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Cited by 73CAR-T cell therapy researchImmunotherapy and Immune ResponsesCancer Immunotherapy and Biomarkers

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

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Wermke, Martin, Araujo, Dejka M., Chatterjee, Manik, Tsimberidou, Apostolia M., Holderried, Tobias A. W., Jazaeri, Amir A., Reshef, Ran, Bokemeyer, Carsten +32 more·2025·Nature Medicine
DOI 10.1038/s41591-025-03650-6PMC PMC12283372
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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 . 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.

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  • Autologous cell therapies are typically non-genetically modified, patient-specific, and manufactured in small batches.

    “Autologous cell therapies, including autologous chondrocytes, BMSCs, ADSCs, and immune cell products such as CIK cells and DCs, are typically non-genetically modified, patient-specific, and manufactured in small batches (Marlovits et al., 2006; Wermke et al., 2025).”

    From Isolator-based point-of-care manufacturing: a practical solution for GMP-compliant cell and extracellular vesicles therapy production (2025) · cites this paper as Wermke et al., 2025

    The Results (Manufacturing characteristics of TCR T drug product; page unavailable) describe a product made from patients’ own cells and report individual patient product characteristics, supporting the patient-specific aspect. The Methods (Manufacturing of IMA203 products; page unavailable) explicitly state that the T cells are genetically modified, contrary to the non-genetically-modified description. Neither section establishes that autologous cell therapies generally are manufactured in small batches. (LLM, conf=0.87)

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Authors
Wermke, M., Araujo, D. M., Chatterjee, M., Tsimberidou, A. M., Holderried, T. A. W., Jazaeri, A. A., Reshef, R., Bokemeyer, C., Alsdorf, W., Wetzko, K., Brossart, P., Aslan, K., Backert, L., Bunk, S., Fritsche, J., Gulde, S., Hengler, S., Hilf, N., Hossain, M. B., Hukelmann, J., Kalra, M., Krishna, D., Kursunel, M. A., Maurer, D., Mayer-Mokler, A., Mendrzyk, R., Mohamed, A., Pozo, K., Satelli, A., Letizia, M., Schuster, H., Schoor, O., Wagner, C., Rammensee, H.-G., Reinhardt, C., Singh-Jasuja, H., Walter, S., Weinschenk, T., Luke, J. J., & Britten, C. M.
Affiliations
  • University Hospital Carl Gustav Carus (DE)
  • The University of Texas MD Anderson Cancer Center (US)
  • Comprehensive Cancer Center Mainfranken (DE)
  • University Hospital Bonn (DE)
  • Columbia University Irving Medical Center (US)
  • University Medical Center Hamburg-Eppendorf (DE)
  • Immatics Biotechnologies (Germany) (DE)
  • University of Tübingen (DE)
  • University of Pittsburgh (US)
Corresponding author
Britten, Cedrik M.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2025-04-09
Volume
31
Issue
7
Pages
2365-2374
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-025-03650-6
PMC
PMC12283372
OpenAlex
W4409279341
Cited by
73
References
3
Citations by year
2026: 53 · 2025: 20
FWCI
30.23
Type
journal article
Language
en
Update notices
correction (2025-04-29)
Open access
Licence
Locations
  • Nature Medicine (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders
Cancer Prevention and Research Institute of Texas (DP150029)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
PRAME, T cell receptor engineering, autologous T cell therapy, HLA-A*02, melanoma, sarcoma, refractory solid tumors, cytokine release syndrome, T cell persistence, tumor-infiltrating T cells, T cell exhaustion, maximum tolerated dose, dose escalation, neurotoxicity, tumor-associated antigens, immunotherapy
MeSH terms
Adult, Aged, Antigens, Neoplasm, Female, Humans, Male, Melanoma, Middle Aged, Neoplasms, Receptors, Antigen, T-Cell, Sarcoma, T-Lymphocytes, Transplantation, Autologous, HLA-A2 Antigen, Immunotherapy, Adoptive, Maximum Tolerated Dose

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