Pancreatic cancer has the worst prognosis of all cancers and is the fourth leading cause of cancer-related deaths in the United States. Patients usually present with advanced disease, making curative attempts difficult. Surgery is the only curative therapy since radiotherapy and chemotherapy remain largely ineffective coupled with undesirable side effects. Despite the great excitement over targeted therapies such as kinase inhibitors, resistance always arises, making them at best debulking agents. Further, targeted therapies often do not increase long-term survival, while immunotherapies may. Indeed, immunotherapy has been shown to overcome resistance. A number of active monoclonal antibodies (mAb) such as Herceptin, Erbitux, and Rituxan and several others are already approved for treatment of certain cancers. However, to generate long term sustained anti-tumor response, mAbs require T cell help. There is clinical evidence for mAbs-driven T cell immunity. IL-2 is a well-established cytokine that can potentiate mAbs via improved NK ADCC. However, in clinical trials, IL2 has shown minimal clinical benefit when administered in combination with mAbs mostly because IL-2 does not stay in circulation for long. Dr. Wittrup (collaborator) has been successful in increasing IL-2 PK exposure via Fc or Albumin (MSA) fusion. More importantly, we have generated strong preliminary data that Fc/MSA-IL-2 can potentiate several mAb activities in immune competent mouse models of cancer. We have recently patented a unique tMUC1 antibody (designated TAB 004) that reacts strongly with tumor tissue but does not bind to normal epithelia. MUC1 is over-expressed in an altered form in more than 80 and 90% pancreatic ductal adenocarcinoma (PDA) and metastatic lesions, respectively. In addition, we have generated human MUC1-expressing pancreatic ductal adenocarcinoma model (PDA.MUC1 mice). Cell lines from these tumors have also been generated and tagged with luciferase for in vivo imaging. We hypothesize that TAB 004 + Lip-MSA-IL-2 will be therapeutic and will strongly suppress tumor growth by 1) activating effector CD8 T cells and recruiting neutrophils and 2) increasing NK cell ADCC. Specific Aims are 1) to assess tumor growth and metastasis in response to Lip-MSA-IL-2 + TAB 004 in the spontaneous and orthotopic PDA models using the IVIS imaging system; and 2) to assess the immune responses induced by the combination. Successful achievement of Phase I STTR will pave the way for a clinical trial. The implications from these studies could be far-reaching and could lead to an improved therapeutic strategy for pancreatic cancer.
Public Health Relevance Statement: Public Health Relevance: We propose to develop a therapeutic product for the treatment of pancreatic cancer. We will explore if the therapeutic efficacy of a tumor-specific antibody can be enhanced when administered in conjunction with a long lasting liposomal-MSA-IL-2. Data from this study will form the basis for future clinical trials and development of a FDA approved drug for patients with pancreatic cancer.
NIH Spending Category: Biotechnology; Cancer; Digestive Diseases; Immunization; Orphan Drug; Pancreatic Cancer; Precision Medicine; Rare Diseases; Vaccine Related
Project Terms: Achievement; advanced disease; Adverse effects; Albumins; Antibodies; Apical; base; Binding; Biotechnology; Blood Circulation; Cancer Etiology; CD8B1 gene; Cell Line; Cessation of life; chemotherapy; Clinical; Clinical Trials; commercialization; Coupled; curative treatments; cytokine; Data; design; Development; Disease; Disease Outcome; Distant Metastasis; efficacy testing; Epithelial Cells; Epithelium; Erbitux; FDA approved; Future; Generations; Glycoproteins; glycosylation; Goals; head-to-head comparison; Hormonal; Human; human disease; IL2 gene; imaging system; Immune; Immune response; Immunity; Immunization; Immunotherapy; improved; in vivo; in vivo imaging; Institutes; Interleukin-2; Journals; kinase inhibitor; Laboratories; Lead; Legal patent; Lip structure; Liposomes; Luciferases; Malignant neoplasm of pancreas; Malignant Neoplasms; Modality; Modeling; Monoclonal Antibodies; mouse model; Mucin 1 protein; Mucins; Mus; Natural Killer Cells; Neoplasm Metastasis; neutrophil; Normal Cell; novel; Operative Surgical Procedures; outcome forecast; Pancreatic Ductal Adenocarcinoma; pancreatic neoplasm; Patients; Peroxidases; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Protein Region; public health relevance; Radiation therapy; Recruitment Activity; Recurrence; Resistance; response; Roche brand of rituximab; Science; Small Business Technology Transfer Research; Surface; T-Cell Activation; T-Lymphocyte; targeted treatment; Technology; Technology Transfer; Testing; Therapeutic; Therapeutic Effect; Tissues; Trastuzumab; Treatment Efficacy; treatment strategy; tumor; Tumor Cell Line; Tumor Debulking; tumor growth; Tumor Tissue; United States; Unresectable
