Background and Significance:Patients with R/R TCL have few therapeutic options. Most immunotherapies are ineffective in TCL and targeted therapies are challenging to develop, due to the risk of normal T-cell ablation. MB-105, a CD5-directed CAR T-cell product, resisted fratricide through rapid internalization and degradation of CD5 in cis and only transiently induced ablation of healthy T cells. In the initial study conducted by Baylor College of Medicine, CD5.CAR T cell treatment was tolerable with no unexpected toxicity, resulting in objective responses in 4 out of 9 patients (44%) (Hill 2024). During phase 1, manufacturing refinements improved CAR T cell potency and persistence. Efficacy and safety of the optimized product, MB-105, were demonstrated at the highest dose level. Durable responses at all 3 dose levels led us to select a dose between levels 1 and 2 for phase 2. We designed this study to confirm efficacy and safety of MB-105 in a multicenter setting across the United States in patients with R/R peripheral TCL (PTCL) or cutaneous TCL (CTCL).Study Design and Methods:This phase 2 study (MB-105-201; NCT06534060) comprises 3 stages: a safety run-in to confirm tolerability of the phase 1 recommended dose (50 million cells) in 6 patients; Simon stage 1 requiring at least 6 responses in 15 patients, and stage 2, which will enroll 31 more patients for a total of 46. If >18 of the 46 patients respond, the null hypothesis (30% response rate) is rejected. An independent data monitoring committee (IDMC) will oversee the study, reviewing emerging data and making recommendations for each stage of study conduct. The IDMC will meet regularly and administer the prespecified study stopping rules as well as the adaptive elements of the study design. Adaptive elements allow the IDMC to adjust key design features without a formal protocol amendment, such as dose adjustments, modifying monitoring periods, or altering lymphodepletion. The primary objectives are to confirm safety of the recommended dose of MB-105 in the safety run-in (using CTCAE V5 and ASTCT grading), then to evaluate efficacy in Simon stages 1 and 2 per independent central review, using Lugano 2014 and the global criteria (Cheson 2014, Olsen 2022). Secondary objectives are further efficacy assessment including durability, long-term impact in terms of overall survival, and demonstrating manufacturing success.Population:Eligible patients must be adults with measurable R/R TCL that has failed ≥1 or ≥2 prior systemic lines of therapy for PTCL or high volume CTCL, respectively. Baseline biopsy will measure CD5 expression via central lab to support diagnosis, although study entry depends on local pathology. Patients must have adequate organ function and Karnofsky performance status ≥70%. Prior cell therapy or HSCT must be ≥60 days prior to leukapheresis. Key exclusions are Sezary syndrome (due to potential for high levels of circulating tumor cells to impact manufacturing), active CNS involvement, active infections, GVHD >G2 and comorbidities likely to interfere with study participation or endpoints.Trial conduct:Patients who give informed consent will enter screening 1-2 months before treatment, undergo leukapheresis around 1 month prior and may receive bridging therapy while study product is manufactured over 3 weeks. Once MB-105 arrives at the site, patients undergo 3 days' standard fludarabine/cyclophosphamide conditioning followed by 2 days' rest, rituximab prophylaxis (based on EBV serostatus) and CAR-T infusion on Day 0 as an outpatient with standard supportive measures. Safety visits will monitor for CRS/ICANS daily for a week, twice weekly for the first month, then monthly until 6 months post treatment, with additional visits at 9, 12, 18 months and an end of study visit at 2 years. Imaging is at months 1, 2, 3, 6, 9, 12, 18 and 24. Post-MB-105 monitoring includes CAR-T persistence, immune cell populations, viral PCRs, anti-CAR antibodies, cytokines and replication-competent retrovirus.Patients will be asked to participate in long term safety and efficacy follow-up under a separate protocol (MB-105-202). The IND for both MB-105 studies is open, with the first patient visit pending.
