Breakthrough in Overcoming Immune Therapy Resistance

A new study published today in Nature Communications uncovers that the cytokine GDF-15 inhibits T cell infiltration into tumors, opening up promising new pathways for cancer therapy. Researchers from Würzburg University Hospital and the biotech spin-off CatalYm have demonstrated that high GDF-15 levels predict resistance to PD-1-based immune checkpoint blockade therapy. Neutralizing GDF-15 in preclinical mouse models of GDF-15-expressing cancers significantly boosted T cell infiltration and enhanced the therapeutic efficacy of immune checkpoint blockade. This discovery offers a promising target for enhancing the efficacy of immunotherapy across various types.
Breakthrough in overcoming immune therapy resistance. Blocking GDF-15 enables tumor-specific immune cells to overcome a roadblock for attacking cancer cells. Cytotoxic immune cells killing cancer cell get the required push in checkpoint-inhibitor resistant cancer. Andreas Beilhack lab advancing cancer immunotherapy, Würzburg University Hospital, Germany, Europe.

Blocking GDF-15 enables tumor-specific immune cells to overcome a roadblock for attacking cancer cells.

The team lead by our collaboration partner Prof. Jörg Wischhusen, who is also the scientific cofounder of CatalYm, uncovered that GDF-15 disrupts the LFA-1/β2-integrin-mediated adhesion of T cells to endothelial cells, a critical step for T cell extravasation into tumors. This blockage hinders the immune system’s ability to attack cancer cells effectively.

“Our research shows that GDF-15 acts as a gatekeeper, preventing T cells from entering the tumor environment and neutralizing immune therapy’s effectiveness,” said Dr. Markus Haake, former senior scientist in the Wischhusen lab and now Vice President of Pharmacology at CatalYm and lead author of the study. “Neutralizing GDF-15 improves T cell trafficking and enhances therapeutic outcomes in preclinical models.”

In melanoma patients, elevated GDF-15 serum levels strongly correlate with poor response rates to PD-1 inhibitors. Neutralizing GDF-15 not only improved T cell infiltration but also enhanced the success of immune therapies in murine models, suggesting a potential for broader applications.

CatalYm’s antibody Visugromab, designed to neutralize GDF-15, is currently undergoing Phase-2 clinical trials (GDFATHER study), showing promise in improving outcomes for patients unresponsive to current treatments.

“Neutralizing GDF-15 could revolutionize cancer therapy, providing new hope for patients who currently have limited options,” added Prof. Dr. Jörg Wischhusen, senior author of the study. “This breakthrough underscores the critical role of GDF-15 in immune therapy resistance and highlights the potential of GDF-15-targeted therapies in oncology.”

For more information, visit the press release in German.

Publication Reference:

Haake M, Haack B, Schäfer T, Harter PN, Mattavelli G, Eiring P, Vashist N, Wedekink F, Genssler S, Fischer B, Dahlhoff J, Mokthari F, Kuzkina A, Welters MJP, Benz TM, Sorger L, Thiemann V, Amanzar G, Selle M, Thein K, Späth J, Gonzalez MC, Reitinger C, Ipsen-Escobedo A, Wistuba-Hamprecht K, Eichler K, Filipski K, Zeiner PS, Beschorner R, Goedemans R, Gogolla FH, Hackl H, Rosswinkel RW, Thiem A, Romer Roche P, Joshi H, Pühringer D, Wöckel A, Diessner JE, Rüdiger M, Leo E, Cheng PF, Levesque PFP, Goebeler M, Sauer M, Nimmerjahn F, Schuberth-Wagner C, Von Felten S, Mittelbronn M, Mehling M, Beilhack A, van der Burg SH, Riedel A, Weide B, Dummer R, Wischhusen J. (2023). Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nature Communications 14(1):4253.