Confirmatory Efficacy and Safety Evaluation of MB-105, a CD5.CAR T Therapy: Multicenter Phase 2 Study in Patients with Relapsed/Refractory T Cell Lymphoma (R/R TCL)

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.

Iyer:Secura Bio: Membership on an entity's Board of Directors or advisory committees; Yingli: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acrotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ono: Research Funding; Trillium: Research Funding; Crispr: Membership on an entity's Board of Directors or advisory committees, Research Funding; Legend: Research Funding; IMPaRT.AI: Other: Stock, Founder; Salarius: Consultancy; Merck: Research Funding; Innate: Research Funding; Seagen/Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; JCO-CCI: Other: Editor. Hill:Kite, a Gilead Company: Speakers Bureau; Gilead Sciences: Speakers Bureau; March Biosciences: Consultancy. Horwitz:Auxilius Pharma, Abcuro Inc., Corvus, Daiichi Sankyo, DrenBio, Farallon Capital Management, L.L.C., Kyowa Hakko Kirin, March Bio, Neovii Pharmaceuticals AG, ONO Pharmaceuticals, Pfizer, SecuraBio, SymBio, Treeline Bio and Takeda Pharmaceuticals.: Consultancy; Auxilius Pharma, Abcuro Inc., Corvus, CTI BioPharma Corp, Daiichi Sankyo, DrenBio, Kyowa Hakko Kirin, March Bio, ONO Pharmaceuticals, Pfizer, SecuraBio, SymBio and Takeda Pharmaceuticals.: Honoraria; ADC Therapeutics, Affimed, Celgene, Crispr Therapeutics, Daiichi Sankyo, Kyowa Hakko Kirin, Takeda, Seattle Genetics, Trillium Therapeutics, and SecuraBio.: Research Funding. Jain:Acrotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; SecuraBio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowakirin: Research Funding; SIRPant Immunotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Crispr therapeutics: Membership on an entity's Board of Directors or advisory committees; Myeloid Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mersana Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abcuro Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Poh:Dren Bio: Research Funding; Astex: Research Funding; Incyte: Research Funding; Acrotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ipsen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vose:Novartis: Honoraria; Pfizer: Research Funding; GenMab: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Brenner:AlloVir: Current equity holder in private company, Other: Stock; Maker Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership, Patents & Royalties; Tessa Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Other: Stock; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Stock; Walking Fish Kuur: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Stock; Turnstone Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Stock; Posedia: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Stock; Adaptimmune Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adintus Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Triumvira Immunologics: Membership on an entity's Board of Directors or advisory committees; Bellicum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Memgen LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Brooklyn Immunotherapeutics: Membership on an entity's Board of Directors or advisory committees; Coya: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents & Royalties; Tscan: Membership on an entity's Board of Directors or advisory committees, Other: Stock; KURR: Consultancy; Abintus Bio: Consultancy. Mamonkin:Galapagos NV: Consultancy, Honoraria, Other: Travel; Amgen: Consultancy, Honoraria, Other: Travel; Beam Therapeutics: Patents & Royalties; Allogene Therapeutics: Consultancy, Patents & Royalties: Licensing; Fate Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Patents & Royalties: Licensing, Research Funding; NKILT Therapeutics: Membership on an entity's Board of Directors or advisory committees; March Bio: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership, Patents & Royalties: Licensing, Research Funding; Laverock Therapeutics: Consultancy. Hein:March Biosciences: Current Employment, Current equity holder in private company. Giordano:March Bio: Current Employment. Bexon:March Bio: Consultancy; Sapience: Current holder of stock options in a privately-held company; Vyriad: Consultancy; Bexon Clinical Consulting LLC: Current Employment; AI Proteins: Current holder of stock options in a privately-held company.