IMST-47. IDENTIFICATION AND EXPANSION OF GLIOMA-SPECIFIC T CELLS USING TCR Vβ EXPRESSION

Abstract

Study of T-cell traits that predict response to therapy is complicated by the challenge that brain tumor antigens are largely uncharacterized. In other solid tumors, adoptive cell therapy has been demonstrated to be a highly efficacious immunotherapeutic strategy. Our OBJECTIVE is to demonstrate that we have generated an adoptive cell therapy platform that leads to the expansion and persistence of tumor-specific T lymphocytes without the need for prior antigen identification. Instead, TCR Vβ expression can be used to both identify and enrich for the tumor-specific T cell population. We employ bone marrow-derived dendritic cells pulsed with tumor-derived RNA to ex vivo expand tumor-specific T lymphocytes (TTRNA-T cells). After adoptive transfer of TTRNA-T cells, we are able to isolate the tumor-reactive T cells using flowcytometry based TCR Vβ spectratyping. These T cells can then be reliably expand from splenocytes of previously immunized mice. Functionality assays demonstrate that TTRNA-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 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 TCR Vβ 6+ T cells is associated with long term survival. Failure of the persistence of these T cells is directly associated with tumor escape. In patients that received adoptive cell therapy using our platform, we observed selective relative expansion of specific TCR Vβ families post-vaccination. Our methods allow us to generate highly tumor-reactive 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).