Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours.

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Cancer immunotherapies targeting immune checkpoints have improved treatment outcomes but face limitations due to resistance.
• Tumor microenvironment factors, such as growth differentiation factor 15 (GDF-15), can suppress anti-tumor immune responses.
• Preclinical studies suggest GDF-15 blockade can enhance the efficacy of checkpoint inhibitors like anti-PD-1.

Purpose of the Study:

• To evaluate the safety and efficacy of combining a neutralizing anti-GDF-15 antibody (visugromab) with an anti-PD-1 antibody (nivolumab) in patients with advanced cancers resistant to anti-PD-1/PD-L1 therapy.
• To identify cancer types where GDF-15 plays a significant immunosuppressive role.

Main Methods:

• A first-in-human Phase 1-2a clinical trial (GDFATHER-1/2a) was conducted.
• Patients with advanced cancers refractory to anti-PD-1/PD-L1 therapy received visugromab plus nivolumab.
• In silico screening of The Cancer Genome Atlas database was performed to identify GDF-15-immunosuppressed tumors.

Main Results:

• Durable and deep responses were observed in some patients, particularly those with non-squamous non-small cell lung cancer and urothelial cancer.
• These cancer types were identified as frequently immunosuppressed by GDF-15.
• Treatment led to increased tumor infiltration, proliferation, interferon-γ signaling, and granzyme B expression by cytotoxic T cells.

Conclusions:

• Neutralizing GDF-15 in combination with anti-PD-1 therapy is a promising strategy to overcome resistance to immune checkpoint inhibition.
• This combination therapy demonstrates potential for treating patients with advanced cancers refractory to current immunotherapies.
• Targeting GDF-15 may enhance anti-tumor immunity by improving T cell function within the tumor microenvironment.