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2102 Efficacy and Safety of a Third Generation CD20 CAR-T (MB-106) for Treatment of Relapsed/Refractory Indolent B-Cell Non-Hodgkin Lymphoma: Phase-1 Results from a Multicenter Trial

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster I
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Mazyar Shadman, MD, MPH1, Paolo F. Caimi, MD2, Susan M. O'Brien3, Patrick M. Reagan, MD4, Bruce Dezube, MD5, Punya Navaratnarajah, PhD5*, Tripti Gaur, PhD5*, Suzanne Petrossian, MS5*, Anthony Germani, BS1*, Brian G Till1 and Jeremy S. Abramson, MD6

1Fred Hutchinson Cancer Center, Seattle, WA
2Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH
3Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA
4Wilmot Cancer Institute, University of Rochester Medical Center, Fairport, NY
5Mustang Bio, Worcester, MA
6Massachusetts General Hospital Cancer Center, Boston, MA

Background: Indolent B-cell non-Hodgkin lymphomas (NHL) remain incurable despite multiple therapeutic options, including chemoimmunotherapy, targeted therapies, bispecific antibodies, and CD19-targeted chimeric antigen receptor T (CAR-T) cells. MB-106, a fully human 3rd-generation CD20-targeted CAR-T product with both 4-1BB and CD28 costimulatory domains, had high overall response rate (100%) and complete response (CR) rate (91%) in follicular lymphoma (FL) patients at doses ≥ 3.3×106 cells/kg in a single institution trial (Shadman et al., 17-ICML, 2023). We seek to replicate the favorable efficacy and safety profile of MB-106 in a multicenter trial with centralized manufacturing.

Methods: MB-106 is being evaluated in a Phase 1/2, open label, multicenter study utilizing a 3+3 dose-escalation design in R/R B-cell NHL patients with confirmed CD20 expression. Prior treatment with CD19-targeted CAR-T therapy is permitted. Following lymphodepletion (cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day for 3 days), MB-106 is administered to patients with indolent B-cell NHL at one of two dose levels (DL): DL1, 3.3×106; and DL2, 1.0×107 cells/kg. MB-106 is infused in the outpatient setting if allowed by the institution, except for the first patient in each dose level cohort (overnight observation). Dose-limiting toxicities (DLT) are monitored through day 28. The treatment response is assessed on day 28 and on subsequent visits, and best overall response is reported here. CAR-T persistence is assessed by both flow cytometry and qPCR in peripheral blood mononuclear cells.

Results: Three patients with indolent NHL (2 FL, 1 Waldenström macroglobulinemia [WM]) received MB-106 at DL1. In addition, one patient with hairy cell leukemia variant (HCL-v) received non-conforming material (drug product that failed to meet release criteria) at DL1, following FDA authorization. These four patients were heavily pre-treated with a median of 5.5 prior lines of treatment. High-risk features included progression of disease within 24 months of first-line treatment (POD24, n=1), prior autologous stem cell transplant (n=1) and prior CD19-targeted CAR-T therapy (n=1). No DLTs were observed at DL1. Three patients experienced Grade 1 cytokine release syndrome. There have been no occurrences of immune effector cell-associated neurotoxicity syndrome (ICANS). The 2 FL patients achieved CR by both PET-CT and bone marrow biopsy, one of whom had been previously treated with CD19-targeted CAR-T. The WM patient, who had nine prior treatments, including autologous stem cell transplant, and high disease burden, achieved very good partial response, with complete metabolic response by PET-CT, morphologic clearance of lymphoma in bone marrow, and resolution of the IgM paraprotein. The patient with HCL-v, who had been transfusion dependent, continues to have stable disease with decreased disease in the bone marrow, and achieved complete transfusion independence which is ongoing at 6 months. All patients displayed MB-106 expansion with peak levels between 7-14 days post-infusion. Persistence of CAR T-cells is ongoing at 6 months.

Conclusion: Treatment with MB-106, a third generation CD20 targeting CAR-T, resulted in responses, including CRs, and CAR-T persistence in patients with R/R indolent NHL and was associated with favorable safety profile with no occurrence of Grade 3 or Grade 4 cytokine release syndrome and no ICANS of any grade. CRs have been observed in patients previously treated with CD19-targeted CAR-T in both this multicenter trial and the original single institution trial. Dosing is ongoing in the final dosing level (1.0×107 cells/kg) to establish the recommended Phase 2 dose for a planned pivotal trial in WM. It is anticipated that the complete data set from the Phase 1 indolent NHL arm will be presented.

Disclosures: Shadman: Eli Lilly: Consultancy; BeiGene: Consultancy, Research Funding; Fate Therapeutics: Consultancy; Janssen: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; MorphoSys/Incyte: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Mustang Bio: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; ADC therapeutics: Consultancy; Vincerx: Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; MEI Pharma: Consultancy; Regeneron: Consultancy; TG Therapeutics: Research Funding. Caimi: SOBI: Honoraria; Novartis: Consultancy; Lilly Oncology: Consultancy; BMS: Consultancy; Genentech: Consultancy; ADC Therapeutics: Consultancy; Kite Pharma: Honoraria. O'Brien: Pharmacyclics: Consultancy, Research Funding; Regeneron: Research Funding; Pfizer: Consultancy, Research Funding; Johnson & Johnson: Consultancy; Janssen: Consultancy; Lilly: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Astrazeneca: Consultancy; Abbvie: Consultancy. Reagan: Kite, a Gilead Company: Consultancy, Other: speaker; Genentech: Research Funding; Caribou biosciences: Consultancy; Seagen: Research Funding. Dezube: Mustang Bio: Current Employment, Current equity holder in publicly-traded company. Navaratnarajah: Mustang Bio: Current Employment. Gaur: Mustang Bio: Current Employment. Petrossian: Mustang Bio: Current Employment. Till: Proteios Technology: Consultancy, Current holder of stock options in a privately-held company; Mustang Bio: Consultancy, Patents & Royalties, Research Funding; BMS/Juno Therapeutics: Research Funding. Abramson: Kymera: Consultancy; Lilly: Consultancy; Merck: Research Funding; MorphoSys: Consultancy; Mustang Bio: Consultancy, Research Funding; Ono Pharma: Consultancy; Regeneron: Consultancy, Honoraria; Seagen Inc.: Research Funding; Takeda: Consultancy; Cellectar Biosciences: Consultancy; Kite Pharma: Consultancy; Janssen: Consultancy, Honoraria; Interius: Consultancy; Incyte: Consultancy; Genmab: Consultancy; Genentech: Consultancy; Epizyme: Consultancy; Century Therapeutics: Consultancy; Celgene: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Alimera Sciences: Consultancy; Karyopharm Therapeutics: Consultancy; C4 Therapeutics: Consultancy; Bluebird Bio: Consultancy; AI Therapeutics: Research Funding; Caribou Biosciences: Consultancy; BMS: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy.

*signifies non-member of ASH