IT-19 * TEMOZOLAMIDE RESISTANT INNATE LYMPHOCYTES ADMINISTERED DURING CHEMOTHERAPY IMPROVE SURVIVAL IN HIGH-GRADE GLIOMA

Abstract

Conventional treatment strategies for high-grade primary brain tumors have failed to consistently extend median survival beyond two years. Using a human/mouse xenograft model, we report improved survival using a combination of Temozolomide (TMZ) chemotherapy with a Drug Resistant Cellular Immunotherapy (DRI) consisting of activated MGMT-transduced γδ T cells and NK cells. MGMT genetic engineering enables cytotoxic lymphocyte function in a chemotherapy-rich environment at a time when the tumor is maximally stressed. Intracranial (IC) glioma xenografts were established using either unmodified (P) or a TMZ-resistant clone (T) of human GBM-X12 primary explants propagated in mice. Tumor-bearing mice were treated i.p. with 60mg/kg TMZ on days 6, 8,13, and 15 post-tumor placement and received IC injection of 1 x 106 MGMT-modified DRI on post-injection days 7 and 14. Control mice received non-modified cells, TMZ alone or no therapy. Survival was assessed using Kaplan-Meier analysis. Both GBM-X12P and X12T express stress antigens MIC-A, MIC-B, and ULBP-4 with only ULBP-4 slightly upregulated on X12T upon exposure to TMZ. Both tumors were killed by expanded/activated γδ T cells in vitro at approximately 80% at an effector : target ratio of 20:1. Cell therapy alone did not improve survival beyond that of untreated mice for either tumor. For the unmodified tumor X12P, both TMZ therapy and TMZ + DRI significantly improved survival over untreated controls (p < 0.001), and the combined therapy increased median survival from 57 to 75 days over TMZ alone. Combined therapy with TMZ + DRI also improved survival for X12T (p = 0.0147) over untreated controls, and showed a marginal improvement over TMZ alone (p = 0.0966) and improvement in median survival from 22 to 25 days. In summary, the combination of chemotherapy-induced stress antigen expression and targeted DRI significantly increases time to progression and improves survival in tumor-bearing immunodeficient mice.