Abstract CT232: Phase I study of adoptive immunotherapy for advanced MUC1 positive breast cancer with autologous T cells engineered to express a chimeric antigen receptor, huMNC2-CAR44 specific for a cleaved form of MUC1 (MUC1)

Background: CAR-T cell therapy targeting CD19 results in marked tumor regression for patients (pts) with B-cell malignancies. It would be ideal to extend the success of CAR-T cell therapy to common epithelial cancers. MUC1* is a post-translationally modified/cleaved form of mucin 1 (MUC1) that is frequently expressed on breast tumors, functions as a growth factor receptor, and is a novel antigen for CAR-T cell therapy. Minerva Biotechnologies developed a CAR (huMNC2-CAR44) that specifically recognizes MUC1* and does not bind to full-length MUC1 or MUC1* negative cells. huMNC2-CAR44 product consists of autologous T cells transduced with a proprietary lentiviral vector encoding humanized MNC2-scFv (MUC1* targeting head), CD8 α; leader, hinge and transmembrane domains, 4-1BB, and CD3ζ domains. Methods: NCT04020575 is a phase I study evaluating the safety of adoptively transferred autologous T cells genetically modified to express huMNC2-CAR44 in pts with metastatic breast cancer (MBC). Key eligibility criteria: MBC of known ER, PR and HER2 status which has MUC1* membrane expression ≥30% by IHC, measurable or evaluable disease, receipt of standard systemic therapies known to confer benefit, age >18, informed consent, adequate organ function, and KPS ≥60%. Key exclusions: active autoimmune disease or uncontrolled infection, contraindication to cyclophosphamide, anticipated survival < 3 months, and/or untreated CNS metastases. After screening, leukapheresis is performed, CD8+ and CD4+ T cells are selected, transduced with huMNC2-CAR44, expanded, and antigen stimulated in vitro. Lymphodepletion with cyclophosphamide and fludarabine is followed 36-96 hours later by infusion of huMNC2-CAR44 CAR-T cells in escalating doses (3.3 x 105 CAR+ T cells/kg - 1 x 107 CAR+ T cells/kg). The primary objective is to identify the maximum tolerated dose of huMNC2-CAR44 T cells by CTCAE v5 and Lee criteria. Secondary objectives include persistence/phenotype of adoptively transferred huMNC2-CAR44 T cells and antitumor activity in pts with measurable disease by RECIST 1.1. Selected exploratory objectives include trafficking of huMNC2-CAR44 T cells to tumor sites, effector function in vivo, association between tumor MUC1* expression and huMNC2-CAR44 T cell response, change in tumor immune microenvironment by multiplex IHC in post-treatment tumor biopsies. Dose escalation or de-escalation is tested using standard 3+3 dose-finding targeting a T cell dose that is associated with a true