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<p>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: <a href="https://clinicaltrials.gov/study/NCT03686124">NCT03686124</a>.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月9日

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

摘要

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.