The phase 2A GDFATHER-TRIAL has reported initial promising results for visugromab (CTL-002), a GDF-15 neutralizing antibody, in combination with nivolumab for patients with advanced or metastatic solid tumors that have relapsed or become refractory to prior anti-PD-1/PD-L1 therapy. The study represents a novel approach to overcoming immunotherapy resistance by targeting the Growth and Differentiation Factor 15 (GDF-15) pathway.
Targeting GDF-15 to Overcome Immunotherapy Resistance
Increasing evidence has emerged that GDF-15 plays a critical role in tumoral immunosuppression. The protein not only blocks immune cell entry into the tumor microenvironment but also has a major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block immunotherapy success.
GDF-15 is a TGF-β superfamily member that is physiologically expressed mainly in placenta and linked to feto-maternal tolerance. Under pathophysiologic conditions, prevention of excessive immune cell infiltration during tissue damage and cachexia induction have been ascribed to GDF-15. A recent study elucidated a mechanism by which GDF-15 inhibits LFA-1 activation on CD8+ T cells, thus interfering with effector T cell recruitment to tissues.
Clinical Significance and Rationale
Several cancer entities secrete high levels of GDF-15, correlating with poor prognosis and reduced overall survival. To block this effect, the GDF-15 neutralizing antibody CTL-002 was generated. In preclinical models, CTL-002 demonstrated potent effector T cell shifting into tumor tissue by neutralizing GDF-15.
The GDFATHER-TRIAL builds upon earlier phase I first-in-human clinical trial results of CTL-002 in subjects with advanced-stage solid tumors. The progression to phase 2A represents a significant advancement in evaluating this novel therapeutic approach for patients who have exhausted standard immunotherapy options.
Addressing Unmet Medical Need
The combination of visugromab with nivolumab addresses a critical gap in cancer treatment for patients whose tumors have become resistant to checkpoint inhibitor therapy. The mechanism of action differs from traditional immunotherapy approaches by specifically targeting the GDF-15 pathway that tumors use to evade immune surveillance.
This therapeutic strategy offers potential for patients with anti-PD-1/PD-L1 relapsed or refractory solid tumors, a population with limited treatment options and poor prognosis. By neutralizing GDF-15's immunosuppressive effects, the combination therapy aims to restore the tumor microenvironment's susceptibility to immune-mediated destruction.
The GDFATHER-TRIAL's initial results provide important proof-of-concept data for this novel mechanism of overcoming immunotherapy resistance, potentially opening new avenues for treating patients with checkpoint inhibitor-refractory cancers.
