Addition of interleukin-2 overcomes resistance to neoadjuvant CTLA4 and PD1 blockade in ex vivo patient tumors.

Neoadjuvant immunotherapy with anti-cytotoxic T lymphocyte–associated protein 4 (CTLA4) + anti–programmed cell death protein 1 (PD1) monoclonal antibodies has demonstrated remarkable pathological responses and relapse-free survival in ~80% of patients with clinically detectable stage III melanoma. However, about 20% of the treated patients do not respond. In pretreatment biopsies of patients with melanoma, we found that resistance to neoadjuvant CTLA4 + PD1 blockade was associated with a low CD4/interleukin-2 (IL-2) gene signature. Ex vivo, addition of IL-2 to CTLA4 + PD1 blockade induced T cell activation and deep immunological responses in anti-CTLA4 + anti-PD1–resistant human tumor specimens. In the 4T1.2 breast cancer mouse model of neoadjuvant immunotherapy, triple combination of anti-CTLA4 + anti-PD1 + IL-2 cured almost twice as many mice as compared with dual checkpoint inhibitor therapy. This improved efficacy was due to the expansion of tumor-specific CD8⁺ T cells and improved proinflammatory cytokine polyfunctionality of both CD4⁺ and CD8⁺ T effector cells and regulatory T cells. Depletion studies suggested that CD4⁺ T cells were critical for priming of CD8⁺ T cell immunity against 4T1.2 and helped in the expansion of tumor-specific CD8⁺ T cells early after neoadjuvant triple immunotherapy. Our results suggest that the addition of IL-2 can overcome resistance to neoadjuvant anti-CTLA4 + anti-PD1, providing the rationale for testing this combination as a neoadjuvant therapy in patients with early-stage cancer. Immunotherapy triple threat: Some patients with melanoma do not respond to dual immunotherapy of anti-cytotoxic T lymphocyte–associated protein 4 (CTLA4) and anti–programmed cell death protein 1 (PD1). Kaptein et al. identified a low interleukin 2 (IL-2) gene signature associated with resistance in patients with melanoma. The addition of IL-2 to dual immunotherapy treatment of resistant ex vivo patient samples and mouse models induced immunological responses and extended survival. Therapy expanded tumor-specific CD8⁺ T cells and improved proinflammatory cytokine polyfunctionality of T cells in vivo. Triple-combination immunotherapy can overcome resistance to dual neoadjuvant immunotherapy and warrants further testing in patients with early-stage melanoma. [ABSTRACT FROM AUTHOR]