Kaptein, Jacoberger-Foissac, and Dimitriadis et al. showed that pretreatment biopsies of patients with stage III melanoma resistant to dual ICB (anti-CTLA-4 + anti-PD-1) had a low CD4+ T cell/IL-2 gene profile. Ex vivo, in fragments of dual ICB-resistant patients’ tumor biopsies, adding IL-2 to dual ICB induced T cell activation, particularly of FOXP3+ CD4+ T cells, and cytotoxic mediator production. In a metastatic triple-negative breast cancer mouse model, adding IL-2 to dual ICB boosted efficacy, activated and expanded the TCR repertoire of tumor-specific CD8+ Teff cells that were primed by CD4+ T cells, and increased proinflammatory TH1 cytokine production.
Contributed by Paula Hochman
ABSTRACT: 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.
Author Info: (1) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands. (2) QIMR Berghofer Medical Research Institute, Brisbane, Queensland
Author Info: (1) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands. (2) QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. (3) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands. (4) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands. (5) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands. (6) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands. (7) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands. (8) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands. (9) QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. (10) QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. School of Medicine, University of Queensland, Herston, Queensland 4006, Australia. (11) QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. (12) QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. (13) Melanoma Institute Australia, University of Sydney, Sydney 2006, Australia. Faculty of Medicine and Health, University of Sydney, Sydney 2006, Australia. Royal North Shore and Mater Hospitals, Sydney 2065, Australia. (14) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands. (15) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands. (16) QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. School of Medicine, University of Queensland, Herston, Queensland 4006, Australia.
