Abstract 4777: GDF-15 neutralization enhances the therapeutic activity of antibody-drug conjugates

Abstract Background: Antibody-drug conjugates (ADCs) target cytotoxic payloads like microtubule and topoisomerase I inhibitors to the tumor, thereby inducing selective tumor cell death. ADCs can also trigger anti-tumoral immune responses via induction of immunogenic cell death (ICD). Recent advances in treatment of urothelial cancer demonstrate the high potential of ADCs, e.g. also in combination with PD-(L)1 immune checkpoint inhibitors (ICI). However, significant challenges still remain such as (partial) non-response, high relapse rates and notable toxicity, all highlighting the need to further improve the treatment. GDF-15 acts as a local immunosuppressant, disrupting immune cell infiltration and inhibiting myeloid cell differentiation. GDF-15 blockade in anti-PD1/PD-L1 relapsed/refractory, last-line cancer patients has shown durable anti-tumor responses when combined with PD-1 ICI (NCT04725474). Beyond tumoral overexpression, GDF-15 is also induced by various chemotherapeutic agents. Whether GDF-15 is induced by ADC payloads and could mediate resistance to therapy is currently unknown. Here, we investigated if ADC treatment can induce GDF-15 release from tumor cells and if GDF-15 neutralization may enhance ADC activity. Methods: Human tumor cell lines were treated with ADCs or unconjugated payloads. Cell viability, induction of ICD, and GDF-15 levels were measured in vitro by quantifying intracellular ATP, ecto-Calreticulin (ecto-CRT), and release of HMGB1, extracellular ATP (eATP), and GDF-15 in cell culture supernatants, respectively. Induction of tumoral and serum GDF-15 levels by ADCs was assessed in vivo using xenograft tumor models. The effect of GDF-15 neutralization on the anti-tumoral activity of ADCs was evaluated in syngeneic tumor models by monitoring tumor growth and animal survival. Results: ADCs and unconjugated payloads (MMAE, SN-38, calicheamicin, and PBD dimers) induced concentration-dependent lysis of tumor cells, releasing eATP and HMGB1 and translocating ecto-CRT, indicative of ICD induction. Concomitant with cell death, ADCs and their payloads induced GDF-15 release from tumor cells in vitro. ADC-induced GDF-15 release was confirmed in vivo by increase in tumoral and circulating GDF-15 levels in human tumor xenografted mice. Lastly, combining anti-GDF-15 with ADC treatment improved tumor growth delay markedly in a syngeneic tumor model, accompanied by enhanced immune cell infiltration and activation. Conclusion: ADC treatment induces GDF-15 which contributes to reduction of ADC activity. Blockade of GDF-15 enhances ADC activity and immune cell number and activation in the tumor. Therefore, GDF-15 blockade may hold significant potential as therapeutic strategy to enhance ADC activity in cancer patients. Citation Format: Neha Vashist, Daniel Schätzlein, Amelie Köhler, Sabrina Genssler, José Medina-Echeverz, Eugen Leo, Thorsten Ross, Christine Schuberth-Wagner. GDF-15 neutralization enhances the therapeutic activity of antibody-drug conjugates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4777.