Presentation Title

Genetic Engineering of Immune Cells for Specificity and Costimulation in the HER2+ Breast Tumor Microenvironment

Faculty Mentor

Dr Megan Prosser

Start Date

18-11-2017 12:30 PM

End Date

18-11-2017 1:30 PM

Location

BSC-Ursa Minor 58

Session

Poster 2

Type of Presentation

Poster

Subject Area

biological_agricultural_sciences

Abstract

Cancerous cells are capable of evading immune system detection, thereby lowering the body’s defenses against them. One way in which tumors suppress immune activity is by the enhanced expression of Programmed Death-Ligand 1 (PD-L1), which, when bound to its PD-1 receptor on T cells, exhausts T cells resulting in a lack of antitumor response. Furthermore, T cells will seldom launch an immune response without a costimulatory signal, and these responses are downregulated in the tumor microenvironment. While most cancer treatments nonspecifically target rapidly dividing cells, our approach uses adoptive immunotherapy to target overexpressed antigens, more specifically, Human Epidermal Growth Factor Receptor-2 (HER2) in HER2+ breast cancer. Our methods provide T cells with a second-generation chimeric antigen receptor (CAR) consisting of an extracellular binding domain specific for HER2, an intracellular CD3ζ chain, the signal that communicates cytotoxicity to the T cells, and a costimulatory molecule, 4-1BB. In addition, using the PD-1-PD-L1 interaction, costimulatory chimeras consisting of various combinations of CD28, OX40, and 4-1BB as intracellular compliments to the extracellular PD1 ligand-binding domain are being constructed. Cell lines that express both the CAR and costimulatory chimera are in development and the effectiveness of the T cell response will be assessed through T cell proliferation, cytotoxicity, and cytokine secretion.

Keywords: Chimeric Antigen Receptor, Costimulatory chimera, immunosuppression, Adoptive immunotherapy

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Nov 18th, 12:30 PM Nov 18th, 1:30 PM

Genetic Engineering of Immune Cells for Specificity and Costimulation in the HER2+ Breast Tumor Microenvironment

BSC-Ursa Minor 58

Cancerous cells are capable of evading immune system detection, thereby lowering the body’s defenses against them. One way in which tumors suppress immune activity is by the enhanced expression of Programmed Death-Ligand 1 (PD-L1), which, when bound to its PD-1 receptor on T cells, exhausts T cells resulting in a lack of antitumor response. Furthermore, T cells will seldom launch an immune response without a costimulatory signal, and these responses are downregulated in the tumor microenvironment. While most cancer treatments nonspecifically target rapidly dividing cells, our approach uses adoptive immunotherapy to target overexpressed antigens, more specifically, Human Epidermal Growth Factor Receptor-2 (HER2) in HER2+ breast cancer. Our methods provide T cells with a second-generation chimeric antigen receptor (CAR) consisting of an extracellular binding domain specific for HER2, an intracellular CD3ζ chain, the signal that communicates cytotoxicity to the T cells, and a costimulatory molecule, 4-1BB. In addition, using the PD-1-PD-L1 interaction, costimulatory chimeras consisting of various combinations of CD28, OX40, and 4-1BB as intracellular compliments to the extracellular PD1 ligand-binding domain are being constructed. Cell lines that express both the CAR and costimulatory chimera are in development and the effectiveness of the T cell response will be assessed through T cell proliferation, cytotoxicity, and cytokine secretion.

Keywords: Chimeric Antigen Receptor, Costimulatory chimera, immunosuppression, Adoptive immunotherapy