Background: Melanoma-associated antigens 3 and 6 (MAGE-A3/A6) are among the most commonly expressed cancer testis antigens in a variety of tumors and are associated with poor disease prognosis. Antitumor activity, including partial and complete responses, has been observed with MHC class II-restricted T cell receptor (TCR)-engineered T cells targeting MAGE-A3 and MAGE-A6 (Lu et al. J Clin Oncol. 2017). In this study, the safety and antitumor activity of KITE-718, an autologous TCR-engineered T cell therapy targeting MAGE-A3/A6, will be evaluated in HLA-DPB1*04:01-positive patients with advanced cancers. Methods: Phase 1A of the study (NCT03139370) uses a single-patient dose-escalation scheme to evaluate safety and determine the recommended Phase 1B dose of KITE-718, enrolling up to 30 patients. Phase 1B will include ≈45 patients with non-small cell lung cancer, urothelial cancer, and all other MAGE-A3/A6–positive tumors treated at the recommended KITE-718 dose. For both portions of the study, after leukapheresis patients may receive optional bridging therapy prior to conditioning chemotherapy. After manufacturing, patients will receive cyclophosphamide and fludarabine conditioning chemotherapy followed by KITE-718 at a dose of 1 × 10⁶ to 1 × 10⁸ TCR-transduced T cells/kg. Following KITE-718 infusion, patients will receive daily subcutaneous IL-2 therapy for a maximum of 14 days. The primary endpoint for Phase 1A is incidence of adverse events defined as dose-limiting toxicities. The Phase 1B primary endpoint is investigator assessment of objective response rate per modified RECIST v1.1 or IMWG criteria. Secondary endpoints include duration of response, progression-free survival, overall survival, and safety. Patients aged ≥18 y must be HLA-DPB1*04:01–positive, have relapsed/refractory MAGE-A3/A6–positive advanced cancer, ECOG ≤ 1, and adequate bone marrow and organ function. Patients amenable for loco-regional therapy or with history of stroke, myocardial infarction, or symptomatic deep vein thrombosis/pulmonary embolism are not eligible. The study is open and accruing patients. Clinical trial information: NCT03139370