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MRNA Vaccine with Antigen-Specific Checkpoint Blockade Induces an Enhanced Immune Response against Established Melanoma.

ABSTRACT: We reported a preclinical cancer vaccine that simultaneously introduced an mRNA antigen and an immune checkpoint blocking siRNA into the antigen-presenting cells. This was achieved by formulating both nucleic acid-based immunotherapeutics into a lipid-coated calcium phosphate (LCP) nanoparticle (NP) as a carrier to address the delivery challenge. The PEGylated lipid NPs were functionalized with mannose as the targeting ligand to facilitate the preferential uptake by the dendritic cells (DCs) in the lymph nodes after subcutaneous administration. The calcium phosphate core allowed acid-mediated dissolution in the endo-lysosomal compartment, which prompted rapid release of cargoes after cellular internalization of NP. LCP mRNA vaccine encoding TRP2 elicited a robust antigen-specific cytotoxic T cell response and a humoral immune response in a C57BL/6 mouse model of B16F10 melanoma. The immune responses efficaciously inhibited the melanoma growth. Moreover, co-delivery of PD-L1 siRNA and mRNA vaccine resulted in the downregulation of PD-L1 in the DCs that presented tumor antigens, significantly prompting T cell activation and proliferation. The enhanced T cell response had a profound inhibitory effect on tumor growth and metastasis. Generally, the work provided a paradigm for the development of an mRNA vaccine carrier to boost the anticancer immune response.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5835019 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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mRNA Vaccine with Antigen-Specific Checkpoint Blockade Induces an Enhanced Immune Response against Established Melanoma.

Wang Yuhua Y Zhang Lu L Xu Zhenghong Z Miao Lei L Huang Leaf L

Molecular therapy : the journal of the American Society of Gene Therapy 20171121 2

We reported a preclinical cancer vaccine that simultaneously introduced an mRNA antigen and an immune checkpoint blocking siRNA into the antigen-presenting cells. This was achieved by formulating both nucleic acid-based immunotherapeutics into a lipid-coated calcium phosphate (LCP) nanoparticle (NP) as a carrier to address the delivery challenge. The PEGylated lipid NPs were functionalized with mannose as the targeting ligand to facilitate the preferential uptake by the dendritic cells (DCs) in ...[more]

PMID: 29249397

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Project description:In a syngeneic murine melanoma (MEL) model, we recently reported an in situ vaccination response to combined radiation (RT) and intra-tumoral (IT) injection of anti-GD2 hu14. 18-IL2 immunocytokine (IC). This combined treatment resulted in 71% complete and durable regression of 5-week tumors, a tumor-specific memory T cell response, and augmented response to systemic anti-CTLA-4 antibody checkpoint blockade. While the ability of radiation to diversify anti-tumor T cell response has been reported, we hypothesize that mice rendered disease-free (DF) by a RT-based ISV might also exhibit a heightened B cell response. C57BL/6 mice were engrafted with 2 × 106 GD2+ B78 MEL and treated at a target tumor size of ~200 mm3 with 12 Gy RT, IT-IC on day (D)6-D10, and anti-CTLA-4 on D3, 6, and 9. Serum was collected via facial vein before tumor injection, before treatment, during treatment, after becoming DF, and following rejection of subcutaneous 2 × 106 B78 MEL re-challenge on D90. Flow cytometry demonstrated the presence of tumor-specific IgG in sera from mice rendered DF and rejecting re-challenge with B78 MEL at D90 after starting treatment. Consistent with an adaptive endogenous anti-tumor humoral memory response, these anti-tumor antibodies bound to B78 cells and parental B16 cells (GD2-), but not to the unrelated syngeneic Panc02 or Panc02 GD2+ cell lines. We evaluated the kinetics of this response and observed that tumor-specific IgG was consistently detected by D22 after initiation of treatment, corresponding to a time of rapid tumor regression. The amount of tumor-specific antibody binding to tumor cells (as measured by flow MFI) did not correlate with host animal prognosis. Incubation of B16 MEL cells in DF serum, vs. naïve serum, prior to IV injection, did not delay engraftment of B16 metastases and showed similar overall survival rates. B cell depletion using anti-CD20 or anti-CD19 and anti-B220 did not impact the efficacy of ISV treatment. Thus, treatment with RT + IC + anti-CTLA-4 results in adaptive anti-tumor humoral memory response. This endogenous tumor-specific antibody response does not appear to have therapeutic efficacy but may serve as a biomarker for an anti-tumor T cell response.

Dataset Information

MRNA Vaccine with Antigen-Specific Checkpoint Blockade Induces an Enhanced Immune Response against Established Melanoma.

Publications

mRNA Vaccine with Antigen-Specific Checkpoint Blockade Induces an Enhanced Immune Response against Established Melanoma.

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