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Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours
Ignacio Melero1,2, Maria de Miguel Luken3, Guillermo de Velasco4
1Clínica Universidad de Navarra, CIMA, IDISNA and CIBERONC, Pamplona, Spain. imelero@unav.es.
Abstract:
Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment1. Yet, response rates are still limited, and tumour progression commonly occurs2. Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity. Recently, growth differentiation factor 15 (GDF-15), a cytokine that is abundantly produced by many cancer types, was shown to interfere with antitumour immune response. In preclinical cancer models, GDF-15 blockade synergistically enhanced the efficacy of anti-PD-1-mediated checkpoint inhibition3. In a first-in-human phase 1-2a study (GDFATHER-1/2a trial, NCT04725474 ), patients with advanced cancers refractory to anti-PD-1 or anti-PD-L1 therapy (termed generally as anti-PD-1/PD-L1 refractoriness) were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Here we show that durable and deep responses were achieved in some patients with non-squamous non-small cell lung cancer and urothelial cancer, two cancer entities identified as frequently immunosuppressed by GDF-15 in an in silico screening of approximately 10,000 tumour samples in The Cancer Genome Atlas database. Increased levels of tumour infiltration, proliferation, interferon-γ-related signalling and granzyme B expression by cytotoxic T cells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer.
Insights
Blocking growth differentiation factor 15 (GDF-15) with visugromab combined with anti-PD-1 therapy shows promise for overcoming resistance to cancer immunotherapy. This approach led to durable responses in patients with advanced cancers refractory to existing treatments.
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.
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