IMPS-07T CELL RECEPTOR VARIABLE β CHAIN (TCR Vβ) USAGE TO PREDICT AND GENERATE TUMOR SPECIFIC T LYMPHOCYTES AGAINST INVASIVE GLIOMAS

Abstract

INTRODUCTION: Adoptive cellular therapy has been demonstrated to be a highly efficacious immunotherapy against solid tumors. In this study, we predict T cell populations with high affinity to glioma and generate a T cell population highly enriched for tumor-reactive T cells. OBJECTIVES: Major barriers to therapeutic development against brain tumors are that brain tumors are highly heterogeneous and tumor antigens are largely uncharacterized. The primary objective of this study was to predict and generate a polyclonal population of T lymphocytes that is highly enriched for tumor-specific T cells and overcomes these limitations. METHODS: We spectratyped the TCR Vβ repertoire of glioma infiltrating CD3+ cells in order to identify T cell populations with high affinity to tumor. Based on the identified TCR Vβ family expression, we isolated and reliably expanded these T cells from splenocytes of mice previously immunized with tumor RNA-pulsed dendritic cells. These cells were adoptively transferred into intracranial glioma bearing mice followed by dendritic cell vaccine. RESULTS: In vitro functionality assays demonstrated that T cells with TCR Vβ families predicted to have high affinity to tumors were responsible for anti-tumor immunity. Adoptive cellular therapy using T cells expressing TCR Vβ 5.1, 5.2, TCR Vβ 6, and TCR Vβ 8.1, 8.2 against intracranial tumor led to cures in 60% of treated mice. We further identify that the in vivo expansion of T cells expressing the TCR Vβ 6 family is specifically associated with long term survival. Failure of the persistence of these T cells is directly associated with tumor escape. CONCLUSION: Our methods allow us to generate highly tumor-reactive polyclonal T cell populations without the need for identifying tumor antigens. We are currently employing these analyses in clinical trials of adoptive cellular therapy targeting pediatric and adult gliomas under development at our center (FDA IND BB-14058).