Project Grant R43CA271923

A DUAL ACTION ANTIBODY DRUG CONJUGATE TO TREAT TRIPLE NEGATIVE BREAST CANCER BY ENHANCING TUMOR IMMUNITY - PROJECT SUMMARY TRIPLE NEGATIVE BREAST CANCER (TNBC) IS THE MOST AGGRESSIVE FORM OF BREAST CANCER ACCOUNTING FOR 15% OF ALL BREAST CANCERS AND IS WIDELY PREVALENT IN WOMEN < 50 YEARS OLD. DESPITE NEW TREATMENTS, THE SURVIVABILITY OF TNBC PATIENTS IS POOR. RECENTLY, IMMUNO-ONCOLOGY (IO) THERAPIES DEMONSTRATED THE POTENTIAL TO IMPROVE TREATMENT OUTCOMES BY ENABLING A PATIENT'S IMMUNE SYSTEM TO LAUNCH AN ATTACK AGAINST THE TUMOR. WHILE IO DRUGS IMPROVED TREATMENT OUTCOME, THEIR RESPONSE RATE HAS NOT REACHED FULL POTENTIAL AS THEY ARE UNABLE TO GENERATE IMMUNOGENIC TUMORS. IO DRUGS SOLELY REMOVE IMMUNOSUPPRESSION FROM CANCER CELLS LEAVING IMMUNOSUPPRESSION FROM IMMUNOSUPPRESSOR CELLS INTACT, THUS RETAINING AN IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT (TME) WHEREBY THE IMMUNE SYSTEM IS UNABLE TO LAUNCH AN EFFECTIVE ATTACK AGAINST THE REMAINING TUMOR RESULTING IN REDUCED EFFICACY OF IO DRUGS. TO CIRCUMVENT THIS PROBLEM, VARIOUS STRATEGIES ARE CONSIDERED TO CREATE IMMUNOGENIC TUMORS (E.G., ELIMINATING IMMUNOSUPPRESSOR CELLS ALONE OR COMBINING DRUGS TO ELIMINATE BOTH CANCER CELLS AND IMMUNOSUPPRESSOR CELLS). HOWEVER, CURRENTLY AVAILABLE APPROACHES CAN LEAD TO IMMUNE TOXICITIES DUE TO NON-SPECIFIC ELIMINATION OF IMMUNE CELLS OUTSIDE OF THE TME. THUS, THERE IS A NEED TO DEVELOP TREATMENT STRATEGIES TO SELECTIVELY ELIMINATE IMMUNOSUPPRESSOR CELLS WITHIN THE TME, WHILST ALSO ELIMINATING CANCER CELLS TO EFFECTIVELY CREATE AN IMMUNOGENIC TUMOR TO FACILITATE TUMOR REMOVAL BY THE IMMUNE SYSTEM. TO ADDRESS THIS NEED, TRIO PHARMACEUTICALS (TRIO) IS DEVELOPING A PROPRIETARY DUAL-ACTION DRUG, TUMOR IMMUNOGENICITY ENHANCING ANTIBODY CONJUGATE (TIEAC), THAT GENERATES IMMUNOGENIC TUMORS BY TUMOR- SPECIFIC ELIMINATION OF BOTH CANCER CELLS AND IMMUNOSUPPRESSOR CELLS. FOR THIS PHASE I PROGRAM, TRIO IS DEVELOPING A TIEAC FOR TNBC, REFERRED TO AS TRIO-525. TRIO-525 AIMS TO IMPROVE TREATMENT OUTCOMES IN TNBC PATIENTS BY GENERATING IMMUNOGENIC TUMORS BY TUMOR-SPECIFIC ELIMINATION OF TNBC CELLS AND IMMUNOSUPPRESSOR CELLS. THIS ENABLES IMMUNE EFFECTOR CELLS TO LAUNCH AN EFFECTIVE ATTACK AGAINST THE TUMOR. OUR KEY INNOVATIONS INCLUDE: 1) ELIMINATING TME-RESIDING IMMUNOSUPPRESSOR CELLS BY ENRICHING THE DRUG IN THE TUMOR ANTIGEN RICH TUMOR; 2) SELECTIVE TARGETING OF IMMUNOSUPPRESSOR CELLS BY A NOVEL DESIGN TO BIND A SPECIFIC RECEPTOR TO ALLOW ELIMINATING IMMUNOSUPPRESSOR CELLS WITHOUT DEPLETING OTHER IMMUNE CELLS THEREBY LOWERING IMMUNE TOXICITY. PRELIMINARY DATA SHOWN TRIO-525 EXHIBITS SINGLE-AGENT ACTIVITY IN PRECLINICAL CANCER MODELS WITH TUMOR- SELECTIVE DUAL FUNCTIONALITY FOR ELIMINATING TNBC CELLS AND IMMUNOSUPPRESSOR CELLS. HEREIN, THE OVERALL PHASE I GOAL IS TO ESTABLISH TRIO-525 AS AN EFFECTIVE NOVEL THERAPY FOR TNBC ACCOMPLISHED BY TWO AIMS: I) SELECTIVITY OF TRIO-525 IN DEPLETING IMMUNOSUPPRESSOR CELLS AND AUGMENTING T-CELL RESPONSES IN VITRO; AND II) THERAPEUTIC EFFICACY STUDIES IN CLINICALLY RELEVANT MODELS IN VIVO. SUCCESSFUL COMPLETION OF PHASE I WILL PROVIDE DATA TO DE-RISK TRIO-525 AS A PROMISING THERAPY AND DE-RISK PHASE II PROPOSAL OF SAFETY AND TRANSLATION STUDIES TO ADVANCE THE IND EFFORTS.