Lymph node-targeted codelivery of albumin-binding peptide antigens and di-adjuvant for melanoma combination immunotherapy

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Project Summary Advanced melanoma is a highly aggressive cancer. While immunotherapy such as immune checkpoint blockade (ICB) has benefited some patients, most melanoma patients do not respond to ICB. This is largely due to a lack of preexisting target cells and checkpoints for ICB, tumor antigenic heterogeneity, and tumor immunosuppression. ICB therapeutic efficacy can be promoted by vaccine formulations that deliver tumor antigens to induce new antitumor cells for ICB to target and reduce tumor immunosuppression. Chemically defined peptide vaccines are attractive for relatively easy manufacturing and good pharmaceutical stability. The success of peptide vaccines relies on efficient delivery. Despite clinical testing of various peptide vaccine formulations, their therapeutic efficacy has been limited due to delivery and immunomodulation issues including 1) poor vaccine delivery to the sites of action (lymph nodes and antigen-presenting cells), 2) poor immunostimulant adjuvant efficacy due to restricted target cell subsets in human, 3) limited adjuvant/antigen codelivery to enhance antigen immunogenicity, 4) limited ability to overcome tumor antigenic heterogeneity, and 5) limited ability to deliver heterogeneous antigens. Our strategy is to develop a high efficiency and spatiotemporally targeted peptide vaccine platform that addresses each of these deficiencies to improve ICB therapy: 1) albumin hitchhiking delivers peptide vaccines to lymph nodes and antigen-presenting cells, 2) a di-adjuvant targets a broad spectrum of cell subsets across species, 3) potent di-adjuvant and adjuvant/antigen codelivery enhance antigen immunogenicity, and 4) a modular system delivers heterogeneous multi-antigens to overcome tumor antigenic heterogeneity. In our preliminary studies, we developed albumin-binding vaccines (AlbiVax) to enhance vaccine delivery 100-fold in mice, promote anticancer T cell responses 14-fold, and improve melanoma therapeutic efficacy relative to a clinical benchmark. Moreover, by codelivering a di-adjuvant and antigens using a nanoscaffold, AlbiVax further potentiated antigen immunogenicity and promoted melanoma therapeutic efficacy. Our objective in this study is to engineer multi-antigen/di-adjuvant codelivery AlbiVax (mADC-AlbiVax) as an efficient platform that codelivers a di-adjuvant and multiple heterogenous peptide antigens to lymph nodes and antigen-presenting cells to elicit a potent, broad, and long-lasting immunity for ICB melanoma combination immunotherapy. Aim 1 is to optimize the modular structure of model mADC-AlbiVax for targeted multi-antigen/di-adjuvant codelivery to lymph nodes, antigen-presenting cells, and subcellular locations for optimal antitumor immunomodulation; Aim 2 is to synthesize melanoma mADC-AlbiVax using multiple tumor antigens and measure vaccine codelivery and immunomodulation; Aim 3 is to evaluate the melanoma therapeutic efficacy and safety of melanoma mADC- AlbiVax combined with ICB in multiple mouse models. A significant deliverable of this work will be preclinical validation of an innovative system to codeliver chemically-defined vaccines using clinically tested or used agents for future clinical evaluation. 1