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Enhancing Immune Responses to Cancer Vaccines Using Multi-Site Injections.

ABSTRACT: For a vaccine to be effective it must induce a sufficiently robust and specific immune response. Multi-site injection protocols can increase the titers of rabies virus-neutralizing antibodies. Hypothetically, spreading a vaccine dose across multiple lymphatic drainage regions could also potentiate T cell responses. We used a replication-deficient adenovirus serotype 5-vectored cancer vaccine targeting the melanoma-associated antigen dopachrome tautomerase. Clinically, high numbers of tumor-infiltrating CD8⁺ T cells are a positive prognostic indicator. As such, there is interest in maximizing tumor-specific T cell responses. Our findings confirm a positive correlation between the number of tumor-specific T cells and survival. More importantly, we show for the first time that using multiple injection sites could increase the number of vaccine-induced CD8⁺ T cells specific for a self-tumor antigen. Further, the number of tumor antigen-specific antibodies, as well CD8⁺ T cells specific for a foreign antigen could also be enhanced. Our results show that multi-site vaccination induces higher magnitude immune responses than a single-bolus injection. This provides a very simple and almost cost-free strategy to potentially improve the efficacy of any current and future vaccine. Broader clinical adoption of multi-site vaccination protocols for the treatment of cancers and infectious diseases should be given serious consideration.

SUBMITTER: Mould RC

PROVIDER: S-EPMC5559552 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Enhancing Immune Responses to Cancer Vaccines Using Multi-Site Injections.

Mould Robert C RC AuYeung Amanda W K AWK van Vloten Jacob P JP Susta Leonardo L Mutsaers Anthony J AJ Petrik James J JJ Wood Geoffrey A GA Wootton Sarah K SK Karimi Khalil K Bridle Byram W BW

Scientific reports 20170816 1

For a vaccine to be effective it must induce a sufficiently robust and specific immune response. Multi-site injection protocols can increase the titers of rabies virus-neutralizing antibodies. Hypothetically, spreading a vaccine dose across multiple lymphatic drainage regions could also potentiate T cell responses. We used a replication-deficient adenovirus serotype 5-vectored cancer vaccine targeting the melanoma-associated antigen dopachrome tautomerase. Clinically, high numbers of tumor-infil ...[more]

PMID: 28814733

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Project description:Background Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of anti-tumor vaccines, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to induce and expand tumor-specific T lymphocytes. Combination strategies to maximize the anti-tumor effectiveness of LCMV-based vaccines are required. Methods We assessed the anti-tumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination's efficacy were investigated through bulk RNAseq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the anti-tumor effectiveness of the combining of LCMV-E6E7 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials. Results Intratumoral injection of poly(I:C) enhanced the anti-tumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared to monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leukocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leukocyte migration, and the activation profile of tumor-infiltrating CD8+ T lymphocytes were observed. Indeed, the anti-tumor effect relied on the functions of CD8+ T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included. Conclusion Intratumoral injection of poly(I:C) sensitizes MHClow tumors to the anti-tumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy

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Enhancing Immune Responses to Cancer Vaccines Using Multi-Site Injections.

Publications

Enhancing Immune Responses to Cancer Vaccines Using Multi-Site Injections.

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