Background: Chimeric antigen receptor (CAR) T cell therapy targeting CD19 results in marked tumor regression for patients with CD19+ malignancies. It would be ideal to extend the success of CAR-T cell therapy to 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 a promising antigen for CAR-T cell therapy. Minerva Biotechnologies developed a CAR (huMNC2-CAR44) which recognizes MUC1* and does not bind to full-length or MUC1* negative cells. huMNC2-CAR44 product consists of autologous T cells transduced with a lentiviral vector encoding humanized MNC2-scFv (MUC1* targeting head), sequences from CD8 ?? 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 patients with metastatic MUC1* positive breast cancer. 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 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). Key inclusion criteria include metastatic breast cancer of known ER, PR and HER2 status, MUC1* membrane expression > or = 30% with 2+ staining by IHC, measurable or evaluable disease, receipt of standard systemic therapies known to confer benefit, age > 18, informed consent, adequate organ function, and KPS > or = 60%. Patients with active autoimmune disease, uncontrolled infection, anticipated survival < 3 months, and/or untreated CNS metastases are not eligible. The primary objective is to identify the maximum tolerated (MTD) dose of huMNC2-CAR44 T cells by CTCAE v5 and Lee criteria. Secondary objectives include persistence and phenotype of adoptively transferred huMNC2-CAR44 T cells and preliminary antitumor activity. Exploratory objectives include trafficking of huMNC2-CAR44 T cells to tumor sites, effector function of huMNC2-CAR44 T cells in vivo, association between tumor MUC1* expression and huMNC2-CAR44 T cell persistence and response, change in tumor immune microenvironment by multiplex IHC in pre- and post-treatment tumor biopsies. Dose escalation is completed using a "3+3" design. Once the MTD has been determined, up to 15 more patients will be enrolled in each of 3 expansion cohorts (Luminal, HER2 positive, and TNBC) to inform future huMNC2-CAR44 T cell trials. Study is open to screening and enrollment in dose escalation. Up to 69 patients may be enrolled in dose escalation and expansion phases. Clinical trial information: NCT04020575