Abstract IA28: Nanodisc platform technology for cancer vaccination

Abstract

Recent innovations in DNA/RNA sequencing have allowed for the identification of patient-specific tumor neo-antigens, ushering in the new era of personalized cancer vaccines. Peptide vaccines in general may serve as an ideal platform for neo-antigen vaccines, but the therapeutic efficacy of peptide vaccines have been limited in clinical trials. Here we present an alternative strategy where preformed nanodiscs based on synthetic high density lipoproteins, with an established clinical manufacturing procedure and excellent safety profiles in humans, are readily formulated with adjuvants and antigen peptides. We show that these nanodiscs can efficiently deliver immunostimulatory molecules and antigens, including neo-antigens to draining lymph nodes. Notably, nanodiscs elicited up to 47-fold greater frequency of tumor neoantigen-specific CD8+ T lymphocytes (CTLs) than soluble vaccines in mice and even 31-fold greater than the standard adjuvant in clinical trials (i.e. CpG in Montanide). When nanodisc vaccination was combined with anti-PD-1 immune checkpoint inhibitor, ~88% complete response was observed in MC-38 tumor-bearing mice, compared with 25% response rate in the control group that received soluble vaccine plus anti-PD-1 therapy. In more aggressive B16F10 melanoma model, nanodiscs delivering multiple MHC class I and class II neo-epitopes were combined with α-PD-1/α-CTLA-4 therapy, leading ~90% complete response in B16F10 tumor-bearing mice, compared with ~38% response rate in the control group with soluble vaccine plus α-PD-1/α-CTLA-4 therapy. Furthermore, we have demonstrated the efficacy of nanodisc technology using shared tumor antigens in murine models of HPV+ mucosal tumors. The reproductive tract tumor model was established in C57BL/6 mice by intravaginal administration of luciferase-expressing TC-1 cells, a surrogate for HPV-induced human tumors, such as cervical carcinoma. The lung metastasis model was established by intravenous injection of luciferase-expressing TC-1 tumor cells. In mice bearing intravaginal or lung TC-1 tumors, two nanodisc vaccinations with HPV16 E7 antigen generated the peak frequency of ~35% tetramer+ CTLs in peripheral blood and eliminated established TC-1 tumors in the majority of animals (without immune checkpoint blockade). Owning to the facile production process, robust therapeutic efficacy, and good safety profiles, our nano-vaccine technology offers a powerful and convenient platform for vaccination using personalized as well as shared tumor antigens. Citation Format: James J. Moon. Nanodisc platform technology for cancer vaccination [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA28.