Report describes gdf-15 as a central factor of anti-PD-1 resistance

21 Jul 2023
Report describes gdf-15 as a central factor of anti-PD-1 resistance

CatalYm announced the publication of preclinical data in Nature Communications.  

The study reveals a central role of GDF-15 in the resistance of tumours to current immunotherapy.

These findings further highlight the therapeutic significance of CatalYm’s proprietary anti-GDF-15 antibody candidate, visugromab, currently in advanced phase 2 clinical studies.

This foundational research, which was performed together with founder Jörg Wischhusen and collaborators, is the first to describe a mechanistic link between tumour-produced Growth Differentiation Factor-15 (GDF-15) and the LFA-1/ICAM-1 cell adhesion axis.

The interaction between LFA-1/ICAM-1 is a critical step in the infiltration of T cells into the tumour microenvironment.

This is essential for the extravasation of T cells from the blood vessels into the surrounding tissue.

GDF-15 is primarily known for its function in foeto-maternal tolerance, an immunosuppressive mechanism that protects the foetus from the mother’s immune system. 

The researchers demonstrated that GDF-15 blocks LFA-1-dependent T cell recruitment into the tumour microenvironment, a prerequisite for responses to anti-PD-1/-L1 treatment but also other immunotherapeutic strategies.

Conversely, the blockade of GDF-15 with antibodies like the anti-GDF-15 antibody visugromab improved T cell infiltration into tumours.

Combined with a PD-1 inhibitor, it increased tumour 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, 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 tumour and contribute to the growing body of data supporting GDF-15-neutralising therapy as a promising approach for hard-to-treat tumours resistant or refractory to anti-PD-1/-L1 treatment.

"Our publication is the first to demonstrate the effect of tumour-derived GDF-15 on the LFA-1/ICAM-1 axis. As this axis orchestrates cell-cell-interactions that are essential for immune-mediated tumour control, GDF-15 likely contributes to immune escape across many different tumours and therapies,” said Prof Dr Jörg Wischhusen, Co-Founder of CatalYm and Professor at the Julius-Maximilians-University Würzburg, who is the senior author of the publication.

“Unravelling the details of the underlying biologic pathways is crucial to develop effective therapeutic approaches that can reverse tumour-mediated immunosuppression resulting in drug resistance, one of the major challenges in cancer medicine. We are committed to rapidly advancing our phase 2 evaluation of visugromab on our mission to expand the treatment horizon for current and future immunotherapies,” added Dr Christine Schuberth-Wagner, Chief Scientific Officer at CatalYm.

The published data adds further valuable mechanistic understanding to the clinical findings from CalaYm’s GDFather (GDF-15 Antibody-mediaTed Human Effector Cell Relocation) trials with visugromab in combination with the anti-PD-1 inhibitor nivolumab in patients with advanced solid tumours.

The phase 1 (NCT04725474) study results announced in September 2022 showed an excellent safety and tolerability profile as well as significant clinical benefit in last-line tumour patients that were anti-PD-1/-L1 relapsed or refractory.

Interim data from the phase 2 (NCT04725474) trial recently presented at ASCO continue to demonstrate 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 2a program as well as main biomarker-correlations are expected to become available by late 2023.

Article: Tumour-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment

Source: Trophic Communications