was 63%, the 6-month OS was 78%, and the CR rate was 90%. In a second study exploring KTE-C19,3 the 6-month OS and EFS rates were approximately 65% and 80%, respectively. The CR rate was 70%.
“The response rates are quite excellent across all of these studies. The follow-up is relatively short for these studies; they are all fairly new. That is something to keep in mind for these results,” Park said.
Over a dozen clinical trials are currently enrolling patients with B-cell ALL looking at CD19-targeted CAR T-cell therapies, including 4 phase II investigations. The University of Pennsylvania (NCT02030847), researchers in Sweden (NCT02132624), Juno Therapeutics (NCT02535364), and Seattle Children’s Hospital (NCT02028455) are conducting these trials.
“Encouragingly there are some phase II trials going,” said Park. “All of these trials employ a similar design but there are some differences in the trials and therapies, such as the binding domain, the mode of transduction, cell source, patient population, and method of lymphodepletion.”
CAR T-cell Associated Adverse Events
The major adverse events (AEs) associated with CAR T-cell therapies are cytokine release syndrome (CRS) and neurologic changes. These occur across all of the CAR T-cell therapies, since they each have similar mechanisms of action.
“This is an infusion of T-cells, and if you have this type of event, there is really no turning the drug off or holding the drug. Once they are in, they are in,” said Park. “This is the reason we need to modify the studies to mitigate the side effects.”
A correlation exists between CRS and disease burden, which is the rationale that led to dose reductions in those with a higher disease burden. This event can be monitored using C-reactive protein levels, once detected interleuken-6 therapy can effectively treat CRS. “The IL-6 receptor inhibitor tocilizumab is highly effective at reversing the symptoms of cytokine release syndrome,” said Park.
The incidence of these toxicities has varied between clinical trials, with severe CRS occurring in as many as 92% of patients enrolled in one early study. Additionally, this event led to deaths in early studies. However, with proper management techniques now in place, severe CRS has become less common.
In addition to CRS, grade 3/4 neurotoxicity has been seen in approximately 28% of patients in some studies. At this time, the mechanism behind this event is not yet fully understood. Neurotoxicity generally consists of an altered mental state, aphasia, and seizures or seizure-like activity. “These do get better over time, and are not really prolonged in duration,” said Park.
Ongoing Studies Outside of ALL
There are a number of studies exploring CAR-modified T-cells for patients with acute myeloid leukemia (AML). These studies are all phase I, and are being conducted across several sites, including the USA, China, and Australia. These therapies have a variety of CAR targets, including CD33, CD123, CD28, and NKG2D.
At this time, a single target that appears most effective has not yet been identified for patients with AML. Additionally, the off-target toxicity of these therapies remains unclear, specifically whether they could lead to prolonged or permanent myelosuppression. At this point, there is little data supporting the impact of these agents in high volume disease and the durability of response.
A number of preclinical trials are currently in progress to assess strategies to overcome the current limitations of CAR T-cell therapies for AML or solid tumors. These include the exploration of potential "on" and "off" switches to control T-cell activation. Moreover, split receptor/dual antigen-targeting T-cells are in development along with so-called "armored" CARs.
“The armored CAR T-cells involves building in additional cytokines with T-cells to be even more potent, and to take advantage of the innate immune system,” Park said.
With the number of studies currently ongoing, and the level of competition, the field continues to evolve rapidly. Outside of acute leukemia, CAR T-cell therapies are also being explored in non-Hodgkin lymphoma, multiple myeloma, and across a variety of cancers.
- See more at: http://global.onclive.com/conference-coverage/hematology-2016/car-t-cells-rapidly-evolving-as-cancer-therapies#sthash.Jv7BofbG.dpuf
Driving CAR T-cells forward
Nature Reviews Clinical Oncology | Review
Driving CAR T-cells forward
Hollie J. Jackson, Sarwish Rafiq & Renier J. Brentjens
Nature Reviews Clinical Oncology
(2016)
doi:10.1038/nrclinonc.2016.36
Published online
22 March 2016
Abstract
The engineered expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. Early clinical trials using CAR T cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm for this approach. Important lessons have been derived from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in haematological and solid malignancies. In this Review, we discuss these trials and present strategies that can increase the antitumour efficacy and safety of CAR T-cell therapy. Given the fast-moving nature of this field, we only discuss studies with direct translational application currently or soon-to-be tested in the clinical setting.
