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In situ vaccination: Harvesting low hanging fruit on the cancer immunotherapy tree

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After 100 years of debate, it is clear that cancer is recognized by the immune system and this has generated immense interest in cancer immunotherapy. The systemic nature of the immune system gives immunotherapy the ability to treat metastatic disease, which currently requires chemotherapy that frequently fails. Like chemotherapy, most immunotherapy is systemically applied in an effort to generate systemic antitumor immune response. However, local administration of immunostimulatory reagents into a recognized tumor by in situ vaccination (ISV) can also generate systemic antitumor immunity to fight metastatic disease. Conventional vaccines contain antigens and immune adjuvants. With ISV, the tumor itself supplies the antigen and the treatment only applies immune adjuvant directly to the tumor. While current immunotherapy often fails to eliminate cancer because of local immunosuppression mediated by tumors, effective ISV changes the tumor microenvironment from immunosuppressive to immunostimulatory, stimulates presentation of tumor antigens by antigen‐presenting cells to T cells, and generates systemic antitumor immunity that promotes antigen‐specific effector T‐cell attack of both treated and importantly, untreated metastatic tumors. The advantages of ISV are: simple and cost‐effective; minimal systemic side effects; feasible and flexible adjuvant delivery; exploiting all tumor antigens in the tumor avoids the need to identify antigens; utilizing all antigens in the tumor minimizes immune escape; and potential synergy when combined with other therapies. This review puts ISV into the broader context of cancer immunotherapy, including the use of nanoparticles, and outlines research needed in order to manifest the potential of ISV for clinical use. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Comparison of conventional vaccination and in situ vaccination. (a) Conventional vaccines carry antigen and immune adjuvant, and are administered systemically. Conventional vaccines activate and expand effector T cells (Teff) that recognize only the vaccine antigen(s), trigger systemic response against the vaccine antigen(s), and attack cells that express the vaccine antigen(s). (b) In situ vaccine injects only immune adjuvants into the tumor and the tumor itself supplies the antigen. ISV exploits all relevant tumor antigens and activates and expands Teff that recognize all relevant tumor antigens. This generates systemic antitumor immunity against all tumor antigens and helps protect the patient from current or future metastatic tumors expressing any tumor antigens found in the treated tumor
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Strengths of in situ vaccination as compared to more complex therapeutic vaccination strategies. Overall ISV advantages are: (1) ISV exploits all relevant antigens in the tumor, avoiding the need to identify tumor antigens or consider the HLA type; (2) ISV is simple and cost‐effective because it utilizes standard reagents and does not require patient specific vaccines; (3) ISV takes advantage of the entire antigenic repertoire of a tumor to minimize immune escape; (4) ISV utilizes feasible local delivery with minimal systemic side effects; (5) ISV has the potential for synergy when combined with other therapies; and (6) ISV can be effectively performed prior to surgery as neoadjuvant therapy
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In situ vaccination induces and enhances antitumor immune response. ISV of poorly immunogenic tumors initiates and stimulates effective antitumor immune response by: (a) change of tumor microenvironment from immunosuppressive to immunostimulatory by induction of proinflammatory cytokines, polarization of protumorigenic M2 macrophage (Mϕ) to antitumorigenic M1 Mϕ, activation of dendritic cells (DCs), inhibition or removal of immunosuppressive regulatory T cells (Treg) and myeloid‐derived suppressor cells (MDSCs); (b) modulating immune system through leukocyte activation and associated tumor cell death, release of tumor‐antigen (TA), and enhanced tumor immunogenicity; (c) recruitment, maturation, and activation of antigen‐presenting cells (APCs) at the tumor site, and enhancing TA uptake and antigen processing by APCs; (d) increasing APCs trafficking to lymph node, presentation or cross presentation of TA to T cells, activation of antigen‐specific T cells, and differentiation into cytotoxic T‐lymphocyte (CTL), T‐helper (Th) cell, effector memory T cell (TEM), central memory T cell (TCM), and antibody‐secreting B cell in the tumor draining lymph node; (e) expansion and recruitment of immune cells including CTL, Th cells, natural killer (NK) cells, and granulocytes into the treated tumor to kill tumor cells; and (f) attacking tumors at other sites by circulating effector T cells and antibodies, induction and activation of memory T cells (TEM and TCM), and mounting antitumor memory immune response to develop long‐term protection against tumor relapse
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