Intratumorally (i.t.) delivered immunotherapies stimulate in situ immunization by promoting local tumor inflammation, immune cell recruitment, and the generation of systemic antitumor lymphocytic responses. Clinical studies indicate combining i.t. immunotherapy with systemic immune checkpoint blockade (ICB) enhances durable complete response rates (CRR) in treated and distal untreated tumors (abscopal effect), although the number of i.t. therapies tested in this setting remains is limited. The purpose of this study was to evaluate and characterize the immunotherapeutic activity of VAX014, a novel clinical-stage bacterial minicell-based oncolytic agent, following i.t. delivery in two syngeneic murine solid tumor models. The nonimmunogenic B16F10 melanoma and immunogenic MB49 urothelial carcinoma models were used to establish single agent activity of VAX014 in mice bearing a single intradermal (i.d.) tumor, followed by an evaluation of synergy between VAX014 and ICB combinations (CTLA-4 ± PD-1) in mice bearing dual bilateral i.d. B16F10 tumors where only one tumor is treated with VAX014.Weekly i.t. treatment with VAX014 led to significant CD8+ T cell mediated antitumor activity in single i.d. tumor models. A significant reduction in tumor growth rate was observed in all mice (p< 0.0001, 38/38 for B16F10; p< 0.0001, 12/12 for MB49) which ultimately resulted in a durable CRR in 58.0% and 100% in the B16F10 and MB49 models, respectively. B16F10 tumors actively responding to i.t. treatment with VAX014 had a significant increase in CD8+ T cells (p= 0.0004) with a concomitant decrease in CD11b+ myeloid cells (p= 0.039) even after a single i.t. dose of VAX014. VAX014-mediated antitumor activity was specific to the treated tumor type as determined by cytotoxic T lymphocyte assay against the treated tumor cell line versus haplotype matched control target cells (p= 0.0015). Using a bilateral variation of each model, VAX014 exhibited a significant abscopal effect in the immunogenic MB49 model (22.0% CRR and ↓ tumor growth rate in untreated tumors, p= 0.009), an effect that was less pronounced in the nonimmunogenic B16F10 model. Addition of systemic CTLA-4 ICB significantly enhanced abscopal activity in the bilateral B16F10 model whereas PD-1 ICB did not. Remarkably, tripartite combination of VAX014 with CTLA-4/PD-1 ICB resulted in a significant reduction in treated (p< 0.0001) and distal untreated B16F10 tumors (p< 0.0012) as well as an enhanced survival advantage versus CTLA-4/PD-1 ICB combination (p= 0.03). Survival was associated with an improved CRR of both tumors (50.0% vs. 20.0%).In conclusion, these preclinical data provide scientific rationale and set the foundation for i.t. treatment with VAX014 in patients with injectable tumors refractory to standard treatment options and may be particularly effective when combined with systemic ICB.
Citation Format: Shingo Tsuji, Katherine A. Reil, Kinsey L. Nelson, Kathleen L. McGuire, Matthew J. Giacalone. Intratumoral treatment with VAX014 facilitates in situ immunization leading to systemic antitumor responses that enhance systemic immune checkpoint blockade [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 4182.