Personalized vaccine nanodiscs for elimination of established tumors Rui Kuai, Anna Schwendeman and James J. Moon University of Michigan, Ann Arbor, MI 48109, USA
Recent innovations in tumor exome sequencing have signaled the new era of personalized immunotherapy with patient-specific neo-antigens, but a general methodology for stimulating strong CD8α+ cytotoxic T-lymphocyte (CTL) responses remains lacking. Here we have developed synthetic high-density lipoprotein nanodiscs that can be readily coupled with CpG and tumor antigen (Ag) peptides, producing homogeneous, stable, and ultrasmall (~10 nm in diameter) nanodiscs . We demonstrate that these nanodiscs can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cells. Strikingly, nanodiscs elicited up to 47-fold greater frequencies of neoantigen-specific CTLs than soluble vaccines and even 31-fold greater than perhaps the strongest adjuvant in clinical trials (i.e. CpG in Montanide). Moreover, when nanodisc vaccination was combined with an immune checkpoint inhibitor, anti-PD-1 IgG, 88% of animals eliminated MC-38 tumors, compared with only 25% response rate seen with soluble peptide+CpG+α-PD-1 therapy. To treat a more aggressive B16F10 melanoma, multiple MHC class I and class II epitopes were loaded in nanodiscs. Vaccination with multi-epitope nanodiscs combined with α-PD-1/α-CTLA-4 therapy led to complete tumor regression in ~90% B16F10 tumor-bearing mice, compared with ~38% rate observed in the control group. We have also examined the nanodisc technology for elimination of HPV-associated mucosal tumors. Vaccination with nanodiscs delivering HPV E7 antigen induced ~35% E7-tetramer+ CD8+ T cells and eliminated E7-expressing TC-1 tumors established in the lungs and reproductive tract. Overall, our approach offers a powerful and convenient vaccine technology that can be readily applied to patient-tailored neo-antigens as well as shared tumor antigens.