{
  "abstract": "Background Cellular therapies have demonstrated promising activity in treatment-refractory advanced cutaneous melanoma (CM) and synovial sarcoma (SS); there are opportunities to further improve outcomes in this setting by combining cell therapy with other immunotherapy modalities. PRAME is an intracellular protein presented on the surface of tumor cells that are targeted by T cell receptors (TCR). PRAME expression is associated with poorer prognosis and shorter survival; it is expressed in 95% of CM and SS cells. IMA203 is a PRAME-directed TCR T-cell therapy engineered to recognize intracellular PRAME-derived peptides presented by HLA-A*02:01 on the cell surface and initiate a potent and specific anti-tumor response. In a phase 1 trial ( NCT03686124), IMA203 exhibited favorable tolerability and encouraging anti-tumor activity in heavily pretreated patients with advanced melanoma at RP2D. Confirmed ORR was 56% (18/32), mDOR 12.1 months, mPFS 6.1 months, and mOS 15.9 months. Most frequent TEAEs in all indications (N=74) were lymphodepletion-related cytopenias (99%). CRS was mostly lower grade (84% G1/2; 11% G3; no ≥G4) and ICANS was infrequent (10% G1/2; 4% G3; no ≥G4).1 mRNA-4203 is an investigational mRNA/LNP product that encodes a PRAME sequence specifically designed to enhance the cellular kinetics and cytotoxic effects of IMA203 to deliver improved overall efficacy. This ongoing open-label, multicenter, first-in-human phase 1a/b trial (NCT06946225) will investigate the safety, tolerability, and anti-tumor activity of IMA203 in combination with different doses of mRNA-4203 in patients with CM or SS.Methods Eligible patients are HLA-A*02:01+ adults with measurable unresectable or metastatic CM or SS (RECIST 1.1) and ECOG PS 0/1. Patients must have progressed or be intolerant to standard therapy, including ≥1 PD-1 inhibitor for CM, and ≥1 prior systemic therapy for SS. Patients with active brain metastases are excluded. Patients undergo lymphodepletion with cyclophosphamide (500 mg/m 2 and fludarabine 30 mg/m2 x 4 days), followed by a one-time infusion of IMA203 and low-dose IL-2 given subcutaneously x10 days. mRNA-4203 is administered starting 15 days post-IMA203 infusion on Days 1 and 15 of Cycle 1, then Day 1 of each subsequent 28-day cycle through Cycle 12. The primary objectives are to evaluate the safety and tolerability of the combination and determine the recommended mRNA-4203 dose for expansion. Secondary objectives include assessment of clinical activity as measured by ORR, DOR, DCR, and PFS. Additionally, pharmacokinetics of IMA203 transgene levels in peripheral blood will be evaluated. The trial is expected to enroll approximately 15 patients across 4 sites.Acknowledgements Study funding provided by Immatics US, Inc. and Moderna Inc.Trial Registration NCT06946225Reference Wermke M, Alsdorf W, Araujo DM, et al. Phase 1 clinical update of IMA203, an autologous TCR-T targeting PRAME in patients with PD1 refractory metastatic melanoma. Abstract 2508. Presented at: ASCO Annual Meeting; June 2025; Chicago, IL.Ethics Approval The protocol and all amendments were approved by the appropriate institutional review board or independent ethics committee at each participating study site. The study is being conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.",
  "authors": [
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "James W Smithy"
    },
    {
      "affiliations": [
        "University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Rodabe N Amaria"
    },
    {
      "affiliations": [
        "University of California, San Francisco, San Francisco, CA, USA"
      ],
      "name": "Adil Daud"
    },
    {
      "affiliations": [
        "Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates",
        "Cleveland Clinic Foundation, Cleveland, OH, USA"
      ],
      "name": "Adi Diab"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Karam Khaddour"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Patrick A Ott"
    },
    {
      "affiliations": [
        "UC San Francisco Health, San Francisco, CA, USA"
      ],
      "name": "Derrick Tao"
    },
    {
      "affiliations": [
        "Moderna Inc, Cambridge, MA, USA"
      ],
      "name": "Alyssa Flynn"
    },
    {
      "affiliations": [
        "Moderna Inc, Cambridge, MA, USA"
      ],
      "name": "Lin Guey"
    },
    {
      "affiliations": [
        "Moderna Inc, Cambridge, MA, USA"
      ],
      "name": "Brendan Weiss"
    },
    {
      "affiliations": [
        "Immatics Biotechnologies GmbH, Tuebingen, Germany"
      ],
      "name": "Norbert Hilf"
    },
    {
      "affiliations": [
        "Immatics Biotechnologies GmbH, Tuebingen, Germany"
      ],
      "name": "M Alper Kursunel"
    },
    {
      "affiliations": [
        "Immatics Biotechnologies GmbH, Tuebingen, Germany"
      ],
      "name": "Andrea Mayer-Mokler"
    },
    {
      "affiliations": [
        "Immatics Biotechnologies GmbH, Tuebingen, Germany"
      ],
      "name": "Liane Preußner"
    },
    {
      "affiliations": [
        "Immatics Biotechnologies GmbH, Tuebingen, Germany"
      ],
      "name": "Cedrik M Britten"
    },
    {
      "affiliations": [
        "University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Dejka M Araujo"
    }
  ],
  "title": "590 A first-in-human, phase 1 trial of IMA203 PRAME-directed TCR T-cell therapy with PRAME-encoding mRNA-4203 in previously treated, unresectable or metastatic cutaneous melanoma or synovial sarcoma",
  "uid": "11b4c293-7ed9-5ffa-8656-05d0257f366c"
}