Academic Background and Problem Statement

In recent years, immune checkpoint inhibitors (ICIs) have made significant progress in cancer treatment, particularly anti-PD-1 and anti-PD-L1 antibodies, which have become the standard of care for first-line treatment in various cancers. However, despite the notable clinical activity of these therapies in some patients, the overall response rates remain limited, and many patients eventually experience tumor progression or relapse. Studies have shown that soluble and cell-bound factors in the tumor microenvironment (TME) negatively impact cancer immune responses. Among these factors, Growth Differentiation Factor 15 (GDF-15), a cytokine abundantly produced by many cancer types, has been found to interfere with anti-tumor immune responses. Preclinical models have demonstrated that blocking GDF-15 synergistically enhances the efficacy of anti-PD-1 therapy, suggesting that GDF-15 could be a novel target to overcome resistance to immune checkpoint inhibitors.

Source and Author Information

This paper was co-authored by Ignacio Melero and colleagues from multiple research institutions, including Clínica Universidad de Navarra, University of Oxford, and Vall d’Hebron Institute of Oncology. The paper was published online on October 29, 2024, in the journal Nature, titled “Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours.”

Research Process and Experimental Design

1. Preclinical Research and Discovery of GDF-15

In preclinical studies, GDF-15 was found to inhibit T cell migration and function, thereby interfering with anti-tumor immune responses. Specifically, in tumor models expressing GDF-15, blocking GDF-15 significantly enhanced the efficacy of anti-PD-1 therapy. This discovery laid the foundation for subsequent clinical trials.

2. Clinical Trial Design: GDFATHER-1/2a Trial

The GDFATHER-1/2a trial was a first-in-human Phase I/IIa clinical trial (NCT04725474) exploring the GDF-15 neutralizing antibody Visugromab (CTL-002). The trial was divided into two parts: - Phase I (Dose Escalation): A classic “3+3” dose escalation design was used, with 25 patients with advanced solid tumors receiving Visugromab in combination with the anti-PD-1 antibody Nivolumab. Visugromab doses ranged from 0.3 mg/kg to 20 mg/kg, administered every two weeks. - Phase IIa (Expansion): After determining the recommended dose, the antitumor activity of Visugromab in combination with Nivolumab was further evaluated in specific tumor types.

3. Sample Collection and Data Analysis

In the Phase I trial, patients underwent tumor biopsies at baseline, day 14, and day 28 to assess changes in T cell infiltration, proliferation, and function. Using immunohistochemistry and immunofluorescence, researchers quantified the number of CD4+, CD8+, CD3+Ki67+, and CD3+GZMB+ T cells in tumor tissues. Additionally, RNA sequencing was used to analyze changes in interferon-γ (IFN-γ)-related gene expression in tumor tissues.

4. Pharmacokinetics and Pharmacodynamics Modeling

Through serum sample analysis, researchers developed pharmacokinetic (PK) and pharmacodynamic (PD) models for Visugromab, predicting the concentration of free GDF-15 in serum and tumor microvasculature at different doses. The model suggested that a dose of 10 mg/kg every two weeks was necessary to maintain GDF-15 neutralization.

Key Findings

1. Safety Assessment

The combination of Visugromab and Nivolumab was well-tolerated at all dose levels, with no dose-limiting toxicities observed. The most common grade 3 or higher adverse events were acute respiratory failure and gastrointestinal disorders.

2. Antitumor Activity

In the Phase I trial, five patients showed clinical benefit, with three achieving partial responses (PR) and one achieving a complete response (CR). In the Phase IIa trial, overall response rates (ORR) of 14.8% and 18.5% were observed in non-small cell lung cancer (NSCLC) and urothelial carcinoma (UC) patients, respectively. Notably, these patients had previously failed anti-PD-1 or anti-PD-L1 therapy.

3. Changes in the Immune Microenvironment

Neutralization of GDF-15 significantly increased T cell infiltration and proliferation in tumor tissues, particularly CD8+ T cells and CD3+Ki67+ T cells. Additionally, treatment induced the expression of IFN-γ-related genes, indicating that GDF-15 blockade could reverse the immunosuppressive state in the tumor microenvironment.

Conclusions and Significance

This study demonstrates that GDF-15 plays a significant immunosuppressive role in the tumor microenvironment, and its blockade can significantly enhance the efficacy of anti-PD-1 therapy. The combination of Visugromab and Nivolumab showed durable antitumor activity in patients who had failed prior anti-PD-1 or anti-PD-L1 therapy, particularly in NSCLC and UC patients. This finding provides a new therapeutic strategy to overcome resistance to immune checkpoint inhibitors and has important clinical implications.

Research Highlights

1. GDF-15 as a Novel Immune Checkpoint: GDF-15 was identified as a new immunosuppressive factor, and its blockade significantly enhanced the efficacy of anti-PD-1 therapy.
2. First-in-Human Trial of Visugromab: Visugromab demonstrated good safety and significant antitumor activity in patients who had failed prior anti-PD-1 or anti-PD-L1 therapy.
3. Immune Remodeling of the Tumor Microenvironment: Neutralization of GDF-15 significantly increased T cell infiltration and proliferation, reversing the immunosuppressive state in the tumor microenvironment.

Future Research Directions

Although this study has yielded encouraging results, further large-scale clinical trials are needed to validate the efficacy of Visugromab in different tumor types and earlier stages of treatment. Additionally, exploring the potential of GDF-15 as a biomarker and its combination with other immunotherapies will be important directions for future research.