scholarly journals Neurological Adverse Events Following CAR-T Cell Therapy: A Real-World Analysis of Adult Patients Treated with Axicabtagene Ciloleucel or Tisagenlecleucel

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1952-1952 ◽  
Author(s):  
Ajeet Gajra ◽  
Marjorie E Zettler ◽  
Eli G Phillips Jr. ◽  
Andrew J Klink ◽  
Jonathan K. Kish ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Real World ◽  
Case Reports ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Introduction: Neurotoxicity is a major adverse event (AE) of CAR-T therapy with diverse presentation. When severe, it can be fatal, and may lead to neurologic sequelae as well as contribute to increased health care utilization, driving up cost of therapy. In clinical trials, the most common neurologic AEs with axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel) included encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia and anxiety. Fatal and serious cases of cerebral edema, leukoencephalopathy and/ or seizures have been reported with both agents. In this real-world analysis, we reviewed post-marketing case reports from the FDA Adverse Events Reporting System (FAERS). Database involving axi-cel or tis-cel for large B cell lymphoma (LBCL), with the dual objectives of characterizing the various components of neurotoxicity and assessing the association of neurological (neuro) AEs with demographic and treatment factors as well as with other AEs reported with CAR-T cell therapy use. Methods: The FAERS database contains anonymized reports of product-related AEs, classified using the Medical Dictionary for Regulatory Activities (MedDRA) and categorized as serious or non-serious. The FAERS database was queried for cases involving axi-cel or tis-cel (and their respective trade names) from the FDA approval date for the LBCL indication (October 18, 2017 for axi-cel; May 1, 2018 for tis-cel) through March 31, 2019. Cases were excluded if patient age was unknown or if the case was reported outside the US. Of all patients reported to have neuro AEs, the frequency of various components was collected. The association of neuro AEs with patient age, concomitant AEs and key lab abnormalities were evaluated by Fisher's exact test, using a two-sided α=0.05 to determine statistical significance. Median age in each subgroup was compared using the Mann-Whitney U test. Results: In the 397 case reports identified, the majority of reactions (376, 95%) were classified as serious. Overall, 258 (65%) were reported to have neuro AEs, with "neurotoxicity" reported in 170 cases (66%); encephalopathy including CAR-T cell-related, metabolic and toxic in 92 cases (36%); seizures including status epilepticus, myoclonus and partial seizures in 12 cases (5%); stroke including cerebrovascular accident, hemiparesis, basal ganglia, brain stem, cerebellar and cerebral infarcts, motor dysfunction, facial and cranial nerve paralysis in 13 cases (5%); speech disorders including terms of aphasia, dysarthria, speech and language impairment in 55 cases (21%); amnesia and memory impairment in 18 cases (7%); brain or spinal cord edema and increased intracranial pressure in 6 cases (2%). Peripheral neuropathy was reported in 5 cases (2%). Symptoms of headache, tremors, dizziness and somnolence were reported in 30 (12%), 41 (16%) 3 (1%) and 34 (13%) cases respectively. Confusional state, delirium or agitation were reported in 61 cases (24%). Neuro AEs were associated with use of axi-cel vs. tis-cel (69% vs. 24%, p <0.01) and with age ≥65 years (43% vs. 36% in age <65, p=0.02) but did not impact death or hospitalization (Table). Neuro AEs were associated with cytokine release syndrome (CRS, 67% vs. 49% without, p<0.01) as well as with cardiac AEs including tachycardia (p<0.01). There was an association of psychiatric AEs with neuro AEs though some (delirium, agitation, hallucination) may be considered a part of the neuro AEs. There were no associations of febrile neutropenia, thrombocytopenia, serum ferritin and C-reactive protein with neuro AEs (all p values>0.05). Conclusions: Neuro AEs were common with CAR-T cell therapy in the real world and largely resembled those reported in clinical trials. Neuro AEs were associated with the agent used, age ≥65 as well as the presence of CRS, cardiac and psychiatric AEs but not with any of the laboratory values studied. The limitations of this study include its retrospective nature, potential under-reporting to FAERS and the relatively small number of patients in the tis-cel group due to its later approval and shorter time available for uptake compared to axi-cel. Despite these limitations, our findings can serve to inform clinicians' decision making when treating adult patients with CAR-T cell therapy. Further research is needed to better discern the etiopathology and biomarkers of neuro AEs in CAR-T cell therapy. Disclosures Gajra: Cardinal Health: Employment. Zettler:Cardinal Health: Employment. Phillips Jr.:Cardinal Health: Employment. Klink:Cardinal Health: Employment. Kish:Cardinal Health: Employment. Mehta:Cardinal Health: Employment. Feinberg:Cardinal Health: Employment.

scholarly journals Real-World Experiences of CAR T-Cell Therapy for Large B-Cell Lymphoma: How Similar Are They to the Prospective Studies?

