Faculty, Staff and Student Publications

Publication Date

7-1-2025

Journal

Nature Medicine

DOI

10.1038/s41591-025-03650-6

PMID

40205198

PMCID

PMC1228337

PubMedCentral® Posted Date

4-9-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Humans, Male, Middle Aged, Female, Antigens, Neoplasm, T-Lymphocytes, Aged, Adult, HLA-A2 Antigen, Melanoma, Neoplasms, Immunotherapy, Adoptive, Receptors, Antigen, T-Cell, Maximum Tolerated Dose, Sarcoma, Transplantation, Autologous, Cancer immunotherapy, Melanoma, Sarcoma, Head and neck cancer

Comments

This article has been corrected. See Nat Med. 2025 Apr 29;31(7):2453.

Published Open-Access

yes

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41591_2025_Article_3731.pdf (562 kB)
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