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Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE).

ABSTRACT: INTRODUCTION:Autologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL. METHODS AND ANALYSIS:Eligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2?days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3?dose escalation scheme is planned starting at 5×104?CAR T-cells/kg with a maximum dose of 1×106?CAR T-cells/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy. ETHICS AND DISSEMINATION:Ethical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19/STH/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings. TRIAL REGISTRATION NUMBER:NCT04049513.

SUBMITTER: George P

PROVIDER: S-EPMC7044946 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE).

George Philip P Dasyam Nathaniel N Giunti Giulia G Mester Brigitta B Bauer Evelyn E Andrews Bethany B Perera Travis T Ostapowicz Tess T Frampton Chris C Li Peng P Ritchie David D Bollard Catherine M CM Hermans Ian F IF Weinkove Robert R

BMJ open 20200209 2

<h4>Introduction</h4>Autologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase ...[more]

PMID: 32041862

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Project description:BackgroundPatients with relapsed or refractory (R/R) lymphomas have benefited from chimeric antigen receptor (CAR)-T-cell therapy. However, this treatment is linked to a high frequency of adverse events (AEs), such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematologic toxicity. There has been increasing interest in hematological toxicity in recent years, as it can result in additional complications, such as infection or hemorrhage, which remain intractable.MethodsWe conducted a retrospective, single-institution study to evaluate the patterns and outcomes of cytopenia following CAR-T-cell infusion and potential associated factors.ResultsOverall, 133 patients with R/R lymphoma who received CAR-T-cell therapy from June, 2017 to April, 2022 were included in this analysis. Severe neutropenia, anemia and thrombocytopenia occurred frequently (71, 30 and 41%, respectively) after CAR-T-cell infusion. A total of 98% of severe neutropenia and all severe thrombocytopenia cases occurred in the early phase. Early severe cytopenia was associated with CRS incidence and severity, as well as peak inflammatory factor (IL-6, C-reactive protein (CRP), and ferritin) levels. In multivariate analysis, prior hematopoietic stem cell transplantation (HSCT), baseline hemoglobin (HB), and lymphodepleting chemotherapy were independent adverse factors associated with early severe cytopenia. In addition, 18% and 35% of patients had late neutrophil- and platelet (PLT)-related toxicity, respectively. In multivariate analysis, lower baseline PLT count was an independent factor associated with late thrombocytopenia. More severe cytopenia was associated with higher infection rates and poorer survival.ConclusionsThis research indicates that improved selection of patients and management of CRS may help to decrease the severity of cytopenias and associated AEs and improve survival following CAR-T-cell therapy.Clinical trial registrationhttps://www.clinicaltrials.gov/ct2/show/NCT03196830, identifier NCT03196830.

Project description:Axicabtagene ciloleucel is the first U.S. Food and Drug Administration-approved autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for the treatment of patients with relapsed or refractory large B-cell lymphoma after ?2 prior systemic therapies. Although axicabtagene ciloleucel is administered only at authorized treatment centers, community oncologists play a critical role in the CAR T-cell treatment journey, recognizing potentially eligible patients for referral and then, after treatment, closely collaborating with treatment centers to monitor and manage patients long term. ZUMA-1, the pivotal, multicenter, phase I/II study of 108 patients treated with axicabtagene ciloleucel, resulted in an objective response rate of 83%, including 58% complete responses. With a 27.1-month median follow-up, 39% of patients had ongoing responses. CAR T-cell therapy is associated with the potentially life-threatening adverse events (AEs) of cytokine release syndrome and neurologic events, which generally occur early after treatment. In ZUMA-1, cytokine release syndrome and neurologic events were generally reversible and grade ?3 cytokine release syndrome and neurologic events occurred in 11% and 32% of patients, respectively. Frequent prolonged AEs included hypogammaglobulinemia, B-cell aplasia, and cytopenias requiring supportive care until recovery of hematopoietic function. Rate of treatment-related mortality was low, at <2%. With appropriate management of common AEs, axicabtagene ciloleucel offers the potential for long-term durable responses in patients who otherwise lack curative treatment options. IMPLICATIONS FOR PRACTICE: Community oncologists should be familiar with key aspects of chimeric antigen receptor (CAR) T-cell indications and eligibility to help recognize and refer potential patients for this paradigm-changing treatment option at the appropriate time during the disease course. To ensure optimal long-term outcomes for patients who have been treated with CAR T-cell therapy, oncologists must also be familiar with common prolonged AEs and their monitoring and management.