2021 ◽  
Vol 4 (3) ◽  
pp. 150-159
Author(s):  
Kevin Tang ◽  
Loretta J. Nastoupil
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Real World ◽  
Response Rates ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

ABSTRACT Chimeric antigen receptor (CAR) T cell therapy has emerged as a revolutionary treatment option for highly aggressive B cell malignancies. Clinical trials of CD19 CAR T cells for the management of relapsed and/or refractory non-Hodgkin lymphoma (NHL) have shown markedly improved survival and response rates. The goal of this review is to evaluate whether the results from these clinical trials are reflective of real-world practices through the analysis of published literature of the commercially available CAR T cell products. We have found that despite the significantly different patient characteristics, the adverse events and response rates of real-world patients were similar to those of the clinical trials. Of interest, several groups excluded from the clinical trials, such as patients with HIV infection, chronic viral hepatitis, and secondary CNS (central nervous system) lymphoma, had case reports of promising outcomes.

Real-world adverse events associated with CAR T-cell therapy among adults age ≥ 65 years

2020 ◽  
Author(s):  
Marjorie E. Zettler ◽  
Bruce A. Feinberg ◽  
Eli G. Phillips Jr ◽  
Andrew J. Klink ◽  
Sonam Mehta ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Real World ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Real-World Analysis of Adverse Events Associated with CAR T-Cell Therapy Among Adults Age ≥65 Years

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1951-1951 ◽  
Author(s):  
Marjorie E Zettler ◽  
Bruce A Feinberg ◽  
Eli G Phillips Jr. ◽  
Andrew J Klink ◽  
Sonam Mehta ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Real World ◽  
Age Group ◽  
T Cell Therapy ◽  
Younger Patients ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Introduction: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel) are chimeric antigen receptor (CAR) T-cell therapies that target CD19-expressing B cells. Both therapies have been approved by the United States (US) Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after at least 2 lines of systemic therapy. The median age at diagnosis of diffuse LBCL is 66 years, with over half the cases occurring in patients over age 65. Patients >65 years have worse survival than younger patients. Despite this predilection for older age, only one quarter of the patients in the pivotal trials supporting approval of the 2 therapies were age 65 or older. An analysis of the safety of axi-cel in the pivotal ZUMA-1 trial showed no significant differences between the age <65 and ≥65 subgroups; however, the small number of older patients included on the original clinical trials due to the constraints of the stringent eligibility criteria limits the generalizability of these findings (Sano et al, Blood 2018 132:96). In this analysis, we reviewed post-approval adverse events (AEs) involving axi-cel or tis-cel for LBCL and compared reactions and outcomes by age utilizing the FDA Adverse Events Reporting System (FAERS) Database, which was created to support FDA's post-marketing safety surveillance program for drug and therapeutic biologic products. Methods: The FAERS database contains anonymized reports of product-related AEs, classified using the Medical Dictionary for Regulatory Activities (MedDRA) and categorized as serious or non-serious. The database was queried for cases involving axi-cel or tis-cel (and their respective trade names) from the FDA approval date for the LBCL indication (October 18, 2017 for axi-cel; May 1, 2018 for tis-cel) through March 31, 2019. Cases were excluded if the age of the patient was unknown. Cases reported outside the US were excluded. Patient characteristics and adverse events were summarized using descriptive statistics. Comparisons of rates of AEs by age group were made using Fisher's exact test; statistical significance was determined at a two-sided α=0.05. Results: A total of 397 cases were retrieved (360 involving axi-cel, 37 involving tis-cel). The median age of the patients involved was 62 years (range 18-81), with 153 (39%) of the patients age 65 or older. The vast majority of reactions (376, 95%) reported to FAERS were classified as serious. Overall, 141 (36%) cases resulted in hospitalization; 33 (8%) cases had an outcome categorized as life-threatening; 46 (12%) cases resulted in death; 6 (2%) resulted in disability. The most common reaction in each age group was cytokine release syndrome (CRS), reported in 64% and 56% of patients <65 and ≥65 groups, respectively (Table). When a composite definition for CRS was utilized by including individual clinical features that comprise CRS, a higher proportion of patients <65 were noted to have CRS (80% vs. 67%, p<0.01). Pyrexia (41% vs. 24%, p<0.01), tachycardia (17% vs. 8%, p=0.01), hospitalization (42% vs. 25%, p<0.01) and elevated ferritin levels (3% vs. 0%, p=0.03) were significantly more common among the younger age group. Patients ≥65 had a significantly higher proportion of cases of neurotoxicity (50% vs. 39%, p=0.04); atrial fibrillation was also reported more frequently in the older age group compared to younger patients (8% vs. 3%, p=0.02). Conclusions: This large-scale post-marketing report of CAR T-cell therapy associated AEs in the real world suggests differences based on age: patients ≥65 had a higher incidence of neurotoxicity and atrial fibrillation while younger patients had increased incidence of some CRS components, especially pyrexia and tachycardia. There was no demonstrable difference in deaths between the 2 groups, but younger patients had higher rates of hospitalization. This report provides real-world evidence for use of CAR T-cell therapy in patients ≥65 and can inform clinical care based on patterns of AEs observed. Potential under-reporting of cases to the FAERS database, the retrospective design of this study and limited data available in the case reports preclude interpretation of causality. Despite these limitations, our findings identified real-world trends in reported signals that complement clinical trial safety data and support further pharmacoepidemiologic study. Disclosures Zettler: Cardinal Health: Employment. Feinberg:Cardinal Health: Employment. Phillips Jr.:Cardinal Health: Employment. Klink:Cardinal Health: Employment. Mehta:Cardinal Health: Employment. Gajra:Cardinal Health: Employment.

