Abstract 7260: An HSV-1-based vector for local delivery of IL-12 and IL-2 reshapes the immune landscape leading to tumor clearance and systemic immune surveillance
Authors: Previte Dana M. , Parry Trevor J. , Krishnan Suma M. 
Published: March 2024

Abstract
Clinical use of recombinant interleukin (IL)-12 and -2 therapy has been hindered due to unfavorable kinetics and toxicity associated with systemic exposure. Durable targeted delivery to the tumor microenvironment (TME) is a promising therapeutic strategy to overcome these clinical limitations, prompting the development of KB707, a replication-defective herpes simplex virus type 1 (HSV-1)-based vector encoding human IL-12 and -2, for the treatment of solid tumors. Prior studies in mice demonstrated that local vector-encoded cytokine administration enhanced murine IL-12/IL-2 expression while limiting systemic exposure compared to conventional protein therapy. In a syngeneic, B16-F10 melanoma mouse model, intratumoral murine KB707-equivalent treatment led to improved survival in a unilateral tumor model and an abscopal effect in a bilateral tumor model. Additionally, the majority of previously treated animals survived rechallenge with B16-F10 in the absence of further therapy, indicative of systemic anti-tumor immune memory. Together, these results suggested that vector-mediated delivery of IL-12 and -2 could elicit both local and systemic anti-tumor immune responses. To elucidate the underlying changes to the immune landscape, B16-F10 tumor-bearing animals were treated intratumorally with vector or vehicle control on day 0 and were sacrificed on day 7; a second cohort of tumor-bearing animals received two vector doses (days 0 and 7) and were sacrificed on days 8, 10, 12, or 14. Immune cell profiling of samples taken from the tumor, tumor draining lymph node (dLN), spleen, and whole blood were analyzed by flow cytometry, and serum cytokine analysis was conducted by multiplex ELISA. Flow cytometric analysis of tumors revealed that vector treatment resulted in increased frequencies of proliferating and activated effector CD8+ and CD4+ T cells, peaking 24 hours post-second dose. These results correlated with high levels of the proinflammatory cytokines IFNγ and TNFα in the serum of vector recipient animals. The blood, spleens, and dLNs also showed increased frequencies of activated effector CD8+ and CD4+ T cells, peaking 24-72 hours post-second dose. Interestingly, although IL-2 alone has been shown to promote immune suppression and tumor outgrowth by mediating regulatory T cell (Treg) expansion and infiltration in certain contexts, the frequency of Tregs in treated vs. control tumors was substantially reduced after first and repeat dosing. Together, these results support a mechanism by which vector-driven local expression of IL-12 and IL-2 can expand and activate effector T cells both in the TME and systemically while simultaneously repressing Tregs, consistent with the previously described inhibition of primary tumor outgrowth, abscopal effects on secondary tumors, and prevention of recurrence observed with this therapeutic approach.
Citation Format: Dana M. Previte, Trevor J. Parry, Suma M. Krishnan. An HSV-1-based vector for local delivery of IL-12 and IL-2 reshapes the immune landscape leading to tumor clearance and systemic immune surveillance [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 7260.