A Phase 2 multi-center trial of CD5 CAR T-cell therapy in patients with T-cell lymphoma

Abstract Relapsed and refractory T-cell lymphoma (r/r TCL) represents a significant clinical challenge, with limited therapeutic options and a 3-year survival rate of less than 20%. Although chimeric antigen receptor (CAR) T-cell therapies have demonstrated success in treating B-cell malignancies, their application to T-cell cancers is limited by the shared expression of targetable antigens between healthy and malignant T-cells, leading to CAR T-cell fratricide and increased risk of severe immunodeficiency. CD5 is a key surface marker expressed in 85% of TCL. The innovative CD5 CAR T-cell therapy (MB-105) developed at Baylor College of Medicine (BCM) and licensed to March Biosciences, has addressed the unique challenges of treating T-cell malignancies. Unlike conventional CAR-T strategies, MB-105 is engineered to resist fratricide, allowing selective targeting and eradication of malignant T-cells while preserving normal T-cells. The MB-105 manufacturing process has been optimized throughout the Phase 1 study to boost CAR T-cell fitness and improve clinical activity. This approach has demonstrated safety and promising efficacy in a Phase 1 trial conducted at BCM. Under the original manufacturing process, MB-105 was well tolerated at all dose levels and demonstrated robust anti-tumor activity against T cell malignancies with 4/17 patients (24%) achieving a complete response (CR), primarily in TCL, and 2/3 CR patients alive 5 years later. Manufacturing improvements increased fitness and activity of MB-105, resulting in an overall response rate (ORR) of 66% (4/6 patients) and a CR rate of 50% (3/6 patients), supporting the safety and efficacy of this improved product. Based on the Phase 1 results, March Biosciences obtained IND clearance to advance MB-105 to a Phase 2 multicenter trial to validate the safety and efficacy of MB-105 at the recommended Phase 2 dose (RP2D) in TCL patients. This study will use a Simon two-stage design (Stage 1, Phase 2a-15 patients; Stage 2, 2b-31 patients), with primary endpoints focusing on safety and ORR. Secondary endpoints include disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS). In addition, this study will explore the pharmacokinetics and pharmacodynamics of MB-105, focusing on the expansion, persistence, cellular and genetic composition of CAR T-cells pre- and post-infusion as well as measuring serum cytokine levels and CD5 expression on tumor cells to correlate with clinical outcomes. The insights from this study will guide the continued development and optimization of MB-105 as a novel therapeutic option for patients with aggressive TCL, addressing an urgent unmet need in this orphan disease. Upon successful completion of the Phase 2a/Stage 1 portion of the trial under this SBIR, March Biosciences will be positioned to advance MB-105 into later-stage clinical trials, ultimately providing a scalable, effective treatment for patients with r/r TCL, aiming to support a Regenerative Medicine Advance Therapy (RMAT) designation application and a potential Accelerated Approval pathway.