scholarly journals Efficacy and safety of CD22 chimeric antigen receptor (CAR) T cell therapy in patients with B cell malignancies: a protocol for a systematic review and meta-analysis

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Komal Adeel ◽  
Nathan J. Fergusson ◽  
Risa Shorr ◽  
Harold Atkins ◽  
Kevin A. Hay
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background Chimeric antigen receptor (CAR) T cell therapy has had great success in treating patients with relapsed or refractory B cell malignancies, with CD19-targeting therapies now approved in many countries. However, a subset of patients fails to respond or relapse after CD19 CAR T cell therapy, in part due to antigen loss, which has prompted the search for alternative antigen targets. CD22 is another antigen found on the surface of B cells. CARs targeting CD22 alone or in combination with other antigens have been investigated in several pre-clinical and clinical trials. Given the heterogeneity and small size of CAR T cell therapy clinical trials, systematic reviews are needed to evaluate their efficacy and safety. Here, we propose a systematic review of CAR T cell therapies targeting CD22, alone or in combination with other antigen targets, in B cell malignancies. Methods We will perform a systematic search of EMBASE, MEDLINE, Web of Science, Cochrane Register of Controlled Trials, clinicaltrials.gov, and the International Clinical Trials Registry Platform. Ongoing and completed clinical trials will be identified and cataloged. Interventional studies investigating CD22 CAR T cells, including various multi-antigen targeting approaches, in patients with relapsed or refractory B cell malignancies will be eligible for inclusion. Only full-text articles, conference abstracts, letters, and case reports will be considered. Our primary outcome will be a complete response, defined as absence of detectable cancer. Secondary outcomes will include adverse events, overall response, minimal residual disease, and relapse, among others. Quality assessment will be performed using a modified Institute of Health Economics tool designed for interventional single-arm studies. We will report a narrative synthesis of clinical studies, presented in tabular format. If appropriate, a meta-analysis will be performed using a random effects model to synthesize results. Discussion The results of the proposed review will help inform clinicians, patients, and other stakeholders of the risks and benefits of CD22 CAR T cell therapies. It will identify gaps or inconsistencies in outcome reporting and help to guide future clinical trials investigating CAR T cells. Systematic review registration PROSPERO registration number: CRD42020193027

