Interleukin-2 (IL-2) immunotherapy can result in remarkable long-term responses in some cancer patients by stimulating the immune response to kill tumor cells. However, current rIL-2 therapy is limited to highly selected patients due to its requirements for high and frequent dosing, which can result in severe side effects. Moreover, rIL-2 also activates CD4+ regulatory T cells, which suppress the immune response. To ameliorate the liabilities of the current rIL-2 drug, we have designed a long-acting IL-2 analog that selectively preserves immune response activation (CD8+ T, NK cells), without activating regulatory T cells and endothelial cells; thereby, minimizing immune suppression and vascular leak syndrome. We propose to optimize combination of rIL2 analog treatment plus antitumor antibody to safely and effectively kill tumor cells via a concerted innate and adaptive response involving neutrophils, NK cells, macrophages, and CD8+ T cells. In this study, the Specific Aim is to use the syngeneic mouse model of B16-F10 to determine whether the combination of the proprietary IL-2 analog with an antitumor antigen antibody effectively eradicates established tumors without inducing adverse side effects. Our long-term goal is to develop the proprietary IL-2 analog as a safe immunotherapy to cure cancer or extend survival of patients.
Public Health Relevance Statement: Principal Investigator/Program Director (Last, First, Middle: Chen, Ridong Narrative We will determine whether treatment with a proprietary rIL-2 analog plus an antitumor antigen antibody can safely and effectively eradicate established tumors in mice.
Project Terms: Affinity; Aldesleukin; Alleles; analog; Antibodies; Antibody Therapy; antibody-dependent cell cytotoxicity; anticancer activity; Antigens; Binding; Binding Sites; Biodistribution; Blood Vessels; cancer immunotherapy; Cancer Patient; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cetuximab; Chimeric Proteins; Clinical; Colon Adenocarcinoma; cost; CT26; Cyclic GMP; cytotoxic; Data; design; Disease remission; Dose; Drug Combinations; Endothelial Cells; Eragrostis; Escherichia coli; Evaluation; FOXP3 gene; Goals; Half-Life; Hepatic; Hour; Human; IL2RA gene; Immune; Immune response; immunogenic; Immunosuppression; Immunosuppressive Agents; Immunotherapy; improved; In complete remission; Infusion procedures; innovation; Interleukin-2; Interleukins; Intravenous; Investigational Drugs; Longterm Follow-up; Lymphoma; macrophage; Malignant Neoplasms; Mammalian Cell; MC38; melanocyte; melanoma; Modeling; mouse model; Mus; Mutation; Natural Killer Cells; neoplastic cell; neutrophil; Patients; Pharmaceutical Preparations; Phase; Plasma; pre-clinical; preservation; prevent; Principal Investigator; programs; Proteins; Protocols documentation; Pulmonary Edema; receptor; Recombinant Proteins; Regimen; Regulatory T-Lymphocyte; Renal carcinoma; Renal Cell Carcinoma; response; rituximab; Safety; Serum Albumin; side effect; success; Syndrome; Therapeutic Effect; Therapeutic Index; Thymus Gland; Toxic effect; Toxicology; Trastuzumab; Treatment Efficacy; tumor; Tumor Antibodies; Tumor Antigens; Tyrosine; TYRP1 gene; Withholding Treatment; Work
