Autologous T cell therapy for PRAME+ advanced solid tumors in HLA-A*02+ patients: a phase 1 trial

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<sup>+</sup> patients with PRAME<sup>+</sup> 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 .

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Publication Details

Journal
Nature Medicine
Published
2025-04-09
DOI
https://doi.org/10.1038/s41591-025-03650-6
Citations
29
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
30.32

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article

Autologous T cell therapy for PRAME+ advanced solid tumors in HLA-A*02+ patients: a phase 1 trial

Amir A. Jazaeri, Arun Satelli, Peter Brossart, Steffen Walter et al.
29 citations
Nature Medicine
CAR-T cell therapy research
30.32
article

Autologous T cell therapy for PRAME+ advanced solid tumors in HLA-A*02+ patients: a phase 1 trial

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

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<sup>+</sup> patients with PRAME<sup>+</sup> 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 .

Nature MedicineVol. 31(7)
The University of Texas MD Anderson Cancer Center (US), Universität Hamburg (DE), University Hospital Bonn (DE), Columbia University Irving Medical Center (US), Comprehensive Cancer Center Mainfranken (DE), University Medical Center Hamburg-Eppendorf (DE), National Center for Tumor Diseases (DE), Universitätsklinikum Würzburg (DE), UPMC Hillman Cancer Center (US), Immatics Biotechnologies (Germany) (DE), University Hospital Carl Gustav Carus (DE), Technische Universität Dresden (DE), University of Tübingen (DE)
Cancer Prevention and Research Institute of Texas
Openalex Percentile: Top 0%
CAR-T cell therapy research
30.32
DOIOpen Access PDFOpenAlex
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