{
  "abstract": "Background PRAME is an intracellular protein that is presented on the surface of tumor cells that are targeted by T cell receptors (TCRs). 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 the phase 1 trial ( NCT03686124), IMA203 exhibited favorable tolerability and encouraging clinical activity in patients with advanced melanoma with confirmed ORR 56%, mDOR 12.1 months, mPFS 6.1 months and mOS 15.9 months.1 Given the clear association of higher infused T cell dose with better patient response,2 we investigated how starting material and process optimization influence manufacturing performance and final product phenotype.Methods Leukapheresis samples and final IMA203 T-cell products from 73 patients enrolled in the phase 1 trial were analyzed. Cellular phenotypes were assessed via flow cytometry. Manufacturing performance was evaluated through fold expansion (total fold increase during process) and final manufactured cell dose, and their relationships with input cell composition.Results Manufactured cell dose was significantly correlated with the initial CD8+ T cell count and ex vivo fold expansion. A young CD8+ T cell phenotype—enriched for CD62L+, naïve/SCM, and central memory (CM) subsets—was associated with superior expansion capacity. Additionally, higher proportion of CD8+ cells expressing CD27+ and CD28+ costimulatory/proliferative markers positively influenced expansion during manufacturing. Conversely, terminal effector (TEMRA)-enriched leukapheresis material showed reduced proliferative capacity.Crucially, robust ex vivo proliferation did not significantly drive terminal differentiation. Instead, final products maintained or further enriched their naïve/SCM and CM characteristics. Overall, IMA203 manufacturing induced a favorable shift toward both naïve and effector phenotypes, marked by elevated expression of CD62L, CD28, and CD45RO. Simultaneously, markers associated with exhaustion or senescence, including PD-1 and CD57, were significantly reduced in the final product.Conclusions These findings underscore the pivotal role of leukapheresis material quality when manufacturing cells. Specifically, high CD8+ T cell count and a young, costimulation-competent phenotype drive manufacturing success and improve final product characteristics. Notably, IMA203 manufacturing achieved a 95% success rate at the RP2D (1-10x10 9 TCR T cells).1 Furthermore, the process consistently yielded final IMA203 product with enriched effector memory and co-stimulatory profiles, reflecting both phenotypic fitness and process robustness. This supports the importance of an optimized TCR T-cell product manufacturing process alongside quality starting material, thereby achieving a high success rate, and promising clinical activity.Acknowledgements Study funding provided by Immatics US, Inc.Trial Registration NCT03686124References 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.Wermke M, Araujo DM, Chatterjee M, et al. Autologous T cell therapy for PRAME+ advanced solid tumors in HLA-A*02+ patients: a phase 1 trial [published correction appears in Nat Med. 2025 Apr 29. doi: 10.1038/s41591-025-03731-6.]. Nat Med. Published online April 9, 2025. doi:10.1038/s41591-025-03650-6",
  "authors": [
    {
      "affiliations": [
        "Immatics Biotechnologies Gmbh, Tuebingen, Germany"
      ],
      "name": "M Alper Kursunel"
    },
    {
      "affiliations": [
        "Immatics US, Inc., Stafford, TX, USA"
      ],
      "name": "Brent Chesson"
    },
    {
      "affiliations": [
        "Immatics Biotechnologies Gmbh, Tuebingen, Germany"
      ],
      "name": "Marilena Letizia"
    },
    {
      "affiliations": [
        "Immatics Biotechnologies Gmbh, Tuebingen, Germany"
      ],
      "name": "Katrin Aslan"
    },
    {
      "affiliations": [
        "Immatics US, Inc., Stafford, TX, USA"
      ],
      "name": "Zoe Coughlin"
    },
    {
      "affiliations": [
        "Immatics US, Inc., Stafford, TX, USA"
      ],
      "name": "Justin T Gunesch"
    },
    {
      "affiliations": [
        "Immatics Biotechnologies Gmbh, Tuebingen, Germany"
      ],
      "name": "Norbert Hilf"
    },
    {
      "affiliations": [
        "Immatics US, Inc., Stafford, TX, USA"
      ],
      "name": "Mamta Kalra"
    },
    {
      "affiliations": [
        "Immatics US, Inc., Stafford, TX, USA"
      ],
      "name": "Delfi Krishna"
    },
    {
      "affiliations": [
        "Immatics Biotechnologies Gmbh, Tuebingen, Germany"
      ],
      "name": "Regina Mendrzyk"
    },
    {
      "affiliations": [
        "Immatics US, Inc., Stafford, TX, USA"
      ],
      "name": "Ali Mohamed"
    },
    {
      "affiliations": [
        "Immatics Biotechnologies Gmbh, Tuebingen, Germany"
      ],
      "name": "Cedrik M Britten"
    },
    {
      "affiliations": [
        "Immatics US, Inc., Stafford, TX, USA"
      ],
      "name": "Steffen Walter"
    }
  ],
  "title": "579 Quality of starting material result in high manufacturability and favorable product phenotype of IMA203, a PRAME-directed TCR T-cell therapy",
  "uid": "4145a5ef-0261-5b7e-aa5f-a8d8b0aed803"
}