Abstract 4091: A novel cancer vaccine based on hyaluronic acid nanogel combined with adoptive T cell therapy induces complete regression of established tumors and long-lasting memory CD8+ T cells
Authors: Momose Fumiyasu , Nakai Takashi , Yabuuchi Kohei , Yamane Makiko , Hayashi Tae , Wang Linan , Nakagawa Yoshiyuki , Aso Shogo , Katsumata Toru , Shimoboji Tsuyoshi , Miyahara Yoshihiro 
Published: March 2024

Abstract
Background: We have developed nanosized hydrogel particles (nanogels) to create new nanomaterials for biomedical applications. In particular, Hyaluronic Acid, partially hydrophobized by chemical modification with cholesteryl groups, has a distinguished characteristic to form physically cross-linked NanoGel particles. HANG efficiently forms a stable complex with an antigenic polypeptide (HANG-Vaccine) through hydrophobic interactions. In this study, we investigated the efficacy of HANG-V against tumors resistant to immune checkpoint inhibitors (ICIs) and adoptive TCR-T therapy.
Methods: C57BL/6-derived B16F10 melanoma and BALB/c-derived CMS5a sarcoma are both known to be resistant to ICIs and adoptive TCR-T therapy. The efficacy of HANG-V was tested by using each tumor-bearing mice treatment model. HANG-V was prepared by mixing gp100 or CMS5a neoantigen (Ag) with HANG, respectively.
Results: HANG-V was subcutaneously injected into B16F10-bearing C57BL/6 on days 7, 11, and 15, and CD8+ T cells from Pmel-1 mice were intravenously administered on days 8 and 12. Surprisingly, complete regression of established B16F10 tumors with more than 100 mm2 were observed. Vaccinated mice survived with changing hair color of mice into white, while non-vaccinated mice were all dead by day 25. Moreover, gp100-specific CTLs was observed abundantly in systemic including tumor site. Even two months after the treatment, transferred T cells with memory phenotype were persistently detected in peripheral bloods. Furthermore, booster vaccination elicited robust expansion of these memory T cells persisting for more than one year. In similar experimental settings, we treated CMS5a tumor-bearing mice by HANG-V combined with adoptive transfer of CD8+ T cells from DUC18 mice, whose T cells are specific for mutated ERK2 neoAg. All mice survived as well with complete reduction of established CMS5a tumors, rejected a rechallenge with CMS5a and induced an Ag-specific CTL responses on more than 2 years. Notably, by using neoantigen-knockout CMS5a, we obtained results suggesting that HANG-V with TCR-T therapy potently induced the so-called “antigen spreading”. Furthermore, induction of Ag-specific CTLs was associated with CD44 hyaluronic acid receptor which expressed in APCs crucial for cross-presentation to CD8+ T cells.
Conclusions: HANG-V strongly enhanced the efficacy of adoptive TCR-T cell therapy against ICI refractory tumors leading to total tumor suppression. Furthermore, HANG-V induced potent and persistent Ag-specific CTLs systemically through interaction with CD44 hyaluronic receptor, allowing long-term protection of tumor recurrence with memory CD8+ T cells. Our studies may propose crucial insights for clinical application of HANG vaccine with adoptive T cell therapy in patient with ICI-resistant tumors with poor prognosis.
Citation Format: Fumiyasu Momose, Takashi Nakai, Kohei Yabuuchi, Makiko Yamane, Tae Hayashi, Linan Wang, Yoshiyuki Nakagawa, Shogo Aso, Toru Katsumata, Tsuyoshi Shimoboji, Yoshihiro Miyahara. A novel cancer vaccine based on hyaluronic acid nanogel combined with adoptive T cell therapy induces complete regression of established tumors and long-lasting memory CD8+ T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4091.