R. Kuai, J.J. Moon, A. Schwendeman
University of Michigan,
United States
Keywords: vaccine, nanodiscs, tumors, cancer
Summary:
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 [1]. 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. Reference: [1] Kuai R, et al. Nature Materials. 2017, 16 (4) 489-496.