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Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study.

ABSTRACT: To improve clinical outcomes and shorten the vein-to-vein time of chimeric antigen receptor T (CAR-T) cells, we developed the FasT CAR-T (F-CAR-T) next-day manufacturing platform. We report the preclinical and first-in-human clinical studies evaluating the safety, feasibility, and preliminary efficacy of CD19 F-CAR-T in B-cell acute lymphoblastic leukemia (B-ALL). CD19 F-CAR-T cells demonstrated excellent proliferation with a younger cellular phenotype, less exhaustion, and more effective tumor elimination compared to conventional CAR-T cells in the preclinical study. In our phase I study (NCT03825718), F-CAR-T cells were successfully manufactured and infused in all of the 25 enrolled pediatric and adult patients with B-ALL. CD19 F-CAR-T safety profile was manageable with 24% grade 3 cytokine release syndrome (CRS) and 28% grade 3/4 neurotoxicity occurring predominantly in pediatric patients. On day 14, 23/25 patients achieved minimal residual disease (MRD)-negative complete remission (CR), and 20 subsequently underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) within 3 months post F-CAR-T therapy. Fifteen of 20 patients were disease-free with a median remission duration of 734 days. One patient relapsed and 4/20 died from transplant-related mortality. Of the three patients who did not undergo allo-HSCT, two remained in CR until 10 months post-F-CAR-T. Our data indicate that anti-CD19 FasT CAR-T shows promising early efficacy for B-ALL. Further evaluations in larger clinical studies are needed.

SUBMITTER: Yang J

PROVIDER: S-EPMC9262977 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients.MethodsWe conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics.ResultsA total of 53 adults received 19-28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden.ConclusionsIn the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .).

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:Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is effective in patients with advanced B-cell acute lymphoblastic leukemia (B-ALL). However, efficacy data is sparse in subgroups of patients with high-risk features such as BCR-ABL+, TP53 mutation, extramedullary disease (including central nervous system leukemia) or posttransplant relapse. It is also uncertain whether there is an added benefit of transplantation after anti-CD19 CAR T-cell therapy. We conducted a phase 1/2 study of 115 enrolled patients with CD19+ B-ALL. A total of 110 patients were successfully infused with anti-CD19 CAR T cells. In all, 93% of patients achieved a morphologic complete remission, and 87% became negative for minimal residual disease. Efficacy was seen across all subgroups. One-year leukemia-free survival (LFS) was 58%, and 1-year overall survival (OS) was 64% for the 110 patients. Seventy-five nonrandomly selected patients (73.5%) subsequently received an allogeneic hematopoietic stem cell transplant (allo-HSCT). LFS (76.9% vs 11.6%; P < .0001; 95% confidence interval [CI], 11.6-108.4) and OS (79.1% vs 32.0%; P < .0001; 95% CI, 0.02-0.22) were significantly better among patients who subsequently received allo-HSCT compared with those receiving CAR T-cell therapy alone. This was confirmed in multivariable analyses (hazard ratio, 16.546; 95% CI, 5.499-49.786). Another variate that correlated with worse outcomes was TP53 mutation (hazard ratio, 0.235; 95% CI, 0.089-0.619). There were no differences in complete remission rate, OS, or LFS between groups of patients age 2 to 14 years or age older than 14 years. Most patients had only mild cytokine release syndrome and neurotoxicity. Our data indicate that anti-CD19 CAR T-cell therapy is safe and effective in all B-ALL subgroups that have high-risk features. The benefit of a subsequent allo-HSCT requires confirmation because of nonrandom allocation. This trial was registered at www.clinicaltrials.gov as #NCT03173417.

Project description:BackgroundAlthough chimeric antigen receptor-modified T cells (CAR T) cell therapy has been widely reported in improving the outcomes of B-cell acute lymphoblastic leukemia (B-ALL), less research about the feasibility and safety of donor-derived CAR T after allogeneic hematopoietic stem cell transplantation (allo-HSCT) was reported.MethodsThis phase 1 clinical trial aims to evaluate safety and efficacy of donor-derived anti-CD19 CAR T cells (GC007g) in B-ALL patients who relapsed after allo-HSCT. This trial is registered with ClinicalTrials.gov, NCT04516551.FindingsBetween 15 March 2021 and 19 May 2022, fifteen patients were screened, three patients were excluded due to withdraw of consent, donor's reason, and death, respectively. Patients received donor-derived CAR T cells infusions at 6 × 105/kg (n = 3) or 2 × 106/kg (n = 6) dose level. The median time from HSCT to relapse was 185 days (range, 81-2063). The median age of patients was 31 years (range 21-48). Seven patients (77.8%) had BCR-ABL fusion gene. CAR T cells expanded in vivo and the median time to reach Cmax was 9 days (range, 7-11). One patient had hyperbilirubinemia after GC007g infusion which was defined as a dose-limiting toxicity. All patients experienced CRS and hematological adverse events. Three patients had acute graft-versus-host-disease (grade I, n = 1; grade II, n = 1; grade IV, n = 1) and all resolved after treatment. They received CAR T cells from matched sister, haploidentical matched father and sisiter, respectively. At 28 days after infusion, all patients achieved complete remission with/without incomplete hematologic recovery (CRi/CR) with undetectable MRD. At a median follow-up of 475 days (range 322-732), seven patients remained in CR/CRi while two had CD19-negative relapse. The overall response rates (ORR) were 100% (9/9), 88.9% (8/9), and 75% (6/8) at 3 month, 6 month, and 12 month, respectively. The 1-year progression-free and overall survival were 77.8% and 85.7%, respectively.InterpretationGC007g expanded and induced durable remission in patients with B-ALL relapsed after allo-HSCT, with manageable safety profiles.FundingGracell Biotechnologies Inc.

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Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study.

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