In situ tumor vaccination with a nano-oligo therapeutic to induce whole-body antitumor immune response - significance/goal

Although immune checkpoint inhibitors (icis) have shown impressive outcomes in melanoma patients, the majority of patients fail to respond, mainly due to the absence of tumor-infiltrating t cells. In order to boost the anti-tumor t cell repertoire, we have developed a novel immuno-nanotherapeutic, called "augmenting immune response and inhibiting suppressive environment of tumors - airise-02", based on our patent-pending nanoparticle (NP) CO-delivering an immune-activating CPG oligo and sirna against STAT3. Airise-02 relies on "in situ tumor vaccination," which exploits a locally treated tumor to prime immune response against tumors throughout the body. Unique to airise-02 is the ability to enter both cancer and antigen presenting cells (e.g., DC, macrophage) upon intratumoral (I.T.) injection, resulting in cancer cell death and tumor antigen release, while being safe to and activating the antigen presenting cells. By knocking down STAT3 with sirna, airise-02 also modulates immunosuppressive environment of the tumor. Given I.T. To only one melanoma tumor, airise-02 caused regression in both treated and untreated distant tumors, demonstrating whole-body immunotherapeutic action. Airise-02 was as effective as two icis (PD-1 + ctla- 4, given I.P.) combined, and led to complete cures in 5 out of 8 mice when given with the icis. The mice have remained tumor-free for at least 17 months, while mice receiving just icis did not survive past 2 months. Airise-02 was also effective in colon and breast cancer mouse models and was well tolerated in monkeys. Approach. This direct phase II sbir focuses on IND-enabling studies of airise-02. In aim 1, we will establish the mechanism of airise-02 by identifying key immune cells required for therapeutic action and confirm efficacy in another clinically relevant melanoma model. In aim 2, we will partner with cmos for manufacturing GMP-compliant airise-02 (SISTAT3, CPG, and NP), sterilization, fill finishes, and stability studies. In aim 3, we will work with charles river toxicology to conduct GLP-compliant toxicology studies of airise-02 in mice and cynomolgus monkeys. The maximum tolerated dose and toxicokinetic profile will be established. Potential toxicity after repeated doses will be assessed by monitoring body weight, general health, injection site reaction, hematology, serum chemistry/cytokines, and histopathology of key organs. In aim 4, we will partner with RTI international and knight cancer institute's center of experimental therapeutics to submit an IND application to enable phase i clinical trial in early 2023. Novelty and impact. Nanoparticle CO-delivery of sirna and adjuvant for in situ cancer vaccination has never been done before. Successful airise-02 will benefit many injectable tumors (e.g., melanoma, breast, lymphoma, head and neck) with metastasis anywhere. Future target discovery can lead to new airise pipelines utilizing other sirnas. Our nanoparticle has been extensively evaluated and synthesized at large-scale, and I.T. Airise-02 limits systemic toxicity, together facilitating rapid translation of airise-02 to the clinic.