Presentation Title

T Cells engineered to express the IL-13Rα2 specific CAR and a PDL1 specific costimulatory chimera show increased anti-tumor activity in the Glioblastoma tumor microenvironment

Faculty Mentor

Megan Prosser

Start Date

18-11-2017 9:45 AM

End Date

18-11-2017 10:00 AM

Location

9-271

Session

Bio Sciences 2

Type of Presentation

Oral Talk

Subject Area

biological_agricultural_sciences

Abstract

Glioblastoma multiforme (GBM) is an aggressive brain cancer with poor prognosis with traditional treatments such as chemotherapy and radiotherapy, which often leave lasting and pervasive damage to the individual. GBM cells upregulate the surface protein interleukin 13 receptor subunit alpha-2 (IL13Rα2), which can be targeted as a novel immunotherapeutic marker for the immune response to be initiated. In this study, IL13Rα2 is targeted using a first generation chimeric antigen receptor (CAR) that contains an intracellular zeta chain domain. However, a limitation to this approach is that the tumor microenvironment 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, 41BB, and OX40, which stimulates the T cell when PD-1 binds to PD-L1. Engineered T cells expressing costimulatory chimeras and IL13Rα2-specific CAR have been created and have been assessed in vitro as a basis for glioblastoma treatment. Tests performed include cytokine secretion and T-cell proliferation assays. Results of these preliminary studies suggest that the PD1-CD28-41BB-OX40 costimulatory chimera may be most advantageous in enhancing anti-tumor responses in the GBM microenvironment.

Summary of research results to be presented

A total of three experimental cell lines and two control cell lines have been successfully established in vitro and have been shown to stably express both the costimulatory chimera and the CAR. Preliminarily, the results from our short term cytokine secretion and T-cell proliferation assays show that the PD1-CD28-41BB-OX40 costimulatory chimera outperforms other experimental and control lines in the GBM microenvironment. Future directions aim to repeat replicates of these assays, develop a successful cytotoxicity assay, and repeat all of these assays using Primary T cells as opposed to H9 lines.

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Nov 18th, 9:45 AM Nov 18th, 10:00 AM

T Cells engineered to express the IL-13Rα2 specific CAR and a PDL1 specific costimulatory chimera show increased anti-tumor activity in the Glioblastoma tumor microenvironment

9-271

Glioblastoma multiforme (GBM) is an aggressive brain cancer with poor prognosis with traditional treatments such as chemotherapy and radiotherapy, which often leave lasting and pervasive damage to the individual. GBM cells upregulate the surface protein interleukin 13 receptor subunit alpha-2 (IL13Rα2), which can be targeted as a novel immunotherapeutic marker for the immune response to be initiated. In this study, IL13Rα2 is targeted using a first generation chimeric antigen receptor (CAR) that contains an intracellular zeta chain domain. However, a limitation to this approach is that the tumor microenvironment 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, 41BB, and OX40, which stimulates the T cell when PD-1 binds to PD-L1. Engineered T cells expressing costimulatory chimeras and IL13Rα2-specific CAR have been created and have been assessed in vitro as a basis for glioblastoma treatment. Tests performed include cytokine secretion and T-cell proliferation assays. Results of these preliminary studies suggest that the PD1-CD28-41BB-OX40 costimulatory chimera may be most advantageous in enhancing anti-tumor responses in the GBM microenvironment.