Abstract 4215: Combination of STING and TLR 7/8 agonists as vaccine adjuvants for cancer immunotherapy

Abstract

Abstract Various classes of molecules including toll-like receptor (TLR) agonists, exosomes, and metallo compounds have been evaluated as adjuvants for cancer vaccines. However, their wide-spread clinical use has been limited by transient immune responses and serious side-effects. Here, we propose the use of a multi-adjuvant approach that combines two different classes of adjuvants, STING and TLR 7/8 agonists, based on their distinct immune cell targets, signalling pathways, and significant roles in the activation and maintenance of immune responses. We evaluated the potential of combining 522, a novel TLR 7/8 agonist, and DMXAA, a STING agonist, for stronger DC activation and greater CD8 T cell responses. Mouse bearing B16F10-OVA (murine melanoma cell line which expresses ovalbumin) tumors were immunized with OVA mixed with 522 or DMXAA or a combination of 522 and DMXAA daily for 5 days. Immunization with OVA+DMXAA+522 resulted in significant tumor growth inhibition (p < 0.05) and improved survival (p<0.05) compared to other controls. Using flow cytometry, the costimulatory molecule expression and immune cell infiltration in mouse lymph node, spleen and tumor were evaluated. Immunization with OVA+DMXAA+522 resulted in the activation of antigen presenting cells (APCs) in lymph nodes, spleen and tumor (additive or equivalent to single treated groups). The combination also elicited stronger antigen specific CD8 T cell and natural killer (NK) cell responses than control or individual treatment groups. OVA + DMXAA+ 522 immunization increased the number of OVA-specific CD44high CD8 T cells by over 4-fold compared to other treatment groups and control mice in spleen and lymph nodes. A reduction in the frequency of M2 macrophages was observed with OVA+DMXAA+522 treatment. Cytokine analysis demonstrated higher levels of pro-inflammatory cytokines like IFNγ and lower levels of pro-tumorigenic cytokines in the serum of OVA+DMXAA+522 immunized mice compared to that in untreated or OVA-only treated mice. Taken together, these results suggest that combination of TLR7/8 and STING agonists is a promising multi-adjuvant approach for cancer vaccination Citation Format: Shubhmita Bhatnagar, Vishnu Revuri, Manan Shah, Peter Larson, David Ferguson, Jayanth Panyam. Combination of STING and TLR 7/8 agonists as vaccine adjuvants for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4215.