Dataset Information

Donor-derived Anti-CD19 CAR T cells GC007g for relapsed or refractory B-cell acute lymphoblastic leukemia after allogeneic HSCT: a phase 1 trial.

ABSTRACT:

Background

Although 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.

Methods

This 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.

Findings

Between 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 C_max 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.

Interpretation

GC007g expanded and induced durable remission in patients with B-ALL relapsed after allo-HSCT, with manageable safety profiles.

Funding

Gracell Biotechnologies Inc.

SUBMITTER: Luo Y

PROVIDER: S-EPMC10776428 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

Donor-derived Anti-CD19 CAR T cells GC007g for relapsed or refractory B-cell acute lymphoblastic leukemia after allogeneic HSCT: a phase 1 trial.

Luo Yi Y Gao Lei L Liu Jia J Yang Luxin L Wang Lu L Lai Xiaoyu X Gao Shichun S Liu Lizhen L Zhao Lu L Ye Yishan Y Wang Manning M Shen Lianjun L Cao W William WW Wang Dongrui D Li Wenling W Zhang Xi X Huang He H

EClinicalMedicine 20231221

<h4>Background</h4>Although 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.<h4>Methods</h4>This phase 1 clinical trial aims to evaluate safety and efficacy of donor-derived anti-CD19 CAR T cells (GC007g) in B-ALL patients who relaps ...[more]

PMID: 38204488

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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:Objective: This study aimed to evaluate the maintenance therapy following an anti-CD19-CAR T-cell therapy for a B-cell acute lymphoblastic leukemia (ALL) patient who relapsed after allogeneic hematopoietic cell transplantation (allo-HSCT) and investigate the effect of donor stem cells and donor T lymphocyte infusion on the amplification of CD19 CAR-T cells. Methods: One refractory B-ALL patient relapsed after murine CD19 CAR-T cell therapy followed by a sibling allo-HSCT. He underwent a humanized CD19 CAR-T cell therapy followed by donor stem cell and donor T lymphocytes infusions as maintenance therapy in our hospital. The level of cytokines, the proportion of CD19 CAR-T cell, the level of CAR19 DNA expression in the peripheral blood, and the proportion of leukemia cells and donor chimerism in the bone marrow were detected. Correspondingly, T lymphocytes from the C57 spleen were separated to modify the CD19 CAR lentivirus and refused into C57 mice, and after 14 days, the B lymphocytes from C57 mice were separated and refused into the same C57 mice. The CD19 CAR T cells, B cells, and CD19 CAR gene counts in the peripheral blood were evaluated at different time points. Results: ①The patient achieved a complete response (CR) 14 days after a humanized CD19 CAR-T therapy with grade 1 cytokine release syndrome (CRS) and restored a donor chimerism to 99.76%. ② Following the remission from humanized CD19 CAR-T therapy, the patient received a maintenance therapy of donor stem cell infusion. Mild graft-versus-host disease (GVHD) manifested 24 days after infusion with an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression in the peripheral blood. It fell with the remission of GVHD. The patient maintained CR and 99.69% donor chimerism during this period. ③ Throughout the subsequent donor T lymphocytes maintenance therapy, mild GVHD surfaced12 days after infusion without an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression in the peripheral blood. The patient maintained CR and 99.87% donor chimerism during this period. ④ In vivo experiments on C57 mice confirmed that the proportion of CD19 CAR-T cells and the level of CAR19 DNA expression were upregulated in mice following CAR-T cell infusion, accompanied by depletion of CD19(+) B lymphocyte. After infusion of CD19(+) B lymphocyte cells, an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression in the peripheral blood were observed again. Conclusions: The infusion of donor stem cells and donor T lymphocytes could be used as a maintenance treatment after CD19 CAR-T cell therapy for B-ALL patients who relapsed after allo-HSCT. Infusion of donor stem cells induced an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression with the occurrence of GVHD. It might lead to further elimination of minimal residual disease.

Project description:BackgroundChimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival.MethodsA single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy.ResultsThe median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021).ConclusionsOur study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.

Dataset Information

Donor-derived Anti-CD19 CAR T cells GC007g for relapsed or refractory B-cell acute lymphoblastic leukemia after allogeneic HSCT: a phase 1 trial.

Background

Methods

Findings

Interpretation

Funding

Publications

Donor-derived Anti-CD19 CAR T cells GC007g for relapsed or refractory B-cell acute lymphoblastic leukemia after allogeneic HSCT: a phase 1 trial.

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