High Effectiveness and Safety of Anti-CD7 CAR T-Cell Therapy in Treating Relapsed or Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Abstract

Abstract Background Compared with the substantial efficacy of chimeric antigen receptor T-cell (CAR-T) therapy that has achieved in B-ALL, whether CAR-T therapy is effective and safe for patients with T-ALL is still being explored in early stage clinical trials. Here, we present outcomes from our phase 1 clinical trial of CD7-targeting CAR-T (CD7CAR) cells therapy for R/R T-ALL (NCT04572308). Methods Peripheral blood (PB) mononuclear cells were obtained by leukapheresis. T cells were separated and transduced with lentivirus. The second-generation CD7CAR is composed of an anti-CD7 single-chain antibody, a IgG4 hinge region, a CD28TM transmembrane domain, an intracellular co-stimulatory domain of 4-1BB and CD3ζ, and the truncated EGFR protein linked by T2A. All patients received intravenous fludarabine (30 mg/m 2/d) and cyclophosphamide (300 mg/m 2/d) for 3 days prior to CD7CAR infusion. Results Seventeen R/R T-ALL patients were enrolled between December 2020 and June 2021. Characteristics of patients are shown in Table 1. Data from 14 patients with a median age of 17 years (range: 3-42 years) were available for evaluation. The rest 3 patients were withdrawn from study within 14 days due to rapid disease progression. High-risk subtype patients enrolled including 1 with Ph-positive T-ALL and 3 with early T-cell precursor (ETP)-ALL. Seven of the 14 patients also had high-risk genotypes, namely SIL-TAL1, EZH2, TP53, RUNX1, BCR-ABL, JAK1 and JAK3. At enrollment, the median percentage of bone marrow (BM) blasts was 11.53% (range: 0.18%-65.03%), and 5 of 14 patients had extramedullary involvements, including optic nerve involvement (N=2), central nervous system leukemia (N=3), diffuse extramedullary involvements (N=2), and bulky lymph nodes in the neck (N=1). Patients were heavily pretreated with a median of 5 prior lines of therapies (range: 3-8 lines) and three relapsed from prior allogeneic hematopoietic stem cell transplantation (allo-HSCT). CD7CAR-T cells were 100% successfully manufactured with a transfection efficiency of 93.8% (range: 59.6%-99.9%). Twelve of 14 participants received bridging chemotherapy. A single dose of CD7CAR-T cells was infused to patients, with 2 receiving a low-dose (0.5x10 5 cells/kg), 11 receiving a medium dose (1-1.5x10 6 cells/kg) and 1 receiving a high-dose (2x10 6 cells/kg). By the data cutoff date (July 12, 2021), the median follow-up time was 105 days (range: 32-206 days, Fig.1A). By day 28 post infusion, 92.9% (13/14) of patients achieved complete remission (CR, N=4) or CR with incomplete hematological recovery (CRi, N=9) in their BM, with all 13 patients achieving minimal residual disease (MRD) negative CR/CRi. Additionally, 4/5 patients with extramedullary involvement also achieved extramedullary remission at a median of day 32 (range: 28-90 days) post infusion. Consolidation allo-HSCT was permitted at the treatment physician's discretion and the patient's preference. A total of 11/14 patients were bridged to consolidation allo-HSCT at a median of 57 days post CD7CAR infusion, of which 9 patients have remained MRD-negative CR/CRi. One patient who had allo-HSCT prior to CD7CAR infusion died following a second haplo-HSCT due to acute graft-versus-host disease. Of the other 3 patients who were not bridged to allo-HSCT, 1 patient relapsed on day 28 due to rapid disease progression after initial CRi on day 14. Thirteen of 14 patients experienced mild CRS (Grade ≤2). One patient had Grade 3 CRS. The median time to onset of CRS was 1 day (range: 0-11 days), with a median duration of 14 days (range: 3-25 days). Neurotoxicity (Grade 1) occurred in only 1 patient. After infusion, the median peak of CAR-T copy number was 2.38 ×10 5copies/µg DNA (range: 0.2-6.67 ×10 5 copies/µg DNA), which occurred on day 20 (range: 10-42 days, Fig.1B). Importantly, CD7CAR persisted well in PB at a median of 52.5 days (range:20-120 days) at last evaluation regardless of transplantation status. Maximum proportion of CD7CAR-T cells proliferation reached 84.95% by flow cytometry (Fig.1C). Conclusions Our results demonstrate that CD7CAR therapy is safe and highly effective in treating patients with heavily pretreated R/R T-ALL, including those with extramedullary involvements, a history of prior allo-HSCT or with high-risk subtypes. More patients and a longer observation time are needed to further evaluate the potential beneficial advantages and side effects of CD7CAR therapy for T-ALL patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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