scholarly journals Qualitative Analysis of the Treatment Experience and Well-Being of Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL) Enrolled in 2 Trials of Lisocabtagene Maraleucel (liso-cel) during the Initial Stages of Therapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Tanya Siddiqi ◽  
Ulrich Jaeger ◽  
Olga Moshkovich ◽  
Jennifer Devlen ◽  
Matthew Miera ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
Research Funding ◽  
Well Being ◽  
Publicly Traded ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Background: Chimeric antigen receptor (CAR) T cell therapy is a novel treatment modality for patients with R/R LBCL. Limited information exists regarding patients' views of CAR T cell therapy. Our research aimed to better understand patients' needs by capturing their expectations/concerns, current well-being, and treatment experiences during the beginning stages of CAR T cell therapy in the clinical trial setting. Methods: Patients with R/R LBCL from 2 ongoing trials of the investigational, CD19-directed CAR T cell therapy liso-cel (TRANSCEND WORLD [NCT03484702] or PLATFORM [NCT03310619]) were invited to participate in an optional interview component. Semistructured interviews were conducted to gain insight about patients' experience with CAR T cell therapy in the clinical trials. Interviews of ≤1 hour (in-person or over the phone) were conducted in parallel with screening procedures (interview 1), after leukapheresis (interview 2), and up to 3 days after liso-cel infusion (interview 3). Interviews were audio recorded and transcribed. MAXQDA (VERBI GmbH, Berlin, Germany) qualitative analysis software was used to manage and thematically organize interview transcript data to identify key concepts related to each research objective. Previously reported results of interview 1 showed a high perception of unmet needs, lack of alternative options, and expectations for positive outcomes. The analysis presented here primarily focused on interviews 2 and 3. Denominators shown in the Results vary by question as some patients skipped questions. Results: A total of 75 interviews were analyzed, including 35, 24, and 16 patients at interviews 1, 2, and 3, respectively, across sites in the US (n = 14), Europe (n = 26), and Japan (n = 2). Among 42 patients who completed ≥1 interview, the mean age was 62 years and 69% were male. Treatment Experience: Of 24 patients who completed interview 2, 22 (92%) reported positive experiences during leukapheresis and 16 (67%) reported the procedure was as expected. Patients thought the most difficult part of leukapheresis was the length of the procedure (n = 8/21 [38%]). Of 15 patients who provided feedback on lymphodepleting chemotherapy, a majority reported that it was as expected (n = 8 [53%]) or easier than expected (n = 3 [20%]); when asked about the most difficult part, many patients (n = 7/17 [41%]) discussed side effects (eg, nausea, fatigue, and lack of appetite). Of patients who described liso-cel infusion as different than expected, differences included easier (n = 12/13 [92%]) or quicker (n = 3/12 [25%]) than expected, and 5/12 (42%) reported few/no side effects within 3 days post-infusion. Over half of patients (n = 8/14 [57%]) reported that the infusion, as a whole, was not difficult. Changes over Time: At interviews 1, 2, and 3, respectively, 47% (n = 14/30), 47% (n = 9/19), and 69% (n = 9/13) of patients reported hoping for successful treatment. Similarly, patients generally had fewer concerns later in the process, with 21 (64%) and 11 (33%) of 33 patients reporting side-effect and treatment efficacy concerns, respectively, during interview 1 vs 5 (33%) and 3 (20%) of 15 patients, respectively, during interview 3. At time of enrollment, most patients (n = 21/34 [62%]) were able to function normally or with minimal impact from their lymphoma, although most reported some symptoms like fatigue, pain, or stomach problems. At interview 1, 14 (40%) of 35 patients were employed; most patients reported no changes in their work life at interviews 2 (n = 19/20 [95%]) and 3 (n = 11/12 [92%]). From enrollment to immediately post-infusion, the physical health of most patients remained stable (n = 4/16 [25%]) or deteriorated (n = 9/16 [56%]). However, most patients (n = 14/15 [93%]) reported feeling positive at interview 3. Conclusions: This study provided the unique opportunity to gather feedback directly from patients participating in clinical trials of liso-cel therapy, specifically during the initial treatment stages. The overall impression of the treatment was positive, with most patients reporting that study procedures were easier than expected. The results of this qualitative research provide useful insight into the motivations, expectations, and experiences of patients with R/R LBCL receiving liso-cel therapy, which can inform the design of health care support systems and future clinical trials to better meet patients' needs. Disclosures Siddiqi: AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Oncternal: Research Funding; TG Therapeutics: Research Funding; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau. Jaeger:F. Hoffmann-La Roche: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria. Moshkovich:Icon Plc: Current Employment. Devlen:Icon Plc: Current Employment, Current equity holder in publicly-traded company. Miera:Icon Plc: Current Employment. Williams:Icon Plc: Current Employment. Hasskarl:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Liu:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Braverman:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Salles:MorphoSys: Consultancy, Honoraria, Other; Kite: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Novartis: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Gilead: Consultancy, Honoraria, Other: Participation in educational events; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Epizyme: Consultancy; Takeda: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Karyopharm: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Genmab: Consultancy.

