Neutralizing GDF-15 can overcome anti-PD-(L)1 resistance in late-stage cancer

Abstract Cancer immunotherapies with antibodies blocking immune checkpoint molecules are active treatments across multiple cancer entities and have markedly improved cancer treatment. Yet, response rates are still limited, and tumor progression commonly occurs. Soluble and cell-bound factors in the tumor microenvironment negatively impact on cancer immunity. Recently, Growth and Differentiation-factor 15 (GDF-15), a cytokine that is abundantly produced by many cancer types, was shown to interfere with anti-tumor immune response. In preclinical cancer models, GDF-15 blockade synergistically enhanced the efficacy of anti-PD-1 mediated checkpoint inhibition. In a first-in-human phase 1/2a study (GDFATHER-1/2a trial, NCT04725474), patients with advanced cancers refractory to anti-PD-(L)1 therapy were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Durable responses were achieved namely in patients with non-squamous non-small cell lung cancer and urothelial cancer, two cancer entities identified as frequently GDF-15 immunosuppressed in an in-silico 11,000 tumor TCGA data base screening. Increased tumor infiltrates, proliferation and Granzyme-B expression in cytotoxic T-cells were observed in response to therapy. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer.