Interim analysis of safety and efficacy in a Phase 2 study of MB-105, a CD5.CAR T therapy for patients with relapsed/refractory T cell lymphoma

Abstract

Abstract Introduction: There are few effective treatments for patients (pts) with relapsed/refractory T-cell lymphoma (R/R TCL). One challenge in targeting T-lineage antigens is the risk of ablating normal T cells. MB-105 is a CD5-directed CAR T-cell product that resists self-targeting through rapid degradation of CD5 protein but retains robust killing of malignant T cells. A phase 1 study at Baylor College of Medicine showed good tolerability and objective response (ORR) in 44% of pts with r/r TCL (Hill 2024). MB-105 incorporates manufacturing refinements from the phase 1 study, which improved product potency. We selected the phase 2 dose and initiated a multicenter study to confirm efficacy and safety of MB-105 in pts with R/R peripheral (PTCL) or cutaneous TCL (CTCL). Methods: This 3-part phase 2 study (MB-105-201) has completed a 6-patient safety run-in to confirm tolerability of the fixed dose of 50x106 CD5.CAR T cells. Eligibility criteria include R/R PTCL failing at least 1 prior systemic therapy or CTCL with at least 2 prior lines, CD5 expression in lymphoma, adequate organ function, Karnofsky (KPS) ≥70% and no transplant, cell therapies or lymphocyte infusions within 100 days. Primary analysis of Simon stage 1 requires at least 6 responses in 15 pts in the primary cohort by independent central review (Cheson 2014, Olsen 2022), and subsequently >18/46 responses, targeting a 50% ORR (null = 30%). An independent committee (IDMC) oversees study conduct. Secondary analyses include assessing investigator ORR, response durability, long-term impact, overall survival, and manufacturing success. Prior to MB-105 dosing, pts receive fludarabine/cyclophosphamide (30/300 mg/m2/day) over 3 days followed by 2 days' rest and single-dose rituximab prophylaxis (if EBV seropositive). Following infusion, pts are monitored as outpatients for safety and efficacy up to 2 years. Monitoring also includes CAR-T persistence, immune reconstitution, viral titers, anti-CAR antibodies, cytokines and replication-competent retrovirus. Results: After leukapheresis, MB-105 was manufactured with a 29-day median vein-to-vein time. Two manufacturing failures led to exclusion of prior bendamustine and increase of baseline CD3 requirement to 400 cells/µL. As of July 31, 2025, 7 pts received MB-105: 4:3 male:female, KPS 70-100%, 5:1:1 white:black:other with measurable R/R PTCL (n=4) or CTCL (n=3) and 2-8 prior systemic regimens. One pt with CTCL received a partial MB-105 dose in error and was not included in the safety run-in or primary efficacy assessments. An additional CTCL pt with 15% CD5 tumor expression was treated on an exploratory CD5low arm but not included in efficacy evaluation; all others had disease with ≥50% CD5 expression and H-scores 190-300 by central review. Of the 5 pts in the primary cohort (≥50% CD5 expression) who received full dose, 4 have been assessed for response and one is pending evaluation. Of those assessed, all 4 have achieved a response by investigator assessment (100% ORR; best response 3 CR and 1 PR). The pt with low CD5 expression had progressive CD5neg disease (PD) at D28. After infusion, MB-105 expanded in peripheral blood, peaking in most pts at day 14 (mean 75%, range 24-87% of total CD3+ T cells by flow cytometry), commonly persisting past day 28 in blood and detectable in lymph node and skin biopsies. CAR-T expansion resulted in a reduction of peripheral T-cell counts and a concomitant selection of CD5-negative T cells, consistent with prior observations. MB-105 related adverse events occurred in 5/6 safety run-in pts and were predominantly Gr1, including 50% of pts with Gr1 CRS and no neurotoxicity. All patients experienced anemia, 3 had neutropenia (2 febrile), and 3 thrombocytopenia, all attributed to lymphodepletion. No cytopenias ≥Gr3 lasted >42 days. Two pts had viral reactivation/infections ≤Gr2 (BK, CMV, EBV). There were 2 deaths: one with CD5neg PD at D98 and one pt with EBVpos B-cell lymphoma at D128. Conclusions: In the safety run-in of this Phase 2 study, MB-105 showed an acceptable safety profile and promising early efficacy of MB-105 in patients with R/R TCL. Correlative data show robust expansion of MB-105 with early evidence suggesting complete clearance of CD5 positive disease in most patients treated to date. The IDMC approved continued accrual to 15 patients in Stage 1. Updated clinical and correlative results of Stage 1 will be presented.