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. Public Health Relevance Statement Narrative: Pancreatic cancer has the worst prognosis of all cancers; the tumor-associated form of MUC1 (tMUC1) is overexpressed and aberrantly glycosylated in >80% of human pancreatic ductal adenocarcinoma (PDA). We propose to use a novel tMUC1/CD3 bispecific antibody, MUCD3, to recruit and re-engage CD3+ T cells to target and kill PDA cells that express tMUC1 both in vitro and in vivo; for treating resistant PDA cells, we propose to combine the MUCD3 bispecific antibody with an immune checkpoint (IDO1) inhibitor or with standard-of-care chemotherapeutic drugs. Preliminary data are very promising and therefore, successful completion of this project will lead to a targeted treatment for refractory PDAs.
Project Terms: inhibitor/antagonist ; inhibitor ; Antibodies ; Antigens ; immunogen ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Cessation of life ; Death ; Diagnosis ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Epithelial Cells ; Fluorouracil ; 5-FU ; 5-Fluracil ; 5FU ; Fluoro Uracil ; Fluoruracil ; Fluouracil ; Glycoproteins ; Goals ; Human ; Modern Man ; Immunotherapy ; Immune mediated therapy ; Immunologically Directed Therapy ; immune therapeutic approach ; immune therapeutic interventions ; immune therapeutic regimens ; immune therapeutic strategy ; immune therapy ; immune-based therapies ; immune-based treatments ; immuno therapy ; In Vitro ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Light ; Photoradiation ; men ; men's ; Mucins ; Mucus Glycoprotein ; Neoplasm Metastasis ; Metastasis ; Metastasize ; Metastatic Lesion ; Metastatic Mass ; Metastatic Neoplasm ; Metastatic Tumor ; Secondary Neoplasm ; Secondary Tumor ; cancer metastasis ; tumor cell metastasis ; Patients ; Phenotype ; Publishing ; Survival Rate ; T-Lymphocyte ; T-Cells ; thymus derived lymphocyte ; Tissues ; Body Tissues ; Tumor Antibodies ; Neoplasm Antibodies ; anti-tumor antibody ; antitumor antibody ; Tumor Antigens ; Tumor-Associated Antigen ; cancer antigens ; tumor-specific antigen ; Woman ; gemcitabine ; Difluorodeoxycytidine ; dFdC ; dFdCyd ; Mediating ; CD3 Antigens ; CD3 ; CD3 Complex ; CD3 molecule ; OKT3 antigen ; T3 Antigens ; T3 Complex ; T3 molecule ; Paclitaxel ; Anzatax ; Asotax ; Bristaxol ; Paclitaxel (Taxol) ; Praxel ; Taxol ; Taxol A ; Taxol Konzentrat ; Organ ; improved ; Apical ; Surface ; Refractory ; Long-Term Survivors ; longterm survivors ; Bispecific Antibodies ; Bi-specific antibodies ; Bifunctional Antibodies ; bsAb ; Predisposition ; Susceptibility ; Epithelial ; Body part ; cancer immunotherapy ; anti-cancer immunotherapy ; anticancer immunotherapy ; immune-based cancer therapies ; immunotherapy for cancer ; immunotherapy of cancer ; Solid Neoplasm ; Solid Tumor ; Antibody Therapy ; antibody based therapies ; antibody treatment ; antibody-based therapeutics ; antibody-based treatment ; Collaborations ; Cell-Mediated Lympholysis ; Cellular Cytotoxicity ; Lymphocyte Cytotoxicity ; Lymphocytotoxicity ; cell mediated cytotoxicity ; Cell-Mediated Cytolysis ; Effector Cell ; Malignant Cell ; cancer cell ; Malignant Pancreatic Neoplasm ; Pancreas Cancer ; Pancreatic Cancer ; pancreatic malignancy ; Malignant neoplasm of pancreas ; Life ; Scientist ; Immunes ; Immune ; Distant ; Drug Sensitization ; interest ; exocrine pancreatic ; Exocrine pancreas ; indoleamine ; membrane structure ; Membrane ; Tumor Cell ; neoplastic cell ; success ; tumor growth ; cell killing ; PBMC ; Peripheral Blood Mononuclear Cell ; Dioxygenases ; expectation ; novel ; Modality ; Abscission ; Extirpation ; Removal ; Surgical Removal ; resection ; Excision ; Modeling ; anti-tumor immune therapy ; anti-tumor immunotherapy ; antitumor immune therapy ; antitumor immunotherapy ; tumor immune therapy ; tumor immunotherapy ; neoplasm immunotherapy ; T-Cell Activation ; Molecular Interaction ; Binding ; Lysis ; Cytolysis ; immunological synapse formation ; Pancreas Ductal Adenocarcinoma ; Pancreatic Ductal Adenocarcinoma ; infiltrating ductal adenocarcinoma ; infiltrating ductal carcinoma ; invasive ductal adenocarcinoma ; invasive ductal carcinoma ; infiltrating duct carcinoma ; Dose ; Data ; breast tumor cell ; Breast Cancer Cell ; MUC-1 ; MUC1 ; MUC1 gene product ; Muc1 Mucin ; Mucin 1 ; Mucin 1 protein ; Stage at Diagnosis ; in vivo ; Antigen Targeting ; triple-negative invasive breast carcinoma ; TNBC ; triple-negative breast cancer ; design ; designing ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; Resistance ; resistant ; combinatorial ; chemotherapy ; mouse model ; murine model ; tumor ; overexpression ; overexpress ; standard of care ; efficacy testing ; chimeric antigen receptor ; chimeric antigen T cell receptor ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; immune checkpoint ; immune check point ; immunecheckpoint ; recruit ; effector T cell ; Teff cell ; engineered T cells ; chimeric antigen receptor T cells ; CAR T cells ; T cells for CAR ; chimeric antigen receptor (CAR) T cells ; CAR T cell therapy ; CAR T therapy ; chimeric antigen receptor (CAR) T cell therapy ; chimeric antigen receptor T cell therapy ; pancreatic ductal adenocarcinoma cell ; PDAC cancer cell ; PDAC cell ; pancreatic ductal adenocarcinoma model ; PDA model ; PDAC Model ; Prognosis ;
