Breaking the Barrier: Neutralizing GDF-15 to Combat Checkpoint Inhibitor Resistance in Solid Tumors

A New Frontier in Cancer Immunotherapy

Immunotherapy has transformed cancer treatment over the last two decades. By harnessing the body’s immune system, therapies such as anti-PD-1 and anti-PD-L1 checkpoint inhibitors have offered hope for patients battling a range of solid tumors. However, despite these breakthroughs, their efficacy is limited. A significant proportion of patients experience tumor progression or relapse, emphasizing the need to address resistance mechanisms within the tumor microenvironment (TME). One emerging culprit is growth differentiation factor 15 (GDF-15), a cytokine overproduced by many tumors to suppress immune activity.

Recent preclinical and clinical studies shed light on the potential of neutralizing GDF-15 to enhance immunotherapy efficacy. Notably, the combination of visugromab, a neutralizing anti-GDF-15 antibody, with nivolumab (an anti-PD-1 antibody) shows promise in overcoming resistance, particularly in tumors heavily influenced by GDF-15, such as non-squamous non-small cell lung cancer (NSCLC) and urothelial carcinoma (UC).

The Role of GDF-15: Immune Suppressor in the Tumor Microenvironment

A Master of Immune Evasion

GDF-15, a member of the transforming growth factor-β (TGF-β) superfamily, plays a pivotal role in immune suppression within the TME. Physiologically, GDF-15 contributes to maternal-fetal tolerance during pregnancy by preventing immune rejection of the fetus. Tumors co-opt this mechanism to evade immune surveillance by inhibiting T-cell infiltration and activity.

In cancer, GDF-15 interferes with the LFA-1–ICAM-1 axis, crucial for T-cell adhesion and migration into tumor tissues. By doing so, it not only limits immune cell infiltration but also disrupts cytotoxic T-cell functionality, dampening the effects of checkpoint inhibitors. The high expression of GDF-15 in many tumors correlates with immune exclusion, tumor progression, and resistance to immunotherapies.

Targeting GDF-15: A Rationale for Neutralization

Neutralizing GDF-15 restores immune cell infiltration and functionality, thereby synergizing with checkpoint inhibitors. Preclinical models demonstrate that GDF-15 blockade enhances T-cell activation, proliferation, and cytotoxicity, laying the groundwork for clinical investigations of visugromab in combination with anti-PD-1 therapies.

The GDFATHER Trial: A Landmark Clinical Study

Phase 1 Insights: Establishing Safety and Tolerability

The GDFATHER trial represents a first-in-human exploration of visugromab. Phase 1 focused on patients with advanced, treatment-refractory solid tumors who had already failed prior anti-PD-1/PD-L1 therapies. Using a dose-escalation approach, patients received visugromab alone for one cycle, followed by its combination with nivolumab in subsequent cycles.

Findings from this phase demonstrated the safety of visugromab across all dose levels. Treatment-emergent adverse events (TEAEs) were generally manageable, with no dose-limiting toxicities reported. Most notably, visugromab’s pharmacodynamics showed promising increases in intratumoral T-cell infiltration and activation, even during the monotherapy phase.

Phase 2a: Identifying Efficacy in Targeted Tumor Types

Building on phase 1 results, the phase 2a trial targeted specific tumor types known to be immunosuppressed by GDF-15: non-squamous NSCLC and UC. Integrative transcriptomic analyses of The Cancer Genome Atlas (TCGA) data revealed these cancers as having a significant inverse relationship between GDF-15 expression and T-cell infiltration.

In these cohorts, the combination of visugromab and nivolumab showed durable responses, particularly in patients whose tumors previously resisted checkpoint inhibitors. Remarkably, response rates in non-squamous NSCLC reached nearly 19%, while UC patients demonstrated a response rate of 18.5%. These outcomes highlight the potential of GDF-15 blockade to restore sensitivity to immune checkpoint inhibition.

Pharmacodynamic Observations: Restoring Immune Functionality

Enhanced T-Cell Proliferation and Cytotoxicity

Sequential biopsies during the trial revealed significant increases in CD8+ T-cell infiltration, proliferation, and granzyme B expression within tumors. These changes were observed as early as day 14 of treatment, with further amplification upon combination therapy with nivolumab.

Interestingly, the absence of T-cell exhaustion markers such as PD-1 and LAG3 suggested that visugromab reactivated immune responses without inducing further exhaustion, a crucial factor for long-term efficacy.

Interferon-γ-Related Gene Induction

Gene expression analyses confirmed the activation of inflammatory pathways, particularly those related to interferon-γ signaling. Elevated levels of chemokines such as CXCL9 and CXCL10 were observed in both serum and tumor biopsies, further corroborating the recruitment and activation of cytotoxic immune cells.

Clinical Activity: Responses Beyond Prior Limitations

Objective Responses in Non-Squamous NSCLC

Among heavily pretreated non-squamous NSCLC patients, durable partial and complete responses were achieved. These responses occurred across both PD-L1-positive and -negative tumors, suggesting that visugromab’s effects may transcend traditional biomarkers of checkpoint inhibitor sensitivity.

Durable Efficacy in Urothelial Carcinoma

Similarly, in the UC cohort, visugromab demonstrated notable activity, with a significant proportion of patients achieving deep tumor regressions and prolonged disease stabilization. The observed response durations far exceeded those typically seen with standard-of-care therapies in refractory settings.

Safety Profile: Navigating Adverse Events

While the combination of visugromab and nivolumab was generally well-tolerated, some TEAEs, including immune-mediated pneumonitis and organ dysfunction, were reported. Importantly, these events were consistent with known risks of immune checkpoint inhibitors, underscoring the manageable safety profile of this novel combination.

Broader Implications: A Paradigm Shift in Immunotherapy

A Biomarker-Driven Approach

The findings from the GDFATHER trial open new avenues for biomarker-driven cancer immunotherapy. While baseline serum GDF-15 levels were not predictive of response, tumor-specific characteristics such as T-cell density and PD-L1 expression may serve as useful indicators for patient selection in future studies.

Expanding the Horizon

The success of visugromab in heavily pretreated patients paves the way for its evaluation in earlier lines of therapy. Additionally, its potential synergy with other immunomodulatory agents, such as anti-TGF-β therapies, warrants exploration in diverse cancer types.

Future Directions: Harnessing GDF-15 Blockade

The results of the GDFATHER trial highlight the transformative potential of neutralizing GDF-15 in overcoming resistance to checkpoint inhibitors. As clinical investigations progress, visugromab may redefine the therapeutic landscape for patients with refractory solid tumors. By addressing one of the most critical barriers in cancer immunotherapy, GDF-15 blockade offers hope for a future where immune resistance is no longer an insurmountable challenge.

Study DOI: https://doi.org/10.1038/s41586-024-08305-z

Engr. Dex Marco Tiu Guibelondo, B.Sc. Pharm, R.Ph., B.Sc. CpE

Editor-in-Chief, PharmaFEATURES