Journal Article

Autologous T cell therapy for PRAME+ advanced solid tumors in HLA-A02+ patients: a phase 1 trial

Tsimberidou, Apostolia M., Schuster, Heiko, Luke, Jason J., Schoor, Oliver, Fritsche, Jens, Reinhardt, Carsten, Hossain, Mohammad B., Mohamed, Ali, Jazaeri, Amir A., Wetzko, Katrin, Bunk, Sebastian, Rammensee, Hans-Georg, Maurer, Dominik, Aslan, Katrin, Mendrzyk, Regina, Kursunel, M. Alper, Brossart, Peter, Hengler, Silvana, Weinschenk, Toni, Satelli, Arun, Mayer-Mokler, Andrea, Hilf, Norbert, Araujo, Dejka M., Krishna, Delfi, Hukelmann, Jens, Alsdorf, Winfried, Holderried, Tobias A. W., Singh-Jasuja, Harpreet, Britten, Cedrik M., Reshef, Ran, Pozo, Karine, Gulde, Swapna, Wagner, Claudia, Walter, Steffen, Letizia, Marilena, Wermke, Martin, Chatterjee, Manik, Bokemeyer, Carsten, Backert, Linus, Kalra, Mamta

2025

Overview

In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02 + patients with PRAME + recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose for extension. Secondary objectives include the evaluation of IMA203 TCR-engineered T cell persistence in peripheral blood, tumor response as well as duration of response. A total of 27 patients were enrolled in the phase 1a dose escalation and 13 patients in the phase 1b dose extension. IMA203 T cells were safe, and the MTD was not reached. Of the 41 patients receiving treatment (that is, who started lymphodepletion), severe cytokine release syndrome was observed in 4.9% (2/41), and severe neurotoxicity did not occur. In the 40 patients treated with IMA203, an overall response rate consisting of patients with unconfirmed or confirmed response (u/cORR) of 52.5% (21/40) and a cORR of 28.9% (11/38) was observed with a median duration of response of 4.4 months (range, 2.4–23.0, 95% confidence interval: 2.6–not reached) across multiple indications. Rapid T cell engraftment and long-term persistence of IMA203 T cells were observed. IMA203 T cells trafficked to all organs, and confirmed responses were more frequent in patients with higher dose. T cell exhaustion was not observed in the periphery; deep responses were enriched at higher PRAME expression; and higher T cell infiltration resulted in longer progression-free survival. Overall, IMA203 showed promising anti-tumor activity in multiple solid tumors, including refractory melanoma. ClinicalTrials.gov identifier: NCT03686124 . In a non-prespecified interim analysis of a phase 1 trial, autologous PRAME-directed TCR T cell therapy was safe and elicited durable responses in patients with recurrent and/or treatment-refractory PRAME + advanced solid tumors, including melanoma and synovial sarcoma.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 692/699/67/1059/2325 / 692/699/67/1536 / 692/699/67/1798 / 692/699/67/1813/1634 / Adult / Aged / Antigen (tumor-associated) / Antigens / Antigens, Neoplasm - immunology / Antitumor agents / Autografts / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell therapy / Chimeric antigen receptors / Clinical trials / Female / Health services / Histocompatibility antigen HLA / HLA-A2 Antigen - immunology / Humans / Immunotherapy, Adoptive - adverse effects / Immunotherapy, Adoptive - methods / Infectious Diseases / Lung cancer / Lymphocytes / Lymphocytes T / Male / Maximum Tolerated Dose / Melanoma / Melanoma - immunology / Melanoma - pathology / Melanoma - therapy / Metabolic Diseases / Metastases / Middle Aged / Molecular Medicine / Neoplasms - immunology / Neoplasms - therapy / Neurosciences / Neurotoxicity / Ovarian cancer / Patients / Peptides / Peripheral blood / Receptors / Receptors, Antigen, T-Cell - genetics / Receptors, Antigen, T-Cell - immunology / Sarcoma / Sarcoma - immunology / Sarcoma - therapy / Skin cancer / Solid tumors / Synovial sarcoma / T cell receptors / T-Lymphocytes - immunology / T-Lymphocytes - transplantation / Therapy / Toxicity / Transplantation, Autologous / Tumors