Wermke Martin, Araujo Dejka M, Chatterjee Manik, Tsimberidou Apostolia M, Holderried Tobias A W, Jazaeri Amir A, Reshef Ran, Bokemeyer Carsten, Alsdorf Winfried, Wetzko Katrin, Brossart Peter, Aslan Katrin, Backert Linus, Bunk Sebastian, Fritsche Jens, Gulde Swapna, Hengler Silvana, Hilf Norbert, Hossain Mohammad B, Hukelmann Jens, Kalra Mamta, Krishna Delfi, Kursunel M Alper, Maurer Dominik, Mayer-Mokler Andrea, Mendrzyk Regina, Mohamed Ali, Pozo Karine, Satelli Arun, Letizia Marilena, Schuster Heiko, Schoor Oliver, Wagner Claudia, Rammensee Hans-Georg, Reinhardt Carsten, Singh-Jasuja Harpreet, Walter Steffen, Weinschenk Toni, Luke Jason J, Britten Cedrik M
Department of Medicine I, University Hospital Carl Gustav Carus TU Dresden, Dresden, Germany.
National Center for Tumor Diseases, Dresden, Germany.
Nat Med. 2025 Apr 9. doi: 10.1038/s41591-025-03650-6.
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 .
与嵌合抗原受体T细胞不同，经T细胞受体（TCR）工程改造的T细胞能够靶向对实体瘤治疗至关重要的细胞内肿瘤相关抗原。然而，迄今为止公布的大多数试验显示临床活性有限。在此，我们报告了一项首次人体、多中心、开放标签、3+3剂量递增/递减的1期试验的中期数据，该试验研究IMA203，这是一种针对HLA - A*02的PRAME复发和/或难治性实体瘤（包括黑色素瘤和肉瘤）患者的自体优先表达抗原黑色素瘤（PRAME）导向的TCR T细胞疗法。主要目标包括评估安全性和耐受性，以及确定最大耐受剂量（MTD）和/或推荐的扩展剂量。次要目标包括评估IMA203 TCR工程改造的T细胞在外周血中的持久性、肿瘤反应以及反应持续时间。共有27例患者入组1a期剂量递增试验，13例患者入组1b期剂量扩展试验。IMA203 T细胞是安全的，未达到MTD。在接受治疗的41例患者（即开始淋巴细胞清除的患者）中，4.9%（2/41）观察到严重细胞因子释放综合征，未发生严重神经毒性。在接受IMA203治疗的40例患者中，观察到总体反应率，包括未确认或确认反应（u/cORR）的患者为52.5%（21/40），确认反应率（cORR）为28.9%（11/38），在多个适应症中反应持续时间中位数为4.4个月（范围：2.4 - 23.0，95%置信区间：2.6 - 未达到）。观察到IMA203 T细胞快速植入和长期持久性。IMA203 T细胞迁移到所有器官，高剂量患者中确认反应更频繁。在外周未观察到T细胞耗竭；在PRAME表达较高的患者中深度反应更丰富；较高的T细胞浸润导致更长的无进展生存期。总体而言，IMA203在包括难治性黑色素瘤在内的多种实体瘤中显示出有前景的抗肿瘤活性。ClinicalTrials.gov标识符：NCT03686124 。
