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

Abstract

<h3>Background</h3> 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. <h3>Materials and Methods</h3> 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. <h3>Results</h3> 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. <h3>Conclusions</h3> 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. <h3>References</h3> Haake M, Haack B, Schäfer T, <i>et al.</i> Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. <i>Nat Commun</i>. 2023;<b>14</b>:4253. Melero I, De Miguel Luken M, De Velasco G, <i>et al.</i> Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours. <i>Nature</i>. Published Online First: 11 December 2024. Lesch S, Benmebarek M-R, Cadilha BL, <i>et al.</i> Determinants of response and resistance to CAR T cell therapy. <i>Semin Cancer Biol</i>. 2020;<b>65</b>: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. <i>Blood Adv</i>. 2024;<b>8</b>:4700–10. <b>A. Oner:</b> B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; CatalYm GmbH. <b>D. Andreu-Sanz:</b> None. <b>P. Mesquita:</b> None. <b>S. Michaelides:</b> None. <b>S. Genssler:</b> A. Employment (full or part-time); Significant; CatalYm GmbH. <b>N. Vashist:</b> A. Employment (full or part-time); Significant; CatalYm GmbH. <b>J. Medina-Echeverz:</b> A. Employment (full or part-time); Significant; CatalYm GmbH. <b>T. Ross:</b> A. Employment (full or part-time); Significant; CatalYm GmbH. <b>M. Haake:</b> A. Employment (full or part-time); Significant; CatalYm GmbH. <b>C. Schuberth-Wagner:</b> A. Employment (full or part-time); Significant; CatalYm GmbH. <b>D. Schätzlein:</b> A. Employment (full or part-time); Significant; CatalYm GmbH. <b>S. Kobold:</b> B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; CatalYm GmbH.