Despite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. Development of CAR-T cell platforms to treat T-cell malignancies often requires additional gene modification to overcome fratricide due to shared T-cell antigens on normal and malignant T-cells. We developed a CD5-directed CAR that produces minimal fratricide by downmodulating CD5 protein levels on transduced T-cells while retaining strong cytotoxicity against CD5 positive malignant cells. In our first-in-human phase 1 study (NCT0308190), second-generation autologous CD5.CAR T-cells were manufactured from patients with r/r T-cell malignancies. Here we report safety and efficacy data from the cohort of patients with mature T-cell lymphoma (TCL). Among the 17 TCL patients enrolled, CD5 CAR-T cells were successfully manufactured for 13 out of 14 attempted line (93%) and administered to 9 (69%) patients. The overall response rate (complete remission or partial response) was 44% with complete responses observed in 2 patients. Another patient successfully proceeded to hematopoietic stem cell transplantation (HSCT) following a second infusion after an initial mixed response. The most common grade 3 or higher adverse events were cytopenias: neutropenia (100%), lymphopenia (100%), thrombocytopenia (78%), and anemia (89%). No grade 3 or higher cytokine release syndrome or neurologic events occurred. Two patients died during the immediate toxicity evaluation period due to rapidly progressive disease. These results demonstrate that CD5.CAR-T cells are safe and can induce clinical responses patients with r/r CD5-expressing TCLs without eliminating endogenous T-cells or increasing infectious complications. More patients and longer follow-up are needed for validation. NCT0308190