P-01.16 GDF-15 inhibition overcomes treatment resistance to platinum-based chemoimmunotherapy

<h3>Background</h3> The combination of PD-(L)1-directed immune checkpoint inhibition (ICI) with first-line platinum-based chemotherapy in metastatic non-small-cell lung cancer (NSCLC) has led to significant improvement of overall survival. However, a significant proportion of tumors remains directly refractory to frontline treatment or experiences relapse post initial remission. Growth Differentiation Factor 15 (GDF-15) is a stress-induced cytokine implicated in resistance to ICI based on the association of elevated baseline expression and its induction on treatment with inferior outcomes to PD-(L)1-directed ICI. GDF-15 acts as a local immunosuppressant, disrupting T cell infiltration and promoting an immunosuppressive tumor microenvironment by interfering with activation and maturation of antigen-presenting cells (APC). GDF-15 inhibition can restore sensitivity to PD-(L)1 therapy in relapsed/refractory patients with metastatic NSCLC (NCT04725474) confirming a critical role of GDF-15 in mediating immunotherapy resistance. Although PD-(L)1 therapy has been approved in combination with platinum-based chemotherapy in the first-line treatment of metastatic NSCLC, platinum-based antineoplastics have been shown to induce GDF-15 expression, potentially limiting activity of chemoimmunotherapy in this setting. Whether GDF-15 neutralization can overcome treatment resistance to combined PD-1 blockade and platinum-based chemotherapy is not known. <h3>Materials and Methods</h3> Tumor cell lines from various cancer types were treated with cisplatin, and GDF-15 release was measured from cell culture supernatants. The impact of combined treatment with anti-PD-1 and cisplatin on GDF-15 levels and the significance of concomitant GDF-15 neutralization on tolerability, tumor growth, and animal survival in preclinical tumor models was investigated. Immune correlates of anti-tumor responses were assessed by flow cytometry of intratumoral and peripheral myeloid and T cells, respectively. <h3>Results</h3> <i>In vitro</i> treatment of tumor cell lines with cisplatin significantly upregulated GDF-15. <i>In vivo</i>, GDF-15 was markedly induced by immunotherapy and cisplatin-treatment alone and further elevated upon combination treatment. Neutralization of GDF-15 alleviated body weight loss observed due to the combination of aPD1 blockade and cisplatin treatment. PD-1 blockade, and cisplatin alone as well as combined treatment with anti-PD-1 and cisplatin had limited effect on tumor growth. In contrast, tumor growth was significantly delayed and animal survival increased upon addition of GDF-15 neutralization to anti-PD-1/cisplatin. Flow cytometric assessment of the tumors and PBMCs revealed that neutralizing GDF-15 together with anti-PD-1/cisplatin resulted in infiltration of activated cDC1s (CD80+) within the tumor and enhanced peripheral adaptive T cell-mediated responses as evidenced by increased activation (CXC3R1+) and proliferation of CD8+ T cells (Ki67+). <h3>Conclusions</h3> These data suggest beneficial activity of GDF-15 blockade with chemoimmunotherapy in enhancing tolerability and cancer immunity, further highlighting that GDF-15 is a critical mediator of cancer immune evasion and treatment resistance. GDF-15 blockade may therefore be an attractive strategy to improve the effectiveness of chemoimmunotherapy in metastatic NSCLC. <b>N. Vashist:</b> A. Employment (full or part-time); Significant; Catalym GmbH. <b>A. Köhler:</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. Genßler:</b> A. Employment (full or part-time); Significant; Catalym GmbH. <b>M. Haake:</b> E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; Catalym GmbH. <b>E. Leo:</b> A. Employment (full or part-time); Significant; Catalym GmbH. <b>T. Ross:</b> A. Employment (full or part-time); Significant; Catalym GmbH. <b>C. Schuberth-Wagner:</b> A. Employment (full or part-time); Significant; Catalym GmbH.