Bioengineering for Optimization of Locoregional Treatment of Advanced Melanoma

/Abstract A versatile drug delivery platform of bioadhesive (BNPs) and non-adhesive (NNPs) biodegradable nanoparticles are engineered with unique properties for selective locoregional delivery of cytotoxic and immune conditioning agents to tumor cells, the tumor microenvironment (TME), and tumor draining lymph nodes (DLN). Features of BNPs (e.g. increased tumor retention) and NNPs (e.g. enhanced DLN accumulation) will be leveraged for the optimized locoregional treatment of advanced malignant melanoma. Further innovation in the delivery platform will be engineered by selectively modifying the NP core to enable mRNA incorporation and delivery and improve these therapies for melanoma and other cancers. Using mouse models recapitulating clinical settings of advanced melanoma, we will study comprehensively the induced immunologic effects within the TME and DLN, and abscopal effects on untreated skin tumors and hematogenously-spread metastatic lesions. We hypothesize that a multi-armed strategy of locoregional delivery in pre-clinical models of locally advanced (stage III) and metastatic (stage IV) melanoma—utilizing our next-generation BNPs and NNPs engineered for the efficient delivery of anti-tumor cytotoxic agents in combination with locoregional immune conditioning—will markedly limit melanoma tumor growth while also synergizing with systemic immune checkpoint inhibitors. We will test this hypothesis in three aims: (1) Assess the capacity of intratumoral delivery of BNP-anti-tumor and NNP- immunomodulatory agents to limit melanoma tumors and facilitate anti-melanoma immunity. Specifically, intratumoral delivery of BNP-exatecan, with and without co-delivered NNP-RG108 or NNP-MPLA, which we have engineered to accumulate in DLN and boost anti-tumor responses, will be tested in YUMM1.7-OVA (with tetramer tracking) and YUMMER1.7 melanoma models. We will assess local (TME, DLN) and systemic anti-tumor immune effects, including abscopal effects on a distant untreated tumor. (2) Develop next-generation locoregional immune enhancing BNPs by engineering incorporation of mRNA (IL-12) into the particle core. By engineering poly(amine-co-ester) (PACE) cores, BNP encapsulating IL-12 mRNA will be developed to enhance uptake by local DC populations and compared to lipid nanoparticle delivery. We will measure the degree to which select BNP-cytotoxic/NNP-DLN conditioning combinations can be enhanced by co-delivery with TME conditioning BNP-IL-12 mRNA, and use TotalSeq-C mouse CiteSeq scRNAseq/TCRseq with BaseScope and DBiTseq to identify tumor specific cells, TME transcriptional changes and spatial organization to better understand locoregional strategies. (3) Assess the capacity of systemically administered immune checkpoint inhibition to augment the anti-tumor effects of intratumoral BNP-cytotoxic agents, with and without BNP/NNP co- delivered local immune conditioning agents, to optimally treat melanoma tumors and limit metastatic melanoma. Through completion of these aims, we will advance our control of locoregional therapies for melanoma, and prepare for translation of these technologies to human melanoma patients. Project Number: 1R01CA292870-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: MICHAEL GIRARDI (+1 co-PI) | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $610,637 | Activity Code: R01 | Study Section: Therapeutic Immune Regulation Study Section[TIR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11293752