CD7 chimeric antigen receptor T cells for relapsed/refractory T-cell lymphomas: Single-arm, open-label, phase I study

Abstract Background: The prognosis of refractory/relapsed T-cell lymphoma is extremely poor, especially for the patients who failed to allogeneic hematopoietic stem cell transplantation(alloHSCT). Aims: In this single-center Phase I study (ChiCTR2200058969), we administered CD7 CAR T cells to evaluate extended safety, PK, tolerability and efficacy in patients with r/r T-cell lymphoma. Methods: CD7 CAR T-cells is a product in which collected mononuclear cells have been transduced with the lentiviral vector carrying a CD7 CAR construct binding domain fused to a domain for anchoring in the endoplasmic reticulum, allowing CD7 to be retained intracellularly, thereby preventing CAR T cell fraticide. CD7 CAR T-cells was evaluated in a phase Ia study with a 3+3 dose-escalation design followed by cohort expansion.The phase Ia study is being conducted with different dose levels (DL): 1×104 (DL1), 5×104 (DL2), 1×105 (DL3) (±30%) CAR+ cells/kg.Data from phase Ia trial will be used to determine the dosing for the phase Ib trial. Infusion of donor-derived CD7 CAR-T cells in patients who have relapsed after alloHSCT, whereas infusion of autologous CAR-T cells in other patients. Results: From August 2020 to August 2024, forty-Eight patients were screened, of which 40 were enrolled. The median age was 32(18-72) years old. The diagnosis included T-LBL(n=35),HSTL(n=1),MEITL(n=1) ,SS(n=1),Extranodal NK/T-cell lymphoma(n=1)and CTCL( n=1).The disease status was progressive disease in all patients who failed to multi-line therapies, including autoHSCT (n=5), and alloHSCT(n=17).24 patients(60%) had a diffused disease and 8 patients(20%) had central nervous system involvement.In order to reduce the tumor burden, 34(85%) patients were treated with bridging therapy before CAR-T cell infusion. 9 patients in dose escalation for three patients were included in each group from DL1 to DL3 in sequence. No dose-limiting toxicity (DLT) occurred.31 paitients in the cohort expansion with a dose of 1×105 (DL3) (±30%) CAR+ cells/kg as a phase Ib study. The incidence of cytokine release syndrome (CRS) was 80% (7.5% grade 3-4).One grade 4 immune effector cell-associated neurotoxicity syndrome events (2.5%). The most common treatment-related adverse event (AE) was neutropenia (77.5%; 75% grade 3-4), thrombocytopenia (65%; 62.5% grade 3-4) , infections (65%; 45% grade 3-4) .Two grade 3-4 aGVHD event occurred (5%). AE was independent of whether CART cells are sufficiently donor-derived(P=0.402). Among 40 evaluable patients, the overall response rate (ORR) at 1-month post-infusion was 92.5% (37/40), with a complete remission (CR) rate of 77.5% (31/40). In the autologous CD7 CAR-T group (n=23), ORR and CR rates were 86.9% (20/23) and 73.9% (17/23), while the donor-derived group (n=17) achieved 100% ORR (CR 14/17, 82.4%). With a median follow-up of 16.34 months (95% CI: 1.78–48.07), the 3-year PFS and OS rates for the overall population were 28.9% and 36.3%, respectively. Of the 23 patients infused with autologous CD7 CAR-T, the 3-year PFS was 31.3% and OS was 47%, respectively. 15/23(65.2%) bridged alloHSCT and 9/15(60%) survived disease-free.2/15(6.7%) relapsed after transplantation and died, 1/23(4.3%) underwent bridging autoHSCT and died of relapsed, and 4/15(26.7%) died of infection and hemorrhage. The other seven patients without bridging transplantation, 1/7(14.3%) survived disease-free and 4/7(57.1%) died of disease recurrence and 2/7(28.6%) died of infection. Of the 17 patients infused with donor-derived CD7 CAR-T, the 3-year PFS was 20.6% and OS was 28.2%, respectively. 4/17 (23.5%) bridging second alloHSCT and 1/4 (25%) survived disease-free, 2/4 (50%) died of relapse and 1/4 (25%) died of PTLD.Of the 13 patients who did not receive a bridging transplant, 2/13(15.4%) survived without disease and 1/13(7.7%) was not followed up. 3/13(23.1%) died of disease relapse and 7/13(53.8%) died of infection. The peak time of CD7 CART cells in vivo was on median 11(range,7-21) days after CAR-T cell infusion.The median peak of CAR-T cells in peripheral blood by flow cytometry was 23.65(range,1.56-219)×106/L, which was no correlation with the T-cell origin of CAR-T cells (P=0.15) .Although CD7-positive normal T cells were depleted, CD7-negative T cells expanded in all patients. Conclusion: Our study showed promising efficacy of CD7 CAR-T cell therapy in r/r T-cell lymphoma.CD7 CAR-T therapy to achieve CR after bridging allogeneic transplantation section improved survival.