Presentation Title

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

Start Date

November 2016

End Date

November 2016

Location

HUB 302-69

Type of Presentation

Poster

Abstract

Adoptive immunotherapy is a field of clinical research that aims to reprogram the immune system to combat cancer, which, in comparison to chemotherapy and radiotherapy, limits harm to the normal body. The specific goal of this research is to target a particular form of breast cancer using an adoptive immunotherapeutic approach specific to human growth factor receptor 2 (HER2). In some aggressive breast cancers there is a mutation that results in an over-expression of the HER2 protein. In this study, HER2 will be targeted using second generation chimeric antigen receptor (CAR) that has both a zetachain and a costimulatory signal, 41BB. A limitation to this approach is that under normal conditions, the tumor microenvironment effectively exhausts the T cells that interact with the tumor through a receptor-mediated response. Programmed Death-Ligand 1 (PD-L1) is a molecule that is expressed on cancerous cells that binds to the Programmed Death 1 (PD-1) on T-cells. When the ligand binds to PD-1 on T cells, there is decreased T-cell proliferation, cytokine production, and anti-tumor activity. This problem can be avoided by creating a costimulatory chimera with a PD-1 extracellular domain fused to an intracellular costimulatory domain such as CD28, 4-1BB, and OX40, which stimulates the T cell when PD-1 binds to PD-L1. Various costimulatory chimeras have been designed and will be examined in conjunction with the HER2 specific CAR in order to assess optimal costimulation of engineered T cells using cytokine and killing assays. Given that the HER2 CAR includes 41BB, the effectiveness of the costimulatory chimeras when paired with a second generation CAR will additionally be analyzed.

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

HUB 302-69

Adoptive immunotherapy is a field of clinical research that aims to reprogram the immune system to combat cancer, which, in comparison to chemotherapy and radiotherapy, limits harm to the normal body. The specific goal of this research is to target a particular form of breast cancer using an adoptive immunotherapeutic approach specific to human growth factor receptor 2 (HER2). In some aggressive breast cancers there is a mutation that results in an over-expression of the HER2 protein. In this study, HER2 will be targeted using second generation chimeric antigen receptor (CAR) that has both a zetachain and a costimulatory signal, 41BB. A limitation to this approach is that under normal conditions, the tumor microenvironment effectively exhausts the T cells that interact with the tumor through a receptor-mediated response. Programmed Death-Ligand 1 (PD-L1) is a molecule that is expressed on cancerous cells that binds to the Programmed Death 1 (PD-1) on T-cells. When the ligand binds to PD-1 on T cells, there is decreased T-cell proliferation, cytokine production, and anti-tumor activity. This problem can be avoided by creating a costimulatory chimera with a PD-1 extracellular domain fused to an intracellular costimulatory domain such as CD28, 4-1BB, and OX40, which stimulates the T cell when PD-1 binds to PD-L1. Various costimulatory chimeras have been designed and will be examined in conjunction with the HER2 specific CAR in order to assess optimal costimulation of engineered T cells using cytokine and killing assays. Given that the HER2 CAR includes 41BB, the effectiveness of the costimulatory chimeras when paired with a second generation CAR will additionally be analyzed.