Project Grant R43CA287501

A NOVEL TARGETED ANTIBODY THERAPEUTIC TO TREAT OVARIAN CANCER - PROJECT SUMMARY OVARIAN CANCER (OVCA) IS THE FIFTH LEADING CAUSE OF CANCER DEATHS FOR WOMEN AND IS ASSOCIATED WITH VERY LOW SURVIVABILITY. CURRENT TREATMENT STRATEGIES FOR OVCA LARGELY INCLUDE SURGERY AND CHEMOTHERAPY. CHEMOTHERAPY, WHICH OFTEN INVOLVES PLATINUM-CONTAINING DRUGS AND TAXANES, CAN BE EFFECTIVE; HOWEVER, MANY PATIENTS EXPERIENCE COMPLICATIONS DUE TO SIDE EFFECTS AND/OR RESISTANCE TO THE CHEMOTHERAPY. ALTERNATIVE OPTIONS ARE NEEDED TO PROVIDE EFFECTIVE TREATMENT STRATEGIES FOR OVCA PATIENTS. IMMUNO-ONCOLOGY (IO) DRUGS HAVE SHOWN TO IMPROVE TREATMENT OUTCOMES FOR SOME CANCERS BY ENABLING A PATIENT'S IMMUNE SYSTEM TO LAUNCH AN IMMUNE ATTACK AGAINST THE TUMOR. HOWEVER, THE EFFICACY OF CURRENT IO DRUGS (E.G., IMMUNE CHECKPOINT INHIBITORS (ICIS)) IS LOW DUE TO THEIR INABILITY TO GENERATE IMMUNOGENIC TUMORS. CURRENT IO DRUGS STOP IMMUNOSUPPRESSION ONLY FROM CANCER CELLS; IMMUNOSUPPRESSION FROM IMMUNOSUPPRESSOR CELLS SUCH AS THE MYELOID DERIVED SUPPRESSOR CELLS (MDSCS) REMAINS INTACT THEREBY SUSTAINING AN IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT. WHILE ELIMINATING MDSCS IS PERCEIVED AS A STRATEGY FOR OVERCOMING IMMUNOSUPPRESSION, CLINICAL TRIALS HAVE SHOWN THAT ELIMINATING MDSCS ALONE IS INSUFFICIENT TO REDUCE TUMOR BURDEN. CURRENT DRUGS THAT CAN ELIMINATE MDSCS ARE UNSUITABLE AS THEY LACK SELECTIVITY TO TARGET MDSCS AND NON-SPECIFICALLY DEPLETE OTHER IMMUNE CELLS. HENCE, TUMOR SPECIFIC ELIMINATION OF ONLY MDSCS WHILST ELIMINATING CANCER CELLS IS A MAJOR UNMET CLINICAL NEED. TRIO PHARMACEUTICALS (TRIO) IS FULFILLING THE NEED BY DEVELOPING A NEW CLASS OF CANCER DRUGS, REFERRED TO AS TRAILBODY, WHICH ARE DESIGNED TO ELIMINATE BOTH CANCER CELLS AND MDSCS BY SELECTIVE ACTIVATION OF TRAIL-R2 MEDIATED APOPTOSIS WITHOUT ENGAGING IMMUNE EFFECTOR CELLS AND CONJUGATED TOXINS. TRAILBODIES TARGET CANCER CELLS BY BINDING A TUMOR SPECIFIC ANTIGEN AND TARGET MDSCS BY BINDING FCGRII. TRAILBODIES ELIMINATE BOTH CANCER CELLS AND MDSCS BY TRAIL-R2 MEDIATED APOPTOSIS UPON ENGAGING THE TUMOR SPECIFIC ANTIGEN AND FCGRII, RESPECTIVELY. IN THIS SBIR PROPOSAL, TRIO IS DEVELOPING A TRAILBODY FOR OVCA: AFOLR1 TRAIL-R2, REFERRED TO AS TRIO-628. TRIO-628 IS DESIGNED TO IMPROVE OVCA TREATMENT EFFICACY BY GENERATING IMMUNOGENIC TUMORS VIA ELIMINATING CANCER CELLS BY TARGETING FOLR1 (OVEREXPRESSED IN OVCA) AND ELIMINATING MDSCS BY TARGETING FCGRII. PRELIMINARY STUDIES HAVE SHOWN A HIGH DEGREE OF SELECTIVITY OF AFOLR1 TRAIL- R2 FOR ITS TARGETS AND ENHANCED ANTI-TUMOR ACTIVITY IN COMPARISON TO LEXATUMUMAB. THE GOAL OF THE PHASE I PROGRAM IS TO ESTABLISH TRIO-628 AS AN OVCA DRUG. THIS GOAL WILL BE MET THROUGH THE EXECUTION OF TWO SPECIFIC AIMS, WHICH WILL INVOLVE IN VITRO ASSESSMENTS OF THE SELECTIVITY OF TRIO-628 IN DEPLETING MDSCS AND ENHANCING TUMOR IMMUNITY AND AN IN VIVO EFFICACY STUDY OF TRIO-228 USING A PLATINUM RESISTANT PATIENT-DERIVED XENOGRAFT MODEL. SUCCESSFUL COMPLETION OF PHASE I WILL PROVIDE CRITICAL IN VIVO PROOF-OF-CONCEPT DATA FOR USING TRIO-628 TO TREAT OVCA AND SUPPORT A PHASE II PROPOSAL FOCUSED ON SAFETY AND TOLERABILITY STUDIES AND TRANSLATION STUDIES TO ADVANCE THE IND EFFORTS.