6508 Background: Patients with relapsed or refractory T-lymphoblastic leukemia/Peripheral T-Cell Lymphoma (R/R T-ALL/PTCL) experience dismal outcomes. Previously, we demonstrated naturally selected anti-CD7 CAR-T could overcome fratricide without gene editing or protein blockade, yielding encouraging clinical activity (Blood, 2022; 2025). CD5 is a critical pan–T-cell marker highly expressed in T-ALL/PTCL and represents a rational target beyond CD7. Methods: We developed SL105 injection, an autologous CD5-directed CAR-T cell product incorporating a tandem camelid-derived dual-epitope nanobody through a natural selection platform. This first-in-human phase I study evaluates the safety, preliminary efficacy, and recommended phase II dose (RP2D) of SL105 injection in patients with R/R T-ALL/PTCL (NCT06874946). Results: As of January 27, 2026, 37 patients provided informed consent; 18 patients received a single infusion of SL105 and completed the 28-day dose-limiting toxicity (DLT) assessment and constituted the enrolled population for analysis. Three dose levels (0.5, 1.0, and 2.0 ×10⁶ CAR-T cells/kg) were evaluated, with a minimum of two patients with T-ALL/LBL or PTCL enrolled at each dose level. Median age was 32 years (range, 16–57); 33.3% had prior hematopoietic stem cell transplantation. Diagnoses included T-ALL/LBL (n=11) and PTCL (n=7). Median follow-up was 6 months (range, 2–11). No DLTs were observed, and the recommended RP2D was established at 2.0 ×10⁶ CAR-T cells/kg. Median time to peak CAR-T expansion was 14 days by qPCR, with a median peak level of 6.3×10⁴ copies/µg (range, 6–5.5×10⁵). Cytokine release syndrome (CRS) occurred in 66.7% of patients; grade 2 CRS was observed in 21.7%, with no grade ≥3 CRS. One patient (5.5%) experienced grade 1 immune effector cell–associated neurotoxicity syndrome (ICANS). Grade 1–4 early immune-cell–associated hematotoxicity (ICAHT) events occurred in 7 (38.9%), 2 (11.1%), 4 (22.2%), and 5 (27.8%) patients, respectively. EBV-related events occurred in 50% of patients, and CMV viremia in 33.3%. The best overall response rate (ORR) was 77.8% (14/18), including a CR/CRi/CMR rate of 61.1% (11/18) and PR with extranodal disease in 16.7% (3/18). All responding patients with bone marrow involvement achieved MRD negativity by flow cytometry. All four non-responders (two T-ALL/LBL and two PTCL) demonstrated low CAR-T expansion, with peak levels <500 copies/µg genomic DNA. At the RP2D, ORR was 100%, with CR/CMR achieved in 85.7% (6/7). Five responding patients underwent consolidative allogeneic HSCT. Conclusions: SL105, an autologous dual-epitope nanobody CD5 CAR-T therapy, demonstrated a favorable safety profile and encouraging efficacy in R/R T-ALL/PTCL. The RP2D has been established, supporting further evaluation in an ongoing phase II study. Clinical trial information: NCT06874946 .
Lv et al. (Wed,) studied this question.