GDF-15’s role in resistance to cancer immunotherapy was reinforced in a Nature Communications study published today. The researchers demonstrated that GDF-15 blocks LFA-1-dependent T cell recruitment into the tumor microenvironment, a prerequisite for responses to anti-PD-1/-L1 treatment and other immunotherapeutic strategies.
This, the authors say, is the first paper to describe a mechanistic link between tumor-produced Growth Differentiation Factor-15 (GDF-15) and the LFA-1/ICAM-1 cell adhesion axis.
The senior author is CatalYm co-founder Jörg Wischhusen, a professor at the Julius-Maximillians-University Würzburg. CatalYm has a pipeline of proprietary anti-GDF-15 antibody candidates, including visugromab, which is in advanced Phase II clinical studies.
The interaction between LFA-1/ICAM-1 is a critical step in the infiltration of T cells into the tumor microenvironment. GDF-15 is primarily known for its function in feto-maternal tolerance, an immunosuppressive mechanism that protects the fetus from the mother’s immune system.
These researchers showed not only that GDF-15 blocks LFA-1-dependent T cell recruitment into the tumor microenvironment, but also that, conversely, the blockade of GDF-15 with antibodies like visugromab improved T cell infiltration into tumors.
Combined with a PD-1 inhibitor, GDF-15 inhibition increased tumor clearance and survival with a synergistic effect. In line with these findings, serum analysis of melanoma patients showed that response to anti-PD-1 negatively correlates with GDF-15 serum levels. Therefore, the researchers suggest, GDF-15 serum levels may be a predictive biomarker for the response to anti-PD-1 therapy and overall survival in these patients.
These findings further underscore the immunosuppressive role of GDF-15 in the tumor and contribute to the growing body of data supporting GDF-15-neutralizing therapy as a promising approach for hard-to-treat tumors resistant or refractory to anti-PD-1/-L1 treatment.
“Our publication is the first to demonstrate the effect of tumor-derived GDF-15 on the LFA-1/ICAM-1 axis. As this axis orchestrates cell-cell-interactions that are essential for immune-mediated tumor control, GDF-15 likely contributes to immune escape across many different tumors and therapies,” said Wischhusen.
“Unraveling the details of the underlying biologic pathways is crucial to develop effective therapeutic approaches that can reverse tumor-mediated immunosuppression resulting in drug resistance, one of the major challenges in cancer medicine,” added Christine Schuberth-Wagner, Chief Scientific Officer at CatalYm.
Visugromab is a humanized monoclonal antibody that neutralizes GDF-15, thereby reversing the immunosuppressive effects that block an efficient anti-tumor immune response in the tumor microenvironment and the draining lymph nodes. Visugromab, its developers say, drives an activated and differentiated immune cell infiltration into the solid tumor as well as enabling priming of T cells and enhances the tumor-killing effects of T cells and NK cells.
The drug is currently being investigated in an ongoing Phase II program that includes confirmatory studies in multiple solid tumor indications and the analysis of a predictive response biomarker to better identify the patients benefiting from this new class of immunotherapy.
Interim data from the Phase II (NCT04725474) trial recently presented at ASCO demonstrated a very good safety and tolerability profile and promising early responses in major cancer indications, including non-small cell lung cancer (NSCLC), bladder cancer and hepatocellular carcinoma (HCC). Mature data readouts for efficacy and safety data of the core Phase IIa program as well as main biomarker-correlations are expected to become available by late 2023.
