Project Grant R41CA265619

THE USE OF TMUC1/CD3 BISPECIFIC ANTIBODY TO CONTROL PANCREATIC DUCTAL ADENOCARCINOMA - BISPECIFIC ANTIBODIES (BSABS) ARE AN EMERGING CANCER IMMUNOTHERAPY STRATEGY TO RE-ENGAGE IMMUNE EFFECTORS WITH TUMOR CELLS THUS TO PROMOTE IMMUNE SYNAPSE FORMATION AND INDUCE TUMOR CYTOLYSIS. THE BSABS TARGET TUMOR ASSOCIATED ANTIGEN (TAA) AND EFFECTOR CELL ANTIGEN SIMULTANEOUSLY. THE SUCCESS OF BSABS THERAPY LARGELY RELIES ON IDENTIFYING TAA AND THE HIGHLY SPECIFIC TAA-TARGETING ANTIBODIES. PANCREATIC CANCER HAS THE WORST PROGNOSIS OF ALL CANCERS. IF THE CANCER IS DETECTED AT AN EARLY STAGE WHEN SURGICAL REMOVAL OF THE TUMOR IS POSSIBLE, THE 5-YEAR SURVIVAL RATE IS 34%. ABOUT 10% OF PEOPLE ARE DIAGNOSED AT THIS STAGE. IF THE CANCER HAS SPREAD TO SURROUNDING TISSUES OR ORGANS, THE 5-YEAR SURVIVAL RATE IS 12%. FOR THE 52% OF PEOPLE WHO ARE DIAGNOSED AFTER THE CANCER HAS SPREAD TO A DISTANT PART OF THE BODY, THE 5-YEAR SURVIVAL RATE IS 3%. IN 2020, IT IS ESTIMATED THAT THERE WILL BE 57,600 NEW CASES (30,400 MEN AND 27,200 WOMEN) AND 47,050 DEATHS DUE TO THIS DISEASE IN THE US. THE MEAN EXPECTATION OF LIFE IS LESS THAN SIX MONTHS AND THERE ARE FEW LONG-TERM SURVIVORS. INFILTRATING DUCTAL ADENOCARCINOMA OF THE PANCREAS (PDA) ACCOUNTS FOR OVER 95% OF ALL EXOCRINE PANCREATIC MALIGNANCIES. MUC1 (CD227) IS A MEMBRANE TETHERED MUCIN GLYCOPROTEIN EXPRESSED ON THE APICAL SURFACES OF NORMAL GLANDULAR EPITHELIA BUT IS OVEREXPRESSED AND ABERRANTLY GLYCOSYLATED IN >80% OF HUMAN PDA. TUMOR ASSOCIATED MUC1 (TMUC1) IS KNOWN TO BE ASSOCIATED WITH THE METASTATIC PHENOTYPE OF CANCER CELLS. THE TMUC1 IS IDENTIFIED AS THE SECOND BEST TARGET FOR IMMUNOTHERAPY BY NCI. RECENTLY IN COLLABORATION WITH DUALOGICS LLC, WE HAVE SUCCESSFULLY DEVELOPED SEVERAL NOVEL BSABS WHICH BIND TMUC1 ON TUMOR CELLS AND CD3 ON T EFFECTOR CELLS. THOSE BSABS SHOW THERAPEUTIC EFFICACY AGAINST TRIPLE NEGATIVE BREAST CANCER CELLS IN VITRO. PDA CELLS HAVE BEEN KNOWN TO BE HIGHLY REFRACTORY TO TREATMENTS. WE HAVE DEMONSTRATED THAT THE INTRINSIC IMMUNE CHECKPOINT FACTORS IN THE PDA CELLS SUCH AS INDOLEAMINE 2, 3 DIOXYGENASE (IDO1) PARTIALLY ACCOUNT FOR THE PDA RESISTANCE TO OUR CHIMERIC ANTIGEN RECEPTOR (CAR) ENGINEERED T CELL-MEDIATED KILLING. FURTHERMORE, WE ALSO SHOWED THAT SUBOPTIMAL DOSES OF CHEMOTHERAPY DRUGS LIKE 5-FLUOROURACIL, GEMCITABINE, AND PACLITAXEL COULD BREAK DOWN THE PDA RESISTANCE AND SYNERGIZE WITH CAR T CELLS FOR PDA CYTOLYSIS. THEREFORE, WE HYPOTHESIZE THAT PDA CAN BE SPECIFICALLY TARGETED WITH THE TMUC1/CD3 BISPECIFIC ANTIBODY, MUCD3. COMBINING MUCD3 WITH IDO1 INHIBITOR (1MT) OR STANDARD-OF-CARE CHEMOTHERAPY WILL ENHANCE THE ANTI-TUMOR EFFICACY OF MUCD3. SPECIFIC AIMS ARE TO DEMONSTRATE MUCD3 MEDIATED TUMOR KILLING OF HUMAN PDA IN VITRO AND IN VIVO IN THE APPROPRIATE MODELS WITH AND WITHOUT COMBINATIONS. WHEN SUCCESSFUL, IT WILL PROVIDE A NEW EFFECTIVE MODALITY FOR CANCER IMMUNOTHERAPY TARGETING AT TMUC1-EXPRESSING SOLID TUMORS.