Zeng, Bijun, Middelberg, Anton P.J., Gemiarto, Adrian, Macdonald, Kelli, Baxter, Alan G., Talekar, Meghna, Moi, Davide, Tullett, Kirsteen M., Caminschi, Irina, Lahoud, Mireille H., Mazzieri, Roberta, Dolcetti, Riccardo, and Thomas, Ranjeny (2018) Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy. Journal of Clinical Investigation, 128 (5). pp. 1971-1984.

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Abstract

Non-antigen-specific stimulatory cancer immunotherapies are commonly complicated by off-target effects. Antigen-specific immunotherapy, combining viral tumor antigen or personalized neoepitopes with immune targeting, offers a solution. However, the lack of flexible systems targeting tumor antigens to cross-presenting dendritic cells (DCs) limits clinical development. Although antigen-anti-Clec9A mAb conjugates target cross-presenting DCs, adjuvant must be codelivered for cytotoxic T lymphocyte (CTL) induction. We functionalized tailored nanoemulsions encapsulating tumor antigens to target Clec9A (Clec9A-TNE). Clec9A-TNE encapsulating OVA antigen targeted and activated cross-presenting DCs without additional adjuvant, promoting antigen-specific CD4(+) and CD8(+) T cell proliferation and CTL and antibody responses. OVA-Clec9A-TNE-induced DC activation required CD4 and CD8 epitopes, CD40, and IFN-alpha. Clec9A-TNE encapsulating HPV E6/ E7 significantly suppressed HPV-associated tumor growth, while E6/ E7-CpG did not. Clec9A-TNE loaded with pooled B16-F10 melanoma neoepitopes induced epitope-specific CD4(+) and CD8(+) T cell responses, permitting selection of immunogenic neoepitopes. Clec9A-TNE encapsulating 6 neoepitopes significantly suppressed B16-F10 melanoma growth in a CD4(+) T cell-dependent manner. Thus, cross-presenting DCs targeted with antigen-Clec9A-TNE stimulate therapeutically effective tumor-specific immunity, dependent on T cell help.

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