CatalYm has published preclinical data in Nature Communications revealing the central role of Growth Differentiating Factor-15 (GDF-15) in tumor resistance to current immunotherapies.
The company said the findings further highlight the therapeutic significance of its anti-GDF-15 antibody candidate, visugromab, which is currently in follow-up phase 2 clinical studies.
The baseline study, conducted with founder Jörg Wischhusen and collaborators, was the first to describe a mechanistic link between tumor-produced GDF-15 and the LFA-1/ICAM-1 cell adhesion axis. The LFA-1/ICAM-1 interaction is an important step in T-cell infiltration into the tumor microenvironment.
It is important for extravasation of T cells from blood vessels into surrounding tissues. GDF-15 is primarily known for its function in fetomaternal tolerance, an immunosuppressive mechanism that protects the fetus from the mother’s immune system.
The investigators demonstrated that GDF-15 blocks LFA-1-dependent recruitment of T cells into the tumor microenvironment, a prerequisite for response to anti-PD-1/-L1 treatment but also to other immunotherapeutic strategies. Conversely, blockade of GDF-15 with antibodies such as the anti-GDF-15 antibody visugromab increases T-cell infiltration into the tumor.
Combined with PD-1 inhibitors, it enhances tumor clearance and survival with a synergistic effect. Consistent with these findings, serum analysis of melanoma patients showed that response to anti-PD-1 was negatively correlated with serum GDF-15 levels. Therefore, serum GDF-15 levels may be a predictive biomarker for response to anti-PD-1 therapy and overall survival in these patients.
A promising approach to tumor treatment
These findings further underscore the immunosuppressive role of GDF-15 in tumors and contribute to a growing body of data supporting GDF-15 neutralizing therapy as a promising approach for difficult-to-treat tumors that are 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. Because this axis regulates cell-cell interactions important for immune-mediated control of tumors, GDF-15 likely contributes to immune escape in many different tumors and therapies,” said Jörg Wischhusen, co-founder of CatalYm and professor at University Hospital/Julius-Maximilians-University Würzburg, who is senior author of this publication.
“Unraveling the details of the underlying biological pathways is critical to developing effective therapeutic approaches that can reverse tumor-mediated immunosuppression resulting in drug resistance, one of the major challenges in cancer treatment. We are committed to accelerating our phase 2 evaluation of visugromab in our mission to broaden the treatment horizon for current and future immunotherapies,” added Christine Schuberth-Wagner, chief scientific officer at CatalYm.
The published data add further valuable mechanistic insight to the clinical findings of the GDFather CalaYm (GDF-15 Antibody-mediated Human Effector Cell Relocation) trial with visugromab in combination with the anti-PD-1 inhibitor nivolumab in patients with advanced solid tumors.
Data until the end of 2023
The results of a phase 1 study announced in September 2022 demonstrated an excellent safety and tolerability profile as well as significant clinical benefit in patients with relapsed or refractory anti-PD-1/-L1 last-line tumors.
Interim data from phase 2 trials continue to demonstrate excellent safety and tolerability profiles and promising early responses in major cancer indications, including small cell lung cancer (NSCLC), bladder cancer and hepatocellular carcinoma (HCC). Mature data readouts of phase 2a core program efficacy and safety data as well as key biomarker correlations are expected to be available by the end of 2023.
In November, the company raised €50 million to support its clinical trials. At the time of the financing, Phil L’Huillier, chief executive officer at CatalYm, said that visugrob “…emerges as a new anticancer immunotherapy drug with the potential to transform the immuno-oncology landscape.”