04 Targeted disruption of tumor-borne GDF-15-mediated immunoresistance restores immune checkpoint inhibitor activity in last-line cancer patients

Background GDF-15 is a divergent member of the TGFbeta superfamily. Under physiological conditions GDF-15 levels are modest but become upregulated during cellular stress and reach high concentrations during pregnancy. Originally named macrophage inhibitory cytokine, GDF-15 has been identified as potent immune modulator in fetomaternal tolerance but also injury and cancer. In addition, GDF-15 has a metabolic function and is associated with weight loss and cachexia in cancer. High GDF-15 levels in solid tumors of various origins negatively correlate with immune cell numbers in the tumor and response to immune checkpoint inhibitors (ICI). As immune activation and infiltration is a requirement for ICI response we postulated that neutralizing GDF-15 increases activation and infiltration of immune cells into the tumor and thereby resensitizes otherwise resistant tumors to anti-PD-1 treatment. Materials and Methods GDF-15 function and its neutralization by antibody were investigated in different in vitro and in vivo experimental models. Effects were analyzed by different techniques including flow cytometry, live imaging microscopy, immunoblot and reporter assays. A clinical phase 1/2a first-in-human trial in advanced stage/metastatic anti-PD/PD-L1 relapsed/refractory (r/r) solid tumors was conducted to investigate the combination of anti-PD-1 nivolumab with anti-GDF-15 Visugromab (NCT04725474). Results Tumor derived GDF-15 blocks immune activation and recruitment and mediates weight loss in syngeneic and humanized mouse models. Specifically, GDF-15 counteracts APC activation evident by inhibition of IFNg or TLR induced surface expression of activation (CD80, CD86) and functional (HLA-DR, FcgRI, II, III) markers as well as inhibition of chemokine expression and release. In addition, GDF-15 decreases LFA-1 affinity for ICAM-1 limiting tumor infiltration by APCs, NK- and T-cells. All effects can be restored by anti-GDF-15 treatment. Clinical testing of visugromab in combination with nivolumab in anti-PD-1 r/r solid tumor patients in ph1/2a trials resulted in 21,1% response in non-sq NSCLC and 14,8% in UC, reinstating activity of CPI in CPI-relapsed/refractory disease to levels at or near to CPI-naive disease. In addition, a clean safety profile and substantial durability of response (DoR) in last-line was observed with still maturing mean DoR surpassing 11.5 months (non-sq NSCLC) and 10.4 months (UC). Conclusions In summary, visugromab demonstrates potent and durable clinical efficacy as well as excellent tolerability in combination with nivolumab supporting further clinical development. M. Haake: A. Employment (full or part-time); Significant; Catalym GmbH. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; Catalym GmbH. N. Vashist: A. Employment (full or part-time); Significant; Catalym GmbH. K. Eichler: A. Employment (full or part-time); Significant; Catalym GmbH. M. Kist: A. Employment (full or part-time); Significant; Catalym GmbH. S. Genßler: A. Employment (full or part-time); Significant; Catalym GmbH. I. Giese: A. Employment (full or part-time); Significant; Catalym GmbH. J. Weigandt: A. Employment (full or part-time); Significant; Catalym GmbH. K. Klar: A. Employment (full or part-time); Significant; Catalym GmbH. P. Fettes: A. Employment (full or part-time); Significant; CatalYm GmbH. T. Ross: A. Employment (full or part-time); Significant; Catalym GmbH. J. Wischhusen: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; CatalYm GmbH. C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Significant; CatalYm GmbH. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; CatalYm GmbH. F. Consultant/Advisory Board; Significant; CatalYm GmbH. E. Leo: E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; CatalYm GmbH. F. Consultant/Advisory Board; Significant; CatalYm GmbH. C. Schuberth-Wagner: A. Employment (full or part-time); Significant; CatalYm GmbH. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; CatalYm GmbH.