scholarly journals Identification of the risks in CAR T-cell therapy clinical trials in China: a Delphi study

2020 ◽  
Vol 12 ◽  
pp. 175883592096657
Author(s):  
Weijia Wu ◽  
Yan Huo ◽  
Xueying Ding ◽  
Yuhong Zhou ◽  
Shengying Gu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
Delphi Method ◽  
Delphi Study ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Aims: Within the past few years, there has been tremendous growth in clinical trials of chimeric antigen receptor (CAR) T-cell therapies. Unlike those of many small-molecule pharmaceuticals, CAR T-cell therapy clinical trials are fraught with risks due to the use of live cell products. The aim of this study is to reach a consensus with experts on the most relevant set of risks that practically occur in CAR T-cell therapy clinical trials. Methods: A Delphi method of consensus development was used to identify the risks in CAR T-cell therapy clinical trials, comprising three survey rounds. The expert panel consisted of principal investigators, clinical research physicians, members of institutional ethics committees, and Good Clinical Practice managers. Results: Of the 24 experts invited to participate in this Delphi study, 20 participants completed Round 1, Round 2, and Round 3. Finally, consensus (defined as >80% agreement) was achieved for 54 risks relating to CAR T-cell clinical trials. Effective interventions related to these risks are needed to ensure the proper protection of subject health and safety. Conclusion: The Delphi method was successful in gaining a consensus on risks relevant to CAR T-cell clinical trials in a geographically diverse expert association. It is hoped that this work can benefit future risk-based quality management in clinical trials and can potentially promote the better development of CAR T-cell therapy products.

Antigenic targets of CAR T Cell Therapy. A retrospective view on clinical trials

2018 ◽  
Vol 369 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Fatemeh Arabi ◽  
Monireh Torabi-Rahvar ◽  
Ali Shariati ◽  
Naser Ahmadbeigi ◽  
Mahmood Naderi
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Retrospective View ◽  
Car T Cell Therapy ◽  
Car T ◽  
Antigenic Targets

scholarly journals CAR T cell therapy in solid tumors: A review of current clinical trials

eJHaem ◽  
2021 ◽  
Author(s):  
Urvi Patel ◽  
John Abernathy ◽  
Bipin N Savani ◽  
Olalekan Oluwole ◽  
Salyka Sengsayadeth ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

