Abstract OT-13-07: 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*)
Authors: Specht Jennifer Marie , Maloney David , Yeung Cecilia , Wu Qian (Vicky) , Bamdad Cynthia 
Published: February 2021

Abstract
Background: Chimeric antigen receptor (CAR) T cell therapy targeting CD19 results in marked tumor regression for patients 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 promising antigen for CAR T cell therapy. Minerva Biotechnologies developed a CAR T (huMNC2-CAR44) that specifically recognizes the cleaved form of 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 α;; leader, hinge and transmembrane domains, 4-1BB and CD3ζ domains. Trial Design: NCT04020575 is a phase I study evaluating the safety and anti-tumor activity of adoptively transferred autologous T cells genetically modified to express huMNC2-CAR44 in patients with metastatic MUC1* 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 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). Eligibility: Key inclusion criteria include metastatic breast cancer of known ER, PR and HER2 status which has MUC1* membrane expression &gt; or = 30% by immunohistochemistry, measurable or evaluable disease, receipt of standard systemic therapies known to confer benefit, age &gt;18, informed consent, adequate organ function, and KPS &gt; or = 60%. Patients with active autoimmune disease or uncontrolled infection, contraindication to cyclophosphamide, anticipated survival &lt; 3 months, and/or untreated CNS metastases are not eligible. Specific Aims: 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 and phenotype of adoptively transferred huMNC2-CAR44 T cells and preliminary antitumor activity in all patients with measurable disease by RECIST 1.1. 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 immunohistochemistry in pre and post-treatment tumor biopsies. Statistical Design: Dose escalation or de-escalation is tested in cohorts of 3 patients each using standard "3+3" dose-finding targeting a T cell dose that is associated with a true DLT rate &lt; 33% and &gt; than 17%. DLT period is between day 0 and 28. 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 estimate the anti-tumor activity in these patient populations and to inform future huMNC2-CAR44 T cell trials. Present accrual: Study is open to screening and enrollment in dose escalation. Up to 69 patients may be enrolled in dose escalation and expansion phases. Contact information: To refer patients or obtain more information, please contact immunotherapy@seattlecca.org.
Citation Format: Jennifer Marie Specht, David Maloney, Cecilia Yeung, Qian (Vicky) Wu, Cynthia Bamdad. 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*) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-13-07.