Project description:BackgroundRecent evidence suggests that resistance to CD19 chimeric antigen receptor (CAR)-modified T cell therapy may be due to the presence of CD19 isoforms that lose binding to the single-chain variable fragment (scFv) in current use. As such, further investigation of CARs recognize different epitopes of CD19 antigen may be necessary.MethodsWe generated a new CD19 CAR T (HI19α-4-1BB-ζ CAR T, or CNCT19) that includes an scFv that interacts with an epitope of the human CD19 antigen that can be distinguished from that recognized by the current FMC63 clone. A pilot study was undertaken to assess the safety and feasibility of CNCT19-based therapy in both pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL).ResultsData from our study suggested that 90% of the 20 patients treated with infusions of CNCT19 cells reached complete remission or complete remission with incomplete count recovery (CR/CRi) within 28 days. The CR/CRi rate was 82% when we took into account the fully enrolled 22 patients in an intention-to-treat analysis. Of note, extramedullary leukemia disease of two relapsed patients disappeared completely after CNCT19 cell infusion. After a median follow-up of 10.09 months (range, 0.49-24.02 months), the median overall survival and relapse-free survival for the 20 patients treated with CNCT19 cells was 12.91 months (95% confidence interval [CI], 7.74-18.08 months) and 6.93 months (95% CI, 3.13-10.73 months), respectively. Differences with respect to immune profiles associated with a long-term response following CAR T cell therapy were also addressed. Our results revealed that a relatively low percentage of CD8+ naïve T cells was an independent factor associated with a shorter period of relapse-free survival (p = 0.012, 95% CI, 0.017-0.601).ConclusionsThe results presented in this study indicate that CNCT19 cells have potent anti-leukemic activities in patients with R/R B-ALL. Furthermore, our findings suggest that the percentage of CD8+ naïve T cells may be a useful biomarker to predict the long-term prognosis for patients undergoing CAR T cell therapy.Trial registrationClinicalTrials.gov : NCT02975687; registered 29 November, 2016. https://clinicaltrials.gov/ct2/keydates/NCT02975687.

Project description:Background:No effective treatment exist for patients with relapsed and refractory B-cell lymphoma, until the advent of anti-CD19 chimeric antigen receptor (CAR) T-cells. Therefore, this study aimed to explore the factors affecting the efficacy of anti-CD19 CAR T-cell and the adverse reactions of the therapy. Methods:We recruited 11 patients with relapsed and refractory B-cell lymphoma. The number of anti-CD19 CAR T-cells, proliferation, and adverse reactions were recorded in detail, to explore the relationship between the factors affecting the efficacy of anti-CD19 CAR T-cell and the long-term survival of patients. Results:The 11 patients in our study had a total overall response rate of 100%, after receiving anti-CD19 CAR T-cells. The median follow-up was 253 days (range, 130-1,017 days). The median overall survival (OS) and median progression-free survival (PFS) were not reached. After 3 months of treatment, the complete remission (CR) rate was 63.6% (7/11). As of December 7, 2019, 5 patients had maintained CR for a period exceeding 1 year, including 2 patients who had maintained CR for more than 1,000 days. The patients who received 3 or 4 lines of chemotherapy were more likely to have sustained remission than the patients who received <2 or >4 lines of chemotherapy. Each of the 4 patients in the study who had diffuse large B cell lymphoma (DLBCL) progression all had high myc protein expression (positive incidence: 30-80%). The incidence of Grade 2 cytokine release syndrome (CRS) was 36.4% (4/11), and Grade 3 CAR T-cell-related encephalopathy syndrome (CRES) was experienced by 1 patient. The occurrence of adverse reactions was not significantly related to the infusion dose, peak amplification time, or maximum copy amount. The immunoglobulin levels of the four patients who died showed a significant downward trend. Interleukin-1? (IL-1?), interferon-? (IFN-?), interleukin-10 (IL-10), and interleukin-17A (IL-17A) appeared to be associated with the occurrence of CRS and CRES. Conclusions:Anti-CD19 CAR T-cell treatment is a new therapy for patients with relapsed and refractory B-cell lymphoma. Among the small sample size in this study, it demonstrated high efficiency and safety.

Project description:Background: The therapeutic efficacy of chimeric antigen receptor (CAR) T-cells targeting CD19 has been illustrated in the treatment of diffuse large B-cell lymphoma (DLBCL). However, there is a 21-35% relapse rate after anti-CD19 CAR T-cell induced remission. In addition, CAR T-cell therapy has severe adverse reactions, such as cytokine release syndrome (CRS) and CART-related encephalopathy syndrome (CRES). Because of the potential mortality associated with severe CRES, patients with primary central nervous system lymphoma (PCNSL) are usually excluded from clinical trials involving CAR T-cell therapy. Here, we report a case of refractory and relapsed primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL). Case Presentation: The patient is a 67-year-old male who was diagnosed with PCNSL in 2011. He achieved complete remission (CR) after receiving 6 cycles of temozolomide and high-dose methotrexate. In December 2016, he experienced his first relapse and was treated with surgery and multicourse chemotherapy. He achieved CR again after the treatment. However, he experienced a second relapse in August 2017. MRI revealed a residual mass of 26 mm*35 mm*30 mm on the right side of the post-operative cavity and stale hemorrhage in the left basal ganglia. After confirming the expression of CD19 and CD70 in his tumor samples, the patient was given lymphodepletion chemotherapy followed by infusion of 4th generation CD19-CAR T-cells (4SCART19) and 4th generation CD70-CAR T-cells (4SCART70). One month later, the patient had symptomatic improvement, and brain MRI showed CR. Both CART19 and CART70 cells were detected in the 10th month after CAR T-cell infusion. Notably, neither CRS nor CRES occurred during treatment and follow-up. To date, the patient has maintained disease-free survival with more than 17 months of follow-up. Conclusions: The results of this study indicate that combination of CD19- and CD70-specific CAR T-cells may effectively target PCNSL and maintain disease-free survival without inducing CRS or CRES. Therefore, central nervous system lymphoma is not an absolute contraindication for dual-target CAR T-cell therapy.

Dataset Information

Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE).

Publications

Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE).

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