Spatial control of synthetic immunogenic cytotoxicity for the treatment of locally advanced lung cancer - Roughly 50,000 patients are diagnosed with locally advanced non-small cell lung cancer (NSCLC) in the US each year. For those with unresectable disease, 5-year survival rates remain below 50% despite aggressive multimodal treatment with chemotherapy, localized X-ray radiation therapy (XRT), and PD1-targeted immune checkpoint inhibition (ICI). Improving durable response hinges on more efficiently killing cancer cells and overcoming ICI resistance, and it is appealing to achieve both by stimulating immunogenic cancer cell death that triggers tumor antigen release and reprograms immunosuppressive signaling. Although XRT is used with increasing spatial precision, co-administered drugs typically distribute throughout the body, and life-threatening off-target side effects remain common in chemoradiotherapy trials. A major unmet need, therefore, lies in developing treatments that efficiently kill cancer cells and stimulate anti-cancer immune responses in tumors while eliminating off-target toxicities. We address these challenges through a new platform for localized drug delivery, termed SPIDER (synthetic potentiated immunogenic depot engaged by radiation). Enabled by radiation-responsive nanoparticles, SPIDER selectively uncages and releases potent drug payloads only when exposed to clinical doses of XRT. Cytotoxic and immunomodulatory prodrugs are covalently anchored to SPIDER nanoparticles in an inactive form, and are selectively and “bioorthogonally” released upon X-ray absorption. Once cleaved, reservoirs of active payloads show sustained release to kill cancer cells, aiming to generate immunostimulatory tumor debris that is co-delivered with synthetic SPIDER adjuvants to antigen-presenting myeloid cells. In preliminary experiments, SPIDER prototypes show sustained pharmacokinetics, efficient tumor accumulation, payload release in irradiated tissue, and metabolic stability with little off-target release in unirradiated tissue; they block tumor progression in syngeneic and orthotopic mouse models; and they enable >10x higher doses of drug to be given with fewer toxicities. Nonetheless, major knowledge gaps remain in understanding mechanisms of cellular response to SPIDER in the tumor microenvironment and how it compares to traditional drug delivery strategies. The three aims of this project are i) to evaluate mechanisms of SPIDER cytotoxicity and immunogenic bystander effects; ii) assess SPIDER toxicity, pharmacokinetics, and short-term tissue responses in lung tumors; and iii) evaluate the longitudinal efficacy and toxicity in treating mouse models of lung adenocarcinoma in combination with XRT and ICI. To achieve these aims, we bring together diverse expertise in drug delivery, radiation and NSCLC medical oncology, medical physics, biostatistics, and cancer immunology. This project advances radiation-activated drug delivery for overcoming radioresistance and immunosuppression in the tumor microenvironment, and achieving its goals will set a foundation of fundamental and translational knowledge to achieve safer and more effective treatments.
