Attamage-A1: Phase I/II study of autologous CD8+ and CD4+ transgenic t cells expressing high affinity MAGE-A1-specific T-cell receptor (TCR) combined with anti-PD(L)1 in patients with metastatic MAGE-A1 expressing cancer.

TPS592 Background: Adoptive cellular therapies can lead to durable responses in treatment refractory leukemias and lymphomas; however, these approaches are still in early stage development for metastatic solid tumors. FH-MagIC TCR-T is an autologous CD8+ and CD4+ T cell product transduced with a transgenic T cell receptor (TCR) targeting MAGE-A1. MAGE-A proteins are classified within the “testis restricted” cancer testis antigens and are broadly expressed in a wide range of malignancies, including urothelial carcinomas, triple negative breast cancers (TNBCs) and non-small cell lung cancers (NSCLCs). Importantly, MAGE-A1 is undetectable in most normal tissues exclusive of the immune privileged testes, thereby making MAGE-A1 an ideal target for T cell immunotherapy approaches. Of note, FH-MagIC TCR-T is specific to the Class I HLA A*02:01-restricted MAGE-A1 epitope. Based on preclinical studies testing FH-MagIC-T in MAGE-A1 expressing tumor models, we have launched a Phase I/II study evaluating this autologous transgenic TCR therapy. Methods: This is a Phase I/II study testing FH-MagIC TCR-T cells in patients with metastatic urothelial carcinoma, TNBC or NSCLC. Eligible patients must have HLA type HLA-A*02:01 and demonstrate expression of MAGE-A1 on archival tumor tissue (≥1+ by immunohistochemistry). Patients must have been offered or received: i) anti-PD(L)1 therapy; ii) enfortumab vedotin (urothelial carcinoma patients); and iii) FDA-approved targeted therapies (e.g. NSCLC patients with actionable mutations in EGFR, ROS1, etc.). For each dose level (DL) in the Phase 1 portion, 1 patient will be treated without lymphodepletion (LD). If no dose limiting toxicities (DLT) are observed, the next 3 patients will receive LD with cyclophosphamide 300mg/m 2 and fludarabine 30mg/m 2 IV days -4 to -2 before T cell infusion. The first 4 patients will be treated at DL1: 1 x 10 9 cells. If no DLTs are observed, the next 4 patients will be treated at DL2: 5 x 10 9 cells. Otherwise, if a DLT is observed at DL1, the next 4 patients will be treated at DL-1: 5 x 10 8 cells. The Phase 2 portion of the trial will test FH-MagIC-TCR T cell product at the RP2D with the addition of standard of care anti-PD(L)1 therapy. Primary objectives are to assess safety (Phase 1) and radiographic response rate (Phase 2) per RECIST v1.1. Secondary objectives will evaluate progression free survival, overall survival, persistence of transgenic T cells in peripheral blood and migration into tumor tissue. For the Phase 2 portion, we assume a 5% null response rate (H0). If the true response rate with TCR-transduced cells is 25% (H1), 15 patients will yield 84% power at a one-sided alpha =.05. Clinical trial information: NCT04639245.