Work

P-02.05 GDF-15 neutralization enhances T cell infiltration in solid tumor models

Year: 2025

Type: conference-paper

Abstract: Background Growth Differentiation Factor 15 (GDF-15) has emerged as a critical immunosuppressive factor in the tumor microenvironment, shown to inhibit endothelial adhesion of leukocytes and limiting T cell infiltration into tumors.1 2 Both chimeric antigen receptor (CAR) T cell therapies and bispecific T-cell engagers have shown remarkable success in hematological malignancies; however, their efficacy in solid tumors remains limited.3 4 Overcoming factors that restrict T cell infiltration and function in solid tumors is crucial for expanding T cell-based therapy applications. Materials and Methods T cell infiltration was examined in two tumor models: a pancreatic ductal adenocarcinoma model in C57BL/6 mice treated with EpCAM-specific CAR-T cells with or without visugromab, a monoclonal antibody targeting GDF-15; and a melanoma model in NOG mice reconstituted with human peripheral blood mononuclear cells and treated with tebentafusp, a bispecific T-cell engager, in combination with visugromab or isotype control. Flow cytometry was used to evaluate T cell infiltration and antigen-presenting cell activation, with serum GDF-15 levels measured via ELISA. Results GDF-15 neutralization enhanced T cell infiltration into tumor tissue across both models. Mice with splenic CAR-T cells subjected to GDF-15 neutralization exhibited a larger fraction of above-threshold CAR-T infiltration at the tumor site. Tebentafusp-treated mice receiving GDF-15 neutralization also demonstrated improved T cell infiltration into tumor tissue. Additionally, GDF-15 neutralization in the tebentafusp model was associated with increased infiltration of activated antigen-presenting cells, as evidenced by elevated numbers of CD80 and CD86-expressing dendritic cells and macrophages. Conclusions Our findings identify GDF-15 as a potential barrier to effective T cell infiltration in solid tumors and suggest that its neutralization may enhance T cell-based therapies by promoting T cell extravasation and facilitating the recruitment and activation of antigen-presenting cells in the tumor microenvironment, potentially expanding the application of these therapeutic modalities beyond their current limitations. References Haake M, Haack B, Schäfer T, et al. Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nat Commun. 2023;14:4253. Melero I, De Miguel Luken M, De Velasco G, et al. Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours. Nature. Published Online First: 11 December 2024. Lesch S, Benmebarek M-R, Cadilha BL, et al. Determinants of response and resistance to CAR T cell therapy. Semin Cancer Biol. 2020;65:80–90. Haydu JE, Abramson JS. The rules of T-cell engagement: current state of CAR T cells and bispecific antibodies in B-cell lymphomas. Blood Adv. 2024;8:4700–10. A. Oner: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; CatalYm GmbH. D. Andreu-Sanz: None. P. Mesquita: None. S. Michaelides: None. S. Genssler: A. Employment (full or part-time); Significant; CatalYm GmbH. N. Vashist: A. Employment (full or part-time); Significant; CatalYm GmbH. J. Medina-Echeverz: A. Employment (full or part-time); Significant; CatalYm GmbH. T. Ross: A. Employment (full or part-time); Significant; CatalYm GmbH. M. Haake: A. Employment (full or part-time); Significant; CatalYm GmbH. C. Schuberth-Wagner: A. Employment (full or part-time); Significant; CatalYm GmbH. D. Schätzlein: A. Employment (full or part-time); Significant; CatalYm GmbH. S. Kobold: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; CatalYm GmbH.

Source: Poster presentations

DOI: 10.1136/jitc-2025-itoc11.29