CARMA-1: The phase I Study of SENL101, a naturally selected nanobody based CD7 CAR-T therapy, in relapsed or refractory T-ALL/lbl

Abstract Introduction Relapsed or refractory T-lymphoblastic leukemia/lymphoma (RR T-ALL/LBL) has a poor prognosis and limited therapeutic options. Fratricide has been a major barrier to CD7-targeted CAR-T therapy in this setting. Our prior investigator-initiated trial demonstrated that a “naturally selected” murine anti-CD7 CAR (NS7CAR) could overcome fratricide without gene editing or protein blockade [Blood. 2022]. SENL101 is a alpaca-derived nanobody-based CD7 CAR-T product, developed from NS7CAR with an optimized manufacturing process. We report results from a Phase I IND trial of SENL101 in R/R T-ALL/LBL(CARMA-1). Methods This open-label, phase I study (NCT06136364) adhered to the 3+3 dose-escalation design (modified Fibonacci method), evaluated the tolerability and safety of SENL101 in adult subjects with RR T-LBL/ALL. The primary objective was to assess the incidence and severity of dose-limiting toxicities (DLTs) and adverse events (AEs) within 28 days post-infusion. Secondary objectives included 3-month overall response rate (ORR), best overall response (BOR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), pharmacodynamics, and pharmacokinetics. Key eligibility required adult subjects (aged 18-75 years) with CD7+ RR T-ALL/LBL confirmed per the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues (2022). Enrolled subjects received lymphodepleting chemotherapy (fludarabine 30mg/m2/day and cyclophosphamide 300mg/m2/day for 3 days) followed by a single infusion of SENL 101. Dose cohorts were: 0.5×106/kg (DL1), 1.0×106/kg (DL2), and 2.0×106/kg (DL3) CAR+ T cells. Results A total of 21 subjects were enrolled and 20 subjects were underwent apheresis. Three subjects withdrew before the conditioning regimen, and one withdrew before cell infusion. As of the cutoff date (June 30,2025), 16 subjects received the infusion of SENL101. Among these 16 subjects (DL1:3; DL2:3; DL3:10), median age was 37.5 years (range: 20-60), including 12 males (75.0%) and 4 females (25.0%). All subjects were CD7-positive. Disease subtypes included T-ALL in 6 subjects (37.5%) and T-LBL in 10 subjects (62.5%). The median line of prior therapy was 2 (range: 1-4) and 7 subjects (43.8%) were refractory to last line of therapy. Four subjects (25.0%) received allogeneic hematopoietic stem cell transplantation previously. The median proportion of primitive and immature lymphocytes of the baseline bone marrow (for T-ALL subjects only) was 29.5% (range: 7.0 - 94.0). Disease manifestations included only bone marrow lesions (n=2, 12.5%), only extramedullary lesions (n=5, 31.3%), and both bone marrow and extramedullary lesions (n=9, 56.3%). No DLTs occurred. The most common treatment-emergent adverse events of grade 3 or more were preconditioning-related hematologic toxicities. Among 16 subjects evaluable for safety, cytokine release syndrome (CRS) occurred in 14 subjects (87.5%); 13 (81.2%) were grade 1 or 2, with grade 3 in 1 patent (6.3%). The median time to CRS onset was 10 days (range 1-18), with median duration of 6 days (range 3-18). All CRS events were rapidly relieved after conventional CRS intervention, including tocilizumab and steroids. No immune effector cell-associated neurotoxicity syndrome (ICANS) events were observed. As of the data cut-off date (June 30,2025), the median follow-up was 4.67 months (range: 1.97, 7.72). An 87.5% best ORR were observed with 10 (62.5%) complete remission/ complete remission with Incomplete hematologic recovery (CR/CRi) and 4 (25.0%) partial remission (PR). The best ORRs of DL1, DL2, and DL3 cohorts were 100% (3/3), 100% (3/3), and 80% (8/10), respectively. Among 15 subjects assessable for Month 3 (M3)-ORR, 11 subjects (73.3%) achieved the M3-ORR, including 9 subjects (60.0%) achieving CR/CRi, and 2 subjects (13.3%) achieving PR. The M3-ORRs of DL1, DL2, and DL3 cohorts were 50% (1/2), 66.7% (2/3), and 80% (8/10), respectively. The median DOR was 3.75 months (0.92, NE), the median PFS was 4.63 months (2.86, NE), and the median OS was (4.63, NE) at the time of cut-off date. Conclusion Based on safety and efficacy data from the dose-escalation phase, the recommended Phase 2 dose (RP2D) of SENL101 was determined to be 2.0×10⁶CAR⁺ T cells/kg. SENL101 demonstrated a manageable safety profile and encouraging anti-leukemic activity in subjects with R/R T-ALL/LBL. A Phase II study is currently being initiated.