Dr Tarhini on the Combination of High-Dose Bolus IL-2 and CTLA-4 Inhibition in Advanced Melanoma

Ahmad Tarhini, MD, PhD, director, Cutaneous Clinical and Translational Research, leader, Neoadjuvant and Adjuvant Translational Science Program, senior member, Moffitt Cancer Center, Research Institute Departments of Cutaneous Oncology and Immunology; professor, Oncologic Sciences, the University of South Florida Morsani College of Medicine; chair, Scientific Committee, Oncology Research Information Exchange Network (ORIEN); chair, ORIEN ImmunoOncology Research Subcommittee, discusses the rationale for investigating high-dose bolus interleukin-2 (IL-2) plus concurrent low-dose ipilimumab (Yervoy), followed sequentially by nivolumab (Opdivo), in patients with advanced melanoma.

At the 2024 ASCO Annual Meeting, investigators presented data on this combination in patients who had previously progressed on anti–PD1-based immunotherapy and BRAF-MEK inhibition. Tarhini states that the hypothesis for the study was that the pro-inflammatory cytokine IL-2 may work synergistically with CTLA-4 blockade to enhance the immunogenicity of the tumor microenvironment (TME). This hypothesis was grounded in preclinical animal model data that have demonstrated the necessity of high concentrations of IL-2 to achieve the antitumor activity associated with CTLA-4 blockade, he explains.

Further supporting this hypothesis, other animal model studies have shown that the combination of IL-2 and PD-L1 blockade may reinvigorate exhausted T cells, leading to an increased expansion of CD8-positive T cells and improved T-cell function, Tarhini continues. The combination may upregulate immune responses, he notes. Additionally, prior research has highlighted the ability of the anti–CTLA-4 agent ipilimumab to induce a significant infiltration of CD8-positive T cells into the TME, supporting the potential benefits of combining these treatments, according to Tarhini.

Building on these findings, investigators designed a phase 2 clinical trial to explore the effects of combining IL-2 with an anti–CTLA-4 agent, Tarhini reports. In this study, IL-2 and ipilimumab were administered concurrently, followed sequentially by anti–PD-1 therapy. This design leveraged the potential synergistic effects of these agents to enhance the overall antitumor immune response, offering a promising approach to improving therapeutic outcomes in patients with cancer, he states. Through this study, investigators provided further insight into the complex interactions within the TME and identified an effective treatment strategy for patients with advanced melanoma, Tarhini concludes.