Cancer Biology and Signal Transduction Blockade of mTOR Signaling via Rapamycin Combined with ImmunotherapyAugmentsAntigliomaCytotoxicandMemory T-Cell Functions

The success of immunotherapeutic approaches targeting glioblastoma multiforme (GBM) demands a robust antiglioma T-cell cytotoxic and memory response. Recent evidence suggests that rapamycin regulates T-cell differentiation. Herein, we tested whether administration of rapamycin could enhance the efficacy of immunotherapy utilizing Fms-like tyrosine kinase 3 ligand (Ad-Flt3L) and thymidine kinase/ganciclovir (Ad-TK/GCV). Using the refractory rat RG2 glioma model, we demonstrate that administration of rapamycin with Ad-Flt3L þ Ad-TK/GCV immunotherapy enhanced the cytotoxic activity of antitumor CD8þ T cells. Rats treated with rapamycin þ Ad-Flt3L þ Ad-TK/GCV exhibited massive reduction in the tumor volume and extended survival. Rapamycin administration also prolonged the survival of Ad-Flt3L þ Ad-TK/GCV–treated GL26 tumor–bearing mice, associated with an increase in the frequency of tumor-specific and IFNgþ CD8þ T cells. More importantly, rapamycin administration, even for a short interval, elicited a potent long-lasting central memory CD8þ T-cell response. The enhanced memory response translated to an increased frequency of tumor-specific CD8þ T cells within the tumor and IFNg release, providing the mice with long-term survival advantage in response to tumor rechallenge. Our data, therefore, point to rapamycin as an attractive adjuvant to be used in combination with immunotherapy in a phase I clinical trial for GBM. Mol Cancer Ther; 13(12); 1–13. 2014 AACR.