Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphomaABSTRACT: The success of targeted therapies for hematological malignancies has heralded their potential as both salvage treatment and early treatment lines, reducing the need for high-dose, intensive, and often toxic chemotherapeutic regimens. For young patients with classic Hodgkin lymphoma (cHL), immunotherapies provide the possibility to lessen long-term, treatment-related toxicities. However, suitable therapeutic targets are lacking. By integrating single-cell dissection of the tumor landscape and an in-depth, single-cell-based off-tumor antigen prediction, we identify CD86 as a promising therapeutic target in cHL. CD86 is highly expressed on Hodgkin and Reed-Sternberg cancer cells and cHL-specific tumor-associated macrophages. We reveal CD86-CTLA-4 as a key suppressive pathway in cHL, driving T-cell exhaustion. Cellular therapies targeting CD86 had extraordinary efficacy in vitro and in vivo and were safe in immunocompetent mouse models without compromising bacterial host defense in sepsis models. Our results prove the potential value of anti-CD86 immunotherapies for treating cHL.
P-02.05 GDF-15 neutralization enhances T cell infiltration in solid tumor models<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.<sup>1 2</sup> 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.<sup>3 4</sup> 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.