Title first‑in‑human Phase 1 dose‑finding study (VIPER 101) of dual‑population autologous CD5‑deleted anti-CD5 CAR‑T (Senza5 CART5) cells in Relapsed/Refractory T‑cell lymphomas

Abstract

Abstract Background. T-cell lymphomas carry a very poor prognosis and lack effective treatments. Despite the transformative success of chimeric antigen receptor (CAR) T-cell therapies in B-cell malignancies, translation to T-cell malignancies has been impeded by target antigen overlap that causes CAR T-cell fratricide and on-target T-cell aplasia. Senza5 CART5 is an autologous, gene-edited, dual-population, rapidly manufactured (5-day) CAR T-cell (CART) product comprised of both a CD5-deleted (CRISPR-Cas9) CAR-expressing (lentivirus transduced) T cell population (CD5⁻ CAR⁺) and a CD5-deleted, non-transduced T-cell population (CD5⁻ CAR⁻). This dual population is designed to enhance both potency and safety as CD5 deletion removes a negative regulator of T-cell effector function (Patel R., Science Immunology, 2024), while the companion CD5⁻ CAR⁻ cells are intended to mitigate on-target T-cell aplasia during immune reconstitution. Methods. In this open-label, dose-finding Phase 1 trial, adults with histologically confirmed relapsed/refractory (r/r) CD5+ T-cell lymphoma after ≥ 1 prior therapy receive lymphodepletion (fludarabine 25 mg/m² + cyclophosphamide 250 mg/m² x 3 days or bendamustine 90 mg/m² x 2 days) followed by a single IV infusion of Senza5 CART5 at doses ranging from 3x106 to 1.25x108 CAR+ cells. Primary endpoints are safety and recommended Phase 2 dose (RP2D); secondary/exploratory endpoints include manufacturing feasibility, in vivo expansion, tissue trafficking, T-cell aplasia mitigation, overall response rate (ORR), and complete response (CR) rate per Lugano criteria. The Viper 101 trial is ongoing (NCT06420089). Results. As of August 5, 2025, 6 patients were manufactured and 5 patients (pts) were treated (1 at a flat dose of 1x107 CAR+ cells and 4 at a flat dose of 3x106 CAR+ cells) with 4 pts evaluable for dose limiting toxicities (safety) and 3 pts evaluable for efficacy. Median age was 65 years (range 55–75); histologies included PTCL-NOS (n=2), TFHL (n=1), AITL (n=1), and MF (n=1). Pts had a median of 3 prior lines (range 2–5), and 2 had prior autologous stem cell transplant. Manufacturing success was 100% (6/6). Treatment-related adverse events (TRAEs) included cytokine-release syndrome (CRS) (Grade 1–2) in 100% of safety-evaluable pts (4/4) that resolved with standard care; no neurotoxicities or hemophagocytic lymphohistiocytosis syndrome were reported. All pts experienced Grade 3–4 transient cytopenias and Grade 1-2 TRAEs of the skin, mouth, and gastrointestinal tract. Infections were observed in 3/4 pts . One pt treated at the 1x107 CAR+ dose experienced a Grade 5 severe AE (infection) on Day 54 while presenting with multineage cytopenias that were considered unrelated to the investigational product. No pts experienced clinical EBV or CMV infections. All safety-evaluable pts (n=4) experienced robust in vivo CART cell expansion (median peak in peripheral blood (PB): 33,664 copies/µg gDNA). On-treatment biopsies confirmed CART trafficking to disease sites, including lymph nodes, skin, and marrow. Of note, no detectable CD5+ cells (normal or malignant) were detected in these biopsies. CART cells persisted and were still detected in the PB at last follow-up (median 1,426 copies/µg gDNA). Due to the risk of on-target T-cell toxicity, immune reconstitution was also monitored. By Day 28, all evaluable pts demonstrated reconstitution of a CD5-negative, CAR-negative (CD5- CAR-) T-cell compartment (both CD4+ and CD8+ subsets). Among efficacy-evaluable pts (n=3), overall response rate (ORR) was 100% (3/3) with all three pts achieving a complete response (CR) at a median follow-up of 4.0 months (range 1.9–5.5). 2/3 pts had FDG-avid lesions on the Day 30 scan, which, upon biopsy, were negative for the original lymphoma, and became PET negative by Day 90. No patients have relapsed at last follow up. Updated clinical outcomes and correlative data for all pts treated will be presented at the meeting. Conclusions. Early results suggest that Senza5 CART5 has manageable toxicities, potent antitumor activity, robust and durable CART expansion, and T-cell reconstitution at low doses of CART cells (3x106 CAR+ cells). While follow-up is limited, these data support further development of Senza5 CART5 for r/r T-cell lymphomas. Moreover, these results underscore the potential for CD5 deletion as a platform to broadly enhance the efficacy of engineered T-cell therapies for additional indications.