Background
VAX014 is a novel, non-viral, clinical-stage oncolytic immunotherapy recently reported to activate the Stimulator of Interferon Genes (STING) pathway, and unlike oncolytic virotherapies, has optimal antitumor activity in tumors expressing STING.1–3 We previously reported a dependence on tumor-intrinsic STING in the antitumor activity of VAX014 following intratumoral (i.t.) administration in wild type (WT) C57BL/6 mice using two syngeneic murine solid tumor models (MB49 and MC38).2 Here, we explore the role of host-intrinsic type-I IFN in response to i.t. treatment with VAX014 in both models in a syngeneic interferon alpha/beta receptor alpha chain (IFNAR1) knockout mouse. We report that VAX014-mediated STING agonism leads to immunologic control of solid tumors in both a type-I IFN-dependent and independent manner.
Methods
The role of host-intrinsic type-I IFN as part of the pharmacodynamic response to i.t. treatment of MB49 or MC38 tumors with VAX014 was evaluated in a syngeneic IFNAR1 knockout mouse. For both models (n=6–8/group/model), a single intradermal tumor was established and allowed to grow up to ~50mm3 before treatment initiation. Weekly i.t. treatment with VAX014 was administered for up to six weeks unless a complete response (CR) was achieved, or the subject succumbed to tumor burden. Individual and mean tumor growth rates as well as survival data were recorded throughout the study.
Results
Surprisingly, the absence of host IFNAR1 had no negative impact on the antitumor activity of VAX014 in the MB49 model, despite the partial dependence of tumor- and host- intrinsic STING in this model.1 The CR rate was maintained at 100% and the kinetics of response were not different than when the model is conducted in the WT host. In stark contrast, antitumor activity of VAX014 in the MC38 model was entirely dependent on IFNAR1 as evidenced by a 0% CR rate and a survival curve mirroring that of saline treated controls.
Conclusions
These findings are consistent with recent reports indicating that STING agonism can activate multiple innate immune signaling pathways to control tumor growth in murine solid tumor models.
References
Nelson K, Parikh A, Tsuji, S, Reil KA, House CD, McGuire KM, Giacalone MJ. VAX014 as a Novel Oncolytic Agent for STING and RIG-I Positive Solid Tumors. Journal for Immunotherapy of Cancer 2023;11(1116):A1229.
Reil KA, et al. Intralesional administration of VAX014 facilitates in situ immunization and potentiates immune checkpoint blockade in immunologically cold tumors. J Immunother Cancer 2023;11(6).
Kaufman HL. Can biomarkers guide oncolytic virus immunotherapy? Clin Cancer Res 2021;27(12):3278–3279.
Ethics Approval
The described studies were approved by the Institutional Animal Care and Use Committees of San Diego State University and Dartmouth College, respectively.