1. Combined immunotherapy: CTLA-4 blockade potentiates anti-tumor response induced by transcutaneous immunization.
- Author
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Rausch J, Lopez PA, Bialojan A, Denny M, Langguth P, Probst HC, Schild H, and Radsak MP
- Subjects
- Adjuvants, Immunologic therapeutic use, Aminoquinolines pharmacology, Aminoquinolines therapeutic use, Animals, Antineoplastic Agents, Immunological therapeutic use, CTLA-4 Antigen immunology, Drug Synergism, Flow Cytometry, Humans, Imiquimod, Immunologic Memory drug effects, Immunotherapy methods, Melanoma, Experimental immunology, Melanoma, Experimental mortality, Membrane Glycoproteins antagonists & inhibitors, Mice, Mice, Inbred C57BL, Ovalbumin pharmacology, Ovalbumin therapeutic use, Peptide Fragments pharmacology, Peptide Fragments therapeutic use, Skin Neoplasms immunology, Skin Neoplasms mortality, T-Lymphocytes, Cytotoxic metabolism, T-Lymphocytes, Regulatory metabolism, Toll-Like Receptor 7 antagonists & inhibitors, Xenograft Model Antitumor Assays, Adjuvants, Immunologic pharmacology, Antineoplastic Agents, Immunological pharmacology, CTLA-4 Antigen antagonists & inhibitors, Melanoma, Experimental therapy, Skin Neoplasms therapy, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Background: The epidermal application of the Toll Like Receptor 7 agonist imiquimod and a T-cell peptide epitope (transcutaneous immunization, TCI) mediates systemic peptide-specific cytotoxic T-cell (CTL) responses and leads to tumor protection in a prophylactic tumor setting. However, it does not accomplish memory formation or permanent defiance of tumors in a therapeutic set-up. As a distinct immunologic approach, CTLA-4 blockade augments systemic immune responses and has shown long-lasting effects in preclinical experiments as well as in clinical trials., Objective: The study investigates the vaccination capacity of TCI in combination with the checkpoint inhibitor CTLA-4 in matters of primary response, memory formation and tumor protection and characterizes the role of regulatory T cells (Tregs)., Methods: After performing TCI with IMI-Sol (containing 5% Imiquimod) and the model epitope SIINFEKL, 6-8 week old C57BL/6 mice received anti-CTLA-4 antibody either s.c or i.p. The CTL responses and frequency of peptide specific CD8
+ T-cells were then evaluated on day 8. To determine anti-tumor effects, a therapeutic tumor challenge with B16 OVA melanoma was performed., Results: The combination of s.c. anti-CTLA-4 antibody and TCI leads to an enhanced systemic cytotoxic response, to memory formation and allows significantly improved survival in a tumor setting with B16 OVA melanoma. Towards the mechanism, we show that in this vaccination protocol the CTLA-4 antibody acts mainly Treg-independent., Conclusion: We demonstrate that the combination of TCI with IMI-Sol and anti-CTLA-4 can confer potent immune responses and tumor-protection. These results might contribute to the development of advanced vaccination approaches targeting tumors or persistent infectious diseases., (Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)- Published
- 2017
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