Metastatic diseases are responsible for 90% of cancer-related deaths and remain as a paramount challenge in patient care. In recent years, immunotherapy showed promising durable responses in cancer patients. However, generation and sustenance of robust antitumor immunity in metastatic cancers is still a challenging task. In this application, we aim to develop an intravenously injectable nano-immune-therapeutic that turns on innate immune pathways for T cell therapy of metastatic cancers. The technology is based on an ultra-pH sensitive (UPS) nanoparticle platform that was invented as a result of our past CPRIT support. By targeting tumor acidic microenvironment, we successfully imaged a ...

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Metastatic diseases are responsible for 90% of cancer-related deaths and remain as a paramount challenge in patient care. In recent years, immunotherapy showed promising durable responses in cancer patients. However, generation and sustenance of robust antitumor immunity in metastatic cancers is still a challenging task.

In this application, we aim to develop an intravenously injectable nano-immune-therapeutic that turns on innate immune pathways for T cell therapy of metastatic cancers. The technology is based on an ultra-pH sensitive (UPS) nanoparticle platform that was invented as a result of our past CPRIT support. By targeting tumor acidic microenvironment, we successfully imaged a broad range of solid cancers with binary demarcation of tumor margins that resulted in improved surgical outcomes in mouse tumor models. Currently, a pH-activatable UPS nanoprobe (ONM-100) has completed the Phase 1 trial in 30 cancer patients with diverse tumor types. The nanoprobe achieved 100% detection of primary cancers as well as identified 30% unknown metastatic diseases. Success in the ONM-100 program established the clinical precedence for the tumor-targeted delivery and activation of a payload in the acidic tumor microenvironment.

This application will investigate the UPS system to deliver drugs that target STING. We will investigate a "hitch-hiking" mechanism to deliver PC7A polymer and a STING ligand to turn a cold tumor into a hot tumor. To establish an intravenously injectable STING agonists, we will develop a series of theranostic hybrid UPS nanoparticles with increased accumulation in metastatic tumors and lymphoid organs. We will investigate the mechanism of the targeting specificity from hybrid UPS NPs by fluorescence imaging and evaluate the innate immune activation in metastatic tumor models. We anticipate success from this study will introduce a tumor-activatable immune therapeutic that produces safe and robust antitumor immunity in metastatic cancers.

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