CD7-Targeted CAR-T Cell Therapy Shows Promising Efficacy and Safety in Treating Refractory/Relapsed Peripheral T-Cell Lymphoma: Phase I Clinical Trial

Introduction Peripheral T-cell lymphomas (PTCL) encompass a broad class of heterogeneous clinicopathologic entities unified in their derivation from a mature, post-thymic T-cell. For patients with relapsed or refractory (R/R) PTCL, outcomes are generally poor, even with an allogeneic hematopoietic stem cell transplantation (allo-HSCT), creating a great need of new therapeutics. CD7 is highly expressed in T-cell acute lymphoblastic leukemia (T-ALL) and a subset of PTCL. We have previously demonstrated that “naturally selected” CD7 CAR-T (NS7CAR-T) therapy shows significant efficacy with a favorable safety profile in 60 patients with T-ALL and T-cell lymphoblastic lymphoma (T-LBL). Here, we conducted a phase I clinical trial (https://clinicaltrials.gov/ NCT04928105) to investigate the safety and efficacy of NS7CAR-T therapy in treating R/R PTCL. Methods Peripheral blood mononuclear cells were obtained from the patients. T-cells were then purified using CD3+ magnetic beads. The second-generation CD7CAR with a 4-1BB costimulatory domain was manufactured following the protocol. Patients who were diagnosed with r/r PTCL and had positive CD7 expression were eligible. Before the CAR-T cell infusion, bridging therapies were permitted for patients with rapid disease progression. All patients received intravenous fludarabine (30mg/m2/d) and cyclophosphamide (300mg/m2/d) lymphodepletion chemotherapy for three consecutive days (day -5 to day -3). The median time from leukapheresis to CAR-T cell infusion was 15 days. Results Between April 2021 and November 2023, 5 patients diagnosed with CD7-positive r/r PTCL were enrolled and received NS7CAR-T cell infusions. The subtypes included PTCL not otherwise specified (PTCL-NOS, n=2), monomorphic epitheliotropic intestinal T cell lymphoma (MEITL, n=1), hepatosplenic T-cell lymphoma (HSTCL, n=1), and NK/T cell lymphoma (n=1). The median age of the enrolled patients was 49 years (39-60 years). Before enrollment, patients had undergone a median of 6 (range: 2-12) prior lines of therapy. One patient had a history of autologous transplant. Regarding the extramedullary disease (EMD) status, 4/5 presented with diffuse EMD, and the other one had localized EMD. Additionally, 3 patients showed minimal residual disease (MRD)-positive involvement in bone marrow (BM) by flow cytometry (FCM) at enrollment, ranging from 0.09 to 1.19%. Four patients received a medium dose (1×106/kg) and 1 received a high dose (2×106/kg). Following infusion, 4/5 patients exhibited good proliferations, with peak levels ranging from 1.61×105 copies/μg to 5.83×105 copies/μg genomic DNA CAR-T cells based on q-PCR and from 57.11% to 93.97% CAR-T cells as detected by FCM, and 1/5 patient had a low proliferation with peak levels of 224 copies/μg genomic DNA CAR-T cells by qPCR and 8.99% by FCM. The median peak time occurred around day 14 (day 14 - day 27) per q-PCR, and around day 14 (day 11 - day 19) by FCM. The median transduction efficiency of the products was 93.5% (range: 89.3%-97.4%). At a median of 34 days post NS7CAR-T cell infusion, three (60%) patients achieved complete remission (CR) per position-emission tomography (PET)/ and/or contrast computed tomography (CT) and BM evaluation, one showed partial remission (PR), and one had no remission (NR). The median observation time was 234 days (range:42-474 days). For the three CR patients, two received consolidation allo-HSCT, including one who remained progression-free survival on day 216, and the other who subsequently relapsed on day 248 and died on day 474 from chronic graft-versus-host disease (GVHD). The remaining CR patient without allo-HSCT progressed to acute leukemia around day 234 and subsequently passed away. The PR patient received salvage allo-HSCT and remained disease-free on day 411. The patient with NK/T cell lymphoma, had NR and subsequently withdrew. Post-infusion, all patients experienced mild cytokine release syndrome (CRS), with four displaying grade I and one having grade II CRS. None of the patients had neurotoxicity. Conclusions Our study highlights that CD7-positive heavy pre-treated R/R PTCL patients could achieve a promising CR and safety profile after CD7-targeted CAR-T therapy, who otherwise have very limited therapy options. More data on additional patients and longer observation times are needed to further evaluate the efficacy and safety of CD7 CAR-T products in treating PTCL.