In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment

• Published in: Vaccine Vol. 33; no. 51; pp. 7415 - 7422
• Main Authors: Vanpouille-Box, Claire, Pilones, Karsten A, Wennerberg, Erik, Formenti, Silvia C, Demaria, Sandra
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 16.12.2015; Elsevier Limited
• Subjects: Abscopal effect; Allergy and Immunology; Animals; Antigens; Apoptosis; Brain research; Breast cancer; Cancer therapies; Chemotherapy; Clinical trials; CTLA-4 Antigen - metabolism; Disease Models, Animal; Head & neck cancer; Humans; Hypotheses; Immmune checkpoint; Immune system; Immunotherapy; Ionizing radiation; Lymphocytes; Medical research; Melanoma; Metastasis; Mice; Neoplasms - therapy; Proteins; Radiation therapy; Radiation-induced vaccination; Radiotherapy - methods; Skin cancer; T-Lymphocytes - immunology; Tumors; Vaccination - methods; Immmune checkpoint; Radiation-induced vaccination; Abscopal effect; Immunotherapy
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2015.05.105

Abstract Targeting immune checkpoint receptors has emerged as an effective strategy to induce immune-mediated cancer regression in the subset of patients who have significant pre-existing anti-tumor immunity. For the remainder, effective anti tumor responses may require vaccination. Radiotherapy, traditionally used to achieve local tumor control, has acquired a new role, that of a partner for immunotherapy. Ionizing radiation has pro-inflammatory effects that facilitate tumor rejection. Radiation alters the tumor to enhance the concentration of effector T cells via induction of chemokines, cytokines and adhesion molecules. In parallel, radiation can induce an immunogenic death of cancer cells, promoting cross-presentation of tumor-derived antigens by dendritic cells to T cells. Newly generated anti-tumor immune responses have been demonstrated post-radiation in both murine models and occasional patients, supporting the hypothesis that the irradiated tumor can become an in situ vaccine. It is in this role, that radiation can be applied to induce anti-tumor T cells in lymphocyte-poor tumors, and possibly benefit patients who would otherwise fail to respond to immune checkpoint inhibitors. This review summarizes preclinical and clinical data demonstrating that radiation acts in concert with antibodies targeting the immune checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4), to induce therapeutically effective anti-tumor T cell responses in tumors otherwise non responsive to anti-CTLA-4 therapy.