scholarly journals Outcomes with "Off the Shelf" Allogeneic CD19 Chimeric Antigen Receptor T Cell Therapy for Hematological Malignancies: A Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4831-4831
Author(s):  
Muhammad Umair Mushtaq ◽  
Moazzam Shahzad ◽  
Ali Hussain ◽  
Amna Y Shah ◽  
Raheel S Siddiqui ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
Research Funding ◽  
Meta Analysis ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background: Chimeric antigen receptor T cell (CAR-T) therapy is an adoptive T cell immunotherapy that employs the genetically modified T cell to attack the cancer cell. It is widely studied across various hematological and solid organ malignancies. Several autologous CD19 CAR-T cell therapy constructs are now approved for various B cell lymphomas, including aggressive B cell lymphomas, indolent follicular lymphoma and mantle cell lymphoma, and acute lymphoblastic leukemia (ALL). Autologous CD19 CAR-T cell therapy has unprecedented success in relapsed and refractory disease. Long time to manufacture (2-5 weeks) and manufacture failure are challenges associated with risk of interim death and deterioration of CAR-T candidates with rapidly progressive disease. T cell fitness of the autologous product in heavily pretreated patients is also potentially compromised. To overcome these shortcomings, universal "off the shelf" allogeneic CAR-T cell therapy constructs are being developed and studied. Donor sources include healthy donors and cord or induced pluripotent stem cells (iPSCs). These CAR-T constructs have additional gene modifications to mitigate the risk of rejection and graft versus host disease (GVHD). We performed a systematic review and meta-analysis to assess the safety and efficacy of allogeneic CD19 CAR-T cell therapy. Methods: Four databases (Web of Science/MEDLINE/PubMed, Embase, and Cochrane Registry of Controlled Trials) were searched for this systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines using MeSH terms and keywords for "Receptors, Chimeric antigen" OR "Artificial-T-cell receptor" OR "immunotherapy, adoptive" OR "CD-19". Our search produced 3506 articles and after removing duplicates, 2243 records were screened. After excluding reviews and irrelevant articles, we included 8 prospective trials of allogeneic CD-19 CAR-T cell therapy enrolling two or more than two patients from Jan 2013 to Nov 2020. We also searched ASH 2020 abstracts to include any additional trials. The methodological quality of the included studies was evaluated using NIH quality assessment tool. Inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). Results: A total of 68 patients from 8 studies were evaluated. Median age was 22.5 (4.8-64) years. (Table 1) The median follow-up time was 10 (2-18) months with median number of prior therapies of 3.2 (2-11) as reported by 5 studies. Underlying diagnosis was acute lymphocytic lymphoma (n=49, 72%), chronic lymphocytic leukemia (n=6, 9%), and non-Hodgkin lymphoma (n=13, 19%). The pooled overall response rate (ORR) was 77% (95% CI 0.63-0.89, I 2 =22%, n=68) with a complete response (CR) of 75% (95% CI 0.57-0.90, I 2 =48%, n=65). The pooled incidence of cytokine release syndrome grade I/II and grade III/IV was 53% (95% CI 0.16-0.89, I 2 =89%, n=65) and 10% (95% CI 0.01-0.25, I 2 =50%, n=65) respectively. Neurotoxicity grade I/II was 12% (95%CI 0.01-0.30, I 2 =47%, p=0.09, n=47) and GVHD grade I/II was 8% (95%CI 0.01-0.19, I 2 =0%, p=0.57 n=53). None of the clinical trials reported the duration of response. Conclusion: "Off the shelf" universal CAR-T therapy is early in development. Our available data suggest that allogeneic CD19 CAR-T constructs offer high ORR and CR rates with acceptable safety profiles. GVHD was mainly low grade (grade I-II). Given these findings, allogeneic CAR-T cell therapy is an attractive option to improve timely access compared to available autologous therapy. Extensive preclinical research to develop novel constructs and several phase I/II clinical trials are ongoing to shape the future of "off the shelf" CAR-T cell therapy. Figure 1 Figure 1. Disclosures Hoffmann: Pharmcyclics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Therapeutics: Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Astelllas Pharma: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Allovir: Consultancy, Honoraria, Research Funding.

scholarly journals Clinical development of CAR T cell therapy in China: 2020 update

2020 ◽  
Author(s):  
Jianshu Wei ◽  
Yelei Guo ◽  
Yao Wang ◽  
Zhiqiang Wu ◽  
Jian Bo ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
T Cell ◽  
Cell Therapy ◽  
Hematological Malignancies ◽  
Clinical Development ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Chimeric antigen receptor (CAR) T-cell therapy has achieved significant success in the treatment of hematological malignancies. In recent years, fast-growing CAR T clinical trials have actively explored their potential application scenarios. According to the data from the clinicaltrials.gov website, China became the country with the most registered CAR T trials in September 2017. As of June 30, 2020, the number of registered CAR T trials in China has reached 357. In addition, as many as 150 other CAR T trials have been registered on ChiCTR. Although CAR T therapy is flourishing in China, there are still some problems that cannot be ignored. In this review, we aim to systematically summarize the clinical practice of CAR T-cell therapy in China. This review will provide an informative reference for colleagues in the field, and a better understanding of the history and current situation will help us more reasonably conduct research and promote cooperation.

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