Introduction
Chimeric antigen receptors (CARs) consist of an extracellular antigen-recognition domain, which is usually an antibody single-chain variable fragment (scFv), but can also be a peptide or another protein, linked to an intracellular signalling domain — usually the CD3ζ (CD3 zeta) chain of the T-cell receptor. The extracellular portion of the CAR permits the recognition of a specific antigen by a T cell and, subsequently, the signalling domains stimulate T-cell proliferation, cytolysis and cytokine secretion to eliminate the target cell. The patients' own T cells (or those from an allogeneic donor) are isolated, activated and genetically modified to generate CAR T cells, which are then infused into the same patient. This approach carries a very low risk of graft-versus-host disease and enables lipid, protein and carbohydrate antigens to be targeted by T cells in an MHC-unrestricted fashion. Additionally, one CAR design can be used to treat all cancers expressing the same antigen. The need to generate T cells for each patient was once considered to be a financial and technical obstruction to this therapeutic approach, but the success of CAR-T-cell therapy for the treatment of B-cell acute lymphoblastic leukaemia (B-ALL) has demonstrated that CAR T cells can be produced efficiently and for a reasonable cost.
CD19-targeted CAR T cells have been investigated clinically for the treatment of B-cell malignancies. CD19-targeted CAR-T-cell therapy has repeatedly demonstrated to produce marked antitumour responses in patients with B-ALL1, 2, 3. Following this success, much attention has been devoted to the development of CAR T cells for the successful treatment of other haematological malignancies and solid tumours. In this Review, we discuss successful CD19-targeted CAR-T-cell therapies, CAR-T-cell designs targeting other molecules for the treatment of haematological malignancies, and novel targets proposed for the treatment of solid tumours. This discussion will be limited to approaches with registered clinical trials. In our opinion, the findings from these trials will be instrumental to increase our understanding and optimize the efficacy of this promising cancer treatment.
Driving CAR T-cells forward
Hollie J. Jackson, Sarwish Rafiq & Renier J. Brentjens
Nature Reviews Clinical Oncology
(2016)
doi:10.1038/nrclinonc.2016.36
Published online
22 March 2016
Abstract
The engineered expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. Early clinical trials using CAR T cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm for this approach. Important lessons have been derived from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in haematological and solid malignancies. In this Review, we discuss these trials and present strategies that can increase the antitumour efficacy and safety of CAR T-cell therapy. Given the fast-moving nature of this field, we only discuss studies with direct translational application currently or soon-to-be tested in the clinical setting.
Introduction
Chimeric antigen receptors (CARs) consist of an extracellular antigen-recognition domain, which is usually an antibody single-chain variable fragment (scFv), but can also be a peptide or another protein, linked to an intracellular signalling domain — usually the CD3ζ (CD3 zeta) chain of the T-cell receptor. The extracellular portion of the CAR permits the recognition of a specific antigen by a T cell and, subsequently, the signalling domains stimulate T-cell proliferation, cytolysis and cytokine secretion to eliminate the target cell. The patients' own T cells (or those from an allogeneic donor) are isolated, activated and genetically modified to generate CAR T cells, which are then infused into the same patient. This approach carries a very low risk of graft-versus-host disease and enables lipid, protein and carbohydrate antigens to be targeted by T cells in an MHC-unrestricted fashion. Additionally, one CAR design can be used to treat all cancers expressing the same antigen. The need to generate T cells for each patient was once considered to be a financial and technical obstruction to this therapeutic approach, but the success of CAR-T-cell therapy for the treatment of B-cell acute lymphoblastic leukaemia (B-ALL) has demonstrated that CAR T cells can be produced efficiently and for a reasonable cost.
CD19-targeted CAR T cells have been investigated clinically for the treatment of B-cell malignancies. CD19-targeted CAR-T-cell therapy has repeatedly demonstrated to produce marked antitumour responses in patients with B-ALL1, 2, 3. Following this success, much attention has been devoted to the development of CAR T cells for the successful treatment of other haematological malignancies and solid tumours. In this Review, we discuss successful CD19-targeted CAR-T-cell therapies, CAR-T-cell designs targeting other molecules for the treatment of haematological malignancies, and novel targets proposed for the treatment of solid tumours. This discussion will be limited to approaches with registered clinical trials. In our opinion, the findings from these trials will be instrumental to increase our understanding and optimize the efficacy of this promising cancer treatment.
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