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Engineering autologous tumor cell vaccine to locally mobilize antitumor immunity in tumor surgical bed.

ABSTRACT: Autologous tumor cell-based vaccines (ATVs) are emerging as a transformable approach for personalized immunotherapy, but their therapeutic efficacy remains unsatisfying in patients with cancer. Here, we design a photodynamic therapy (PDT)-motivated ATV (P-ATV) in Fmoc-KCRGDK-phenylboronic acid (FK-PBA) hydrogel, which mobilizes local immune activation to inhibit relapse of postoperative tumors. The FK-PBA targeting overexpressed sialic acid on tumor cells can enable on-demand gelation in residue tumor areas and maintain continuous vaccination in surgical bed. Unlike neoantigen-based vaccine or adoptive cell therapy that takes several months to prepare, P-ATV can be easily manufactured within a few days and efficiently boost neoepitope-specific CD8⁺ T cells to activate personalized immunotherapy. This simple and powerful approach of engineered ATVs provides an alternative strategy for personalized immunotherapy and is readily transformable to various kinds of cell-based antigens to inhibit the relapse of postoperative tumors.

SUBMITTER: Fang L

PROVIDER: S-EPMC7304971 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Engineering autologous tumor cell vaccine to locally mobilize antitumor immunity in tumor surgical bed.

Fang Lei L Zhao Zitong Z Wang Jue J Zhang Pengcheng P Ding Yaping Y Jiang Yanyan Y Wang Dangge D Li Yaping Y

Science advances 20200619 25

Autologous tumor cell-based vaccines (ATVs) are emerging as a transformable approach for personalized immunotherapy, but their therapeutic efficacy remains unsatisfying in patients with cancer. Here, we design a photodynamic therapy (PDT)-motivated ATV (P-ATV) in Fmoc-KCRGDK-phenylboronic acid (FK-PBA) hydrogel, which mobilizes local immune activation to inhibit relapse of postoperative tumors. The FK-PBA targeting overexpressed sialic acid on tumor cells can enable on-demand gelation in residue ...[more]

PMID: 32596457

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Project description:BackgroundAutologous tumor cell-based vaccines (ATVs) aim to prevent and treat tumor metastasis by activating patient-specific tumor antigens to induce immune memory. However, their clinical efficacy is limited. Mannan-BAM (MB), a pathogen-associated molecular pattern (PAMP), can coordinate an innate immune response that recognizes and eliminates mannan-BAM-labeled tumor cells. TLR agonists and anti-CD40 antibodies (TA) can enhance the immune response by activating antigen-presenting cells (APCs) to present tumor antigens to the adaptive immune system. In this study, we investigated the efficacy and mechanism of action of rWTC-MBTA, an autologous whole tumor cell vaccine consisting of irradiated tumor cells (rWTC) pulsed with mannan-BAM, TLR agonists, and anti-CD40 antibody (MBTA), in preventing tumor metastasis in multiple animal models.MethodsThe efficacy of the rWTC-MBTA vaccine was evaluated in mice using breast (4T1) and melanoma (B16-F10) tumor models via subcutaneous and intravenous injection of tumor cells to induce metastasis. The vaccine's effect was also assessed in a postoperative breast tumor model (4T1) and tested in autologous and allogeneic syngeneic breast tumor models (4T1 and EMT6). Mechanistic investigations included immunohistochemistry, immunophenotyping analysis, ELISA, tumor-specific cytotoxicity testing, and T-cell depletion experiments. Biochemistry testing and histopathology of major tissues in vaccinated mice were also evaluated for potential systemic toxicity of the vaccine.ResultsThe rWTC-MBTA vaccine effectively prevented metastasis and inhibited tumor growth in breast tumor and melanoma metastatic animal models. It also prevented tumor metastasis and prolonged survival in the postoperative breast tumor animal model. Cross-vaccination experiments revealed that the rWTC-MBTA vaccine prevented autologous tumor growth, but not allogeneic tumor growth. Mechanistic data demonstrated that the vaccine increased the percentage of antigen-presenting cells, induced effector and central memory cells, and enhanced CD4+ and CD8+ T-cell responses. T-cells obtained from mice that were vaccinated displayed tumor-specific cytotoxicity, as shown by enhanced tumor cell killing in co-culture experiments, accompanied by increased levels of Granzyme B, TNF-α, IFN-γ, and CD107a in T-cells. T-cell depletion experiments showed that the vaccine's antitumor efficacy depended on T-cells, especially CD4+ T-cells. Biochemistry testing and histopathology of major tissues in vaccinated mice revealed negligible systemic toxicity of the vaccine.ConclusionThe rWTC-MBTA vaccine demonstrated efficacy in multiple animal models through T-cell mediated cytotoxicity and has potential as a therapeutic option for preventing and treating tumor metastasis with minimal systemic toxicity.

Dataset Information

Engineering autologous tumor cell vaccine to locally mobilize antitumor immunity in tumor surgical bed.

Publications

Engineering autologous tumor cell vaccine to locally mobilize antitumor immunity in tumor surgical bed.

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