Abstract PO5-19-03: 1st-in-human CAR T targets MUC1 transmembrane cleavage product

Abstract Background: huMNC2-CAR44 and huMNC2-CAR22 are autologous CAR T cell therapies under study in an ongoing 1st-in-human trial for metastatic breast cancers (NCT04020575), being performed at City of Hope. Both CARs are targeted to the tumor by an antibody, huMNC2, that recognizes a cryptic binding site on MUC1*, which is the transmembrane cleavage product of MUC1. The antibody binds to an epitope that is only unmasked when MUC1 is cleaved to MUC1* by enzymes in the tumor microenvironment. huMNC2 strongly reacts with over 90% of breast cancers. No therapeutic that targets MUC1* had ever been tested in humans before this trial. We note that neither 5E5 nor antibodies that bind to a MUC1 “heterodimer” recognize MUC1*. Eight patients have already been treated with huMNC2-CAR44. The next 8 patients will be treated with huMNC2-CAR22 to enable comparison and inform decision as to which CAR to bring forward for completion of Phase 1 and entry into Phase 2. huMNC2-CAR22 differs from huMNC2-CAR44 in that it is resistant to exhaustion. CAR22 achieves greater in vivo persistence due to Sadelain’s “1XX” mutations of Tyr to Phe in 2 of the 3 ITAMs, which prevent Tyr phosphorylation and signaling, leaving signaling through ITAM 1 alone. Trial Design: Dose escalation or de-escalation is tested in cohorts of 3 patients each using standard “3+3” dose-finding, with the starting dose of 3.3x105 CAR+ T cells/kg up to a maximum of 1.0x107 CAR+ T cells/kg. Patients receive cyclophosphamide (300 mg/m2/day) and fludarabine (30 mg/m2/day) for 3 days prior to CAR T cell infusion. Safety will be evaluated by CTCAE version 5.0 and Lee criteria. Anti-tumor activity will be assessed by imaging studies completed between 1 and 3 months after huMNC2-CAR T cell infusion for determination of response by RECIST 1.1 or by FDG PET modified PERCIST for patients with predominant bone disease. Inclusion Criteria: Patients with confirmed diagnosis of breast cancer, with documented ER, PR, and HER2 status per ASCO/CAP guidelines. Patients with MUC1* expression of at least 30% by IHC. Patients must have received standard metastatic systemic therapy per NCCN guidelines which are known to confer benefit. No maximum on number of prior treatments. Patients must have received at least 2 or 3 prior lines of chemotherapy in the metastatic setting. Exclusion Criteria: Patients requiring 15 mg of prednisone per day or immunosuppressives; patients with major organ dysfunction; Serum creatinine 2 mg/dL; Bilirubin ≥ 1.5 mg/dL; AST/ALT ≥ 2.5 x upper limit normal; 3x upper limit for patients with known liver metastasis; significant pulmonary dysfunction; significant cardiovascular abnormalities; ANC 1000/mm3. Primary Objectives: To determine the safety and maximally tolerated cell dose (MTD) and recommended phase 2 cell dose (RP2D) of ex vivo expanded autologous huMNC2-CAR T cells for patients with advanced MUC1* positive breast cancer using CTCAE version 5.0 and Lee criteria. Secondary: Determine duration of in vivo persistence and phenotype of adoptively transferred huMNC2-CAR T cells. Determine antitumor activity by RECIST 1.1. Determine MTD/RP2D. Contact: City of Hope Comprehensive Cancer Center Joanne Mortimer, MD 1-800-826-4673 Minerva18625@coh.org Citation Format: Cynthia Bamdad, Joanne Mortimer, Yuan Yuan, Jennifer M. Specht, Benoit Smagghe, Stephen Chi-Min Lin, Andrew Stewart, Danica Walkley, Mark Carter, Timothy Synold, Vishwas Parekh, Kevin Yi, Jac-Leen Nash, Michael Nash, Qing Liu-Michael, Stanley Hamilton, Stephen Forman. 1st-in-human CAR T targets MUC1 transmembrane cleavage product abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-03.