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Addition of interleukin-2 overcomes resistance to neoadjuvant CTLA4 and PD1 blockade in ex vivo patient tumors.
- Source :
- Science Translational Medicine; 4/27/2022, Vol. 14 Issue 642, p1-15, 15p
- Publication Year :
- 2022
-
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<superscript>+</superscript> T cells and improved proinflammatory cytokine polyfunctionality of both CD4<superscript>+</superscript> and CD8<superscript>+</superscript> T effector cells and regulatory T cells. Depletion studies suggested that CD4<superscript>+</superscript> T cells were critical for priming of CD8<superscript>+</superscript> T cell immunity against 4T1.2 and helped in the expansion of tumor-specific CD8<superscript>+</superscript> 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<superscript>+</superscript> 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]
Details
- Language :
- English
- ISSN :
- 19466234
- Volume :
- 14
- Issue :
- 642
- Database :
- Complementary Index
- Journal :
- Science Translational Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 156492314
- Full Text :
- https://doi.org/10.1126/scitranslmed.abj9779