Local Delivery Of Anti Ctla4 Mediates Cdc1 Dependent Eradication Of Hnscc With Limited Iraes In A Preclinical Model Of Oral Squamous Cell Carcinoma.

Abstract Head and neck squamous cell carcinoma (HNSCC) ranks 6th in cancer incidence worldwide and has a five-year survival rate of only 63%. Despite advances in curative-intent therapies over the past three decades, rates of recurrence exceed 50% and long-term toxicities remain unacceptably morbid. Immunotherapies - principally immune checkpoint inhibitors (ICI) such as αPD-1 and αCTLA-41 antibodies which restore endogenous antitumor T cell immunity - offer the greatest promise for achieving durable response in HNSCC. However, the clinical application of ICI has been limited by immune-related adverse events (irAEs), which is a consequence of compromised peripheral immune tolerance after ICI therapy. Although irAEs are often reversible they can become severe, at best prompting premature termination of therapy or at worst becoming life-threatening. To address the off-target irAEs inherent to systemic ICI therapy, we developed a novel, local delivery strategy based upon an array of soluble microneedles (MN). Leveraging our recently reported syngeneic, tobacco-signature murine HNSCC model, we characterized the αCTLA-41 anti-tumor response as both CD8 T cell- and conventional dendritic cell type 1-dependent. When comparing αCTLA-4 therapy delivered in the traditional systemic format or with our local-MN delivery system, we found that while both routes of delivery led to >90% tumor responses, local-MN delivery achieved responses with lower total dosing while also limiting distribution of αCTLA-41 antibody from areas distal to draining lymphatic basins. Employing the previously described Foxp3-GFP-DTR GEMM developed for interrogation of murine irAEs, we found that local-MN protected animals from irAEs observed with systemic therapy. Taken together, our findings support the exploration of the microneedle array as a viable delivery strategy for ICI treatment in HNSCC. Citation Format: Mara Gilardi, Zhiyong Wang, Victoria H. Wu, Miguel Angel Lopez-Ramirez, Fernando Soto-Alvarez, Robert Saddawi-Konefka, Dana Steffen, Marco Proietto, Zbigniew Mikulski, Haruka Miki, Jayanth Shankara Narayanan, Alfredo Molinolo, Joseph Wang, J. Silvio Gutkind. Local delivery of anti CTLA4 mediates cDC1 dependent eradication of HNSCC with limited IRAEs in a preclinical model of oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1610.