Lymph Node-Targeted Codelivery of Albumin-Binding Peptide Antigens and Di-Adjuvant for Melanoma Combination Immunotherapy

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Project Summary Melanoma is the most serious type of skin cancer. Advanced melanoma is very aggressive and, despite advances in therapeutics, continues to have a low survival rate. Immunotherapy such as immune checkpoint blockade (ICB) benefited many melanoma patients. While encouraging, there remains an unmet need as most patients do not respond to ICB. ICB therapeutic efficacy can be promoted by vaccine formulations that deliver tumor-associated antigens and neoantigens. Chemically-defined peptide vaccines are attractive for relatively easy manufacturing and good pharmaceutical stability. The success of peptide vaccines relies on the efficiency of delivery. Despite clinical testing of various peptide vaccine formulations, their therapeutic efficacy has been limited due to a number of delivery issues including: 1) poor vaccine delivery to the site of action, 2) limited co- delivery of immunostimulant adjuvants and antigens to enhance antigen immunogenicity, 3) the limited ability to overcome tumor heterogeneity, and 4) the limited ability to deliver physicochemically heterogeneous antigens. Our strategy is to develop a high efficiency and targeted peptide vaccine platform for ICB combination therapy that addresses each of these deficiencies: 1) albumin hitchhiking will be used to deliver peptide vaccines to lymph nodes and antigen-presenting cells (APCs), 2) potent adjuvants and adjuvant/antigen co-delivery will be employed to enhance antigen immunogenicity, 3) a modular system will deliver multi-antigens to overcome tumor heterogeneity, and 4) a widely applicable system will deliver various peptide antigens. In our preliminary studies, we developed albumin-binding vaccines (AlbiVax) to enhance vaccine delivery to lymph nodes and APCs 100- fold in mice, relative to a clinical benchmark. AlbiVax promoted anticancer immune responses 14-fold, and improved melanoma therapeutic efficacy. Moreover, by co-delivering a potent di-adjuvant and antigens using an albumin-hitchhiking nanoscaffold, we further potentiated antigen immunogenicity and promoted melanoma therapeutic efficacy. Our objective in this study is to engineer multi-antigen/di-adjuvant co-delivery AlbiVax (mADC-AlbiVax) as an efficient platform that co-delivers potent adjuvants and heterogenous peptide antigens to lymph nodes and APCs, whereby eliciting potent, broad, and long-lasting immunity for ICB melanoma combination immunotherapy. Aim 1 will optimize the modular structure of model mADC-AlbiVax to co-deliver vaccines to lymph nodes, APCs, and subcellular locations in APCs for optimal antitumor immunomodulation; Aim 2 will synthesize melanoma mADC-AlbiVax, and study vaccine co-delivery and immunomodulation; and Aim 3 will evaluate the melanoma therapeutic efficacy and safety of this vaccine delivery system, alone or combined with ICB, in mouse models. This project led by an independent, productive ESI is supported by extensive preliminary data and a complementary team. A significant deliverable from this work will preclinically establish a vaccine delivery system using chemically-defined vaccines and clinically tested or used agents for future clinical evaluation. 1