Abstract CT096: Phase I first-in-human MUC1* targeted autologous CAR T cells for the treatment of metastatic breast cancers

Abstract Purpose: First-in-human Phase I study for advanced MUC1* positive breast cancer with autologous T cells engineered to express either a chimeric antigen receptor, huMNC2-CAR44 or huMNC2-CAR22, which specifically bind to a cleaved form of MUC1 (MUC1*); evaluate the safety and preliminary anti-tumor activity. Methods: MUC1* (muk 1 star) is the growth factor receptor form of MUC1, created by cleavage and release of the N-terminal portion of MUC1. The targeting antibody, huMNC2, only recognizes the conformational epitope created when MUC1 is cleaved by specific tumor-associated enzymes that are correlated with poor prognosis. huMNC2 does not bind to full-length MUC1, which is expressed on all normal epithelial cells. huMNC2-scFv was incorporated into huMNC2-CAR44, comprising a CD8 hinge and transmembrane region, 4-1BB costimulatory domain and wild-type CD3z. huMNC2-scFv was also incorporated into huMNC2-CAR22 wherein the hinge, transmembrane and co-stimulatory portions were derived from CD28 and CD3z bears the 1XX mutations to increase in vivo persistence. Inclusion criteria require that the patient’s tumor is at least 30% MUC1* positive and that patient has progressed through 2 or 3 prior therapies, while in the metastatic setting. Patients receive standard Cy/Flu lymphodepletion approximately 3-days before CAR T treatment, administered at 1 of 4 dose levels ranging from 3.3X10^5 up to 1.0X10^7 CAR+ T cells. Results: To date, 8 patients have been treated with huMNC2-CAR44. No patients experienced neuro toxicities. No off-target toxicities were observed. 3 patients experienced CRS Grade 1-3. In 6 of the 8 patients, side effects were non-existent or minimal. However, one patient experienced a Grade 5 SAE that was deemed to be possibly related to the treatment. Best responses include Partial Responses and Stable Disease at a low CAR-T dose. Greatest efficacy was observed for patients whose biopsy showed H Scores >120. Patients are currently being enrolled for treatment with huMNC2-CAR22, where the 1XX mutations are expected to increase in vivo persistence, durability of response and reduced incidence of CRS. Conclusions: These data support a conclusion that the MUC1* antibody, huMNC2, is safe and could have high therapeutic value as a CAR T treatment for solid tumors with moderate to high antigen density. As the huMNC2-CAR22 (1XX) trial proceeds, we will assess if patient responses mirror our animal results that show that the 1XX mutations confer increased persistence, reduced exhaustion and the ability to kill tumors with low antigen density. Citation Format: Cynthia Carol Bamdad, Joanne E. Mortimer, Yuan Yuan, Jennifer M. Specht, Andrew K. Stewart, Benoit J. Smagghe, Stephen C. Lin, Mark G. Carter, Tim W. Synold, Mark D. Fleming, Stanley R. Hamilton, Vishwas Parekh, Danica M. Walkley, Qing Liu-Michael, Kevin R. Yi, Jac-Leen S. Nash, Michael J. Nash, Stephen J. Forman. Phase I first-in-human MUC1* targeted autologous CAR T cells for the treatment of metastatic breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT096.