Project Grant R44CA265751

NOVEL NANO-IMMUNOTHERAPY FOR TREATMENT OF NON-SMALL CELL LUNG CANCER - TREATMENT OF NON-SMALL CELL LUNG CANCER (NSCLC) TYPICALLY, WHICH REQUIRES A COMBINATION OF MANY HIGHLY TOXIC DRUGS AND RADIATION THERAPY, IS NOT CURATIVE. IMMUNE CHECKPOINT INHIBITORS (ICIS) TARGETING PD-L1/PD-1 ARE CAUSING A PARADIGM SHIFT IN NSCLC TREATMENT, YET THE 5-YEAR SURVIVAL RATE REMAINS BELOW 20%. THIS FAST-TRACK SBIR APPLICATION AIMS TO DEVELOP A NOVEL NANO-IMMUNOTHERAPY (TERMED ARAC - ANTIGEN RELEASE AGENT AND CHECKPOINT INHIBITOR) THAT CAN GREATLY IMPROVE THE EFFICACY OF ICIS LEADING TO CURATIVE OUTCOMES FOR NSCLC PATIENTS. ARAC IS BUILT UPON OUR CORE NANOPARTICLE PLATFORM CAPABLE OF CO-DELIVERING MULTIPLE THERAPEUTIC AGENTS, WHILE KEEPING A SMALL SIZE IN SALINE (100 NM), SUITABLE FOR INFUSION AND TUMOR ACCUMULATION. THE PROPOSED ARAC-02 WILL CO-DELIVER A POLO-LIKE KINASE 1 (PLK1)-TARGETED THERAPY (VOLASERTIB), A PD-L1 ANTIBODY, AND THE IMMUNE-STIMULANT CPG. VOLASERTIB 1) SELECTIVELY KILLS CANCER CELLS, 2) MODULATES THE IMMUNE-SUPPRESSIVE TUMOR MICROENVIRONMENT, AND 3) UPREGULATES PD-L1 EXPRESSION IN CANCER CELLS, PROVIDING OPPORTUNITY FOR TARGETED DELIVERY WITH PD-L1 ANTIBODY ON THE NANOPARTICLES. CPG IS AN OLIGONUCLEOTIDE THAT ENHANCES ANTIGEN PRESENTATION TO GENERATE TUMOR-SPECIFIC T CELLS. THE NANOPARTICLES CONTAIN A VERY HIGH SURFACE DENSITY OF PD-L1 ANTIBODIES (TWO THOUSAND PER PARTICLE), WHICH PROMOTES BINDING TO PD-L1 MOLECULES ON CANCER CELLS, FOLLOWED BY INTERNALIZATION AND PD-L1 DEGRADATION (AS EFFECTIVE AS 30-FOLD FREE PD-L1 ANTIBODY), RELEASING THE BRAKES AND ALLOWING T CELLS TO ATTACK THE CANCER. WHEN GIVEN INTRAVENOUSLY TO MICE BEARING LUNG TUMORS, THE NANOPARTICLE CO-DELIVERING VOLASERTIB AND PD-L1 ANTIBODY REDUCED THE NECESSARY DOSE FOR EFFICACY OF EACH DRUG BY 5-FOLD. ADDING CPG TO THE NANOCONSTRUCTS TRIGGERS GREATER ADAPTIVE ANTI-CANCER IMMUNITY IN A BILATERAL NSCLC MOUSE MODEL, LEADING TO COMPLETE CURES FOR SOME MICE. THE PLATFORM WAS ALSO FOUND TO BE SAFE IN MONKEYS. IN PHASE I (AIM 1), ARAC-02 WILL BE OPTIMIZED FOR LOADING OF VOLASERTIB, PD-L1 ANTIBODY, AND CPG. MATERIALS WILL BE SCREENED FOR SIZE, TARGETING SPECIFICITY, EFFICACY IN NSCLC CELLS, AND EFFICACY AND SAFETY IN MICE. IN PHASE II, THE PHARMACOKINETIC, BIODISTRIBUTION, EFFICACY, AND SAFETY OF THE OPTIMAL ARAC-02 WILL BE ASSESSED, BOTH ALONE (AIM 2) AND IN COMBINATION WITH THE CURRENT FIRST-LINE IMMUNOTHERAPY (AIM 3). CLINICALLY RELEVANT ORTHOTOPIC NSCLC MOUSE MODELS THAT ARE RESISTANT TO ICIS WILL BE UTILIZED, AND FINDINGS WILL BE VALIDATED IN HUMANIZED MICE BEARING TWO DIFFERENT PATIENT-DERIVED TUMORS THAT REPRESENT HETEROGENEOUS NSCLC IN PATIENTS. THE FREE DRUGS, SINGLE-DRUG-LOADED NANOPARTICLES, AND FIRST-LINE IMMUNOTHERAPY WILL BE USED AS BENCHMARKS. DUE TO ITS UNIQUE ABILITY TO STIMULATE VARIOUS STEPS OF THE ADAPTIVE IMMUNE RESPONSE, ARAC-02 IS ANTICIPATED TO PROVIDE CURATIVE OUTCOMES, ESPECIALLY WHEN USED WITH CURRENT ICIS FOR COMPLETE BLOCKADE. ARAC-02 CAN UPREGULATE PD-L1 LEVELS THEREBY PROMOTING EFFICACY IN A BROAD RANGE OF TUMOR TYPES REGARDLESS OF BASELINE PD- L1 LEVELS. OUTCOMES WILL BE CANDIDATE SELECTION AND CRITICAL DATA TOWARDS AN IND APPLICATION AND CLINICAL TRIALS.