| Literature DB >> 29093005 |
Duane A Mitchell1,2,3, John H Sampson1,2,3, Elizabeth A Reap4,2, Carter M Suryadevara4,2,3, Kristen A Batich4,2,3, Luis Sanchez-Perez4,2, Gary E Archer4,2,3, Robert J Schmittling4,2, Pamela K Norberg4,2, James E Herndon5, Patrick Healy5, Kendra L Congdon4,2, Patrick C Gedeon4,2, Olivia C Campbell4,2, Adam M Swartz4,2,3, Katherine A Riccione4,2, John S Yi6, Mohammed K Hossain-Ibrahim4,2, Anirudh Saraswathula4,2, Smita K Nair4,2,3,6, Anastasie M Dunn-Pirio4,2, Taylor M Broome4,2, Kent J Weinhold6, Annick Desjardins4,2,7, Gordana Vlahovic4,2, Roger E McLendon4,2,3, Allan H Friedman4,2, Henry S Friedman4,2, Darell D Bigner4,2,3, Peter E Fecci4,2,3.
Abstract
Median survival for glioblastoma (GBM) remains <15 months. Human cytomegalovirus (CMV) antigens have been identified in GBM but not normal brain, providing an unparalleled opportunity to subvert CMV antigens as tumor-specific immunotherapy targets. A recent trial in recurrent GBM patients demonstrated the potential clinical benefit of adoptive T-cell therapy (ATCT) of CMV phosphoprotein 65 (pp65)-specific T cells. However, ex vivo analyses from this study found no change in the capacity of CMV pp65-specific T cells to gain multiple effector functions or polyfunctionality, which has been associated with superior antitumor efficacy. Previous studies have shown that dendritic cells (DC) could further enhance tumor-specific CD8+ T-cell polyfunctionality in vivo when administered as a vaccine. Therefore, we hypothesized that vaccination with CMV pp65 RNA-loaded DCs would enhance the frequency of polyfunctional CMV pp65-specific CD8+ T cells after ATCT. Here, we report prospective results of a pilot trial in which 22 patients with newly diagnosed GBM were initially enrolled, of which 17 patients were randomized to receive CMV pp65-specific T cells with CMV-DC vaccination (CMV-ATCT-DC) or saline (CMV-ATCT-saline). Patients who received CMV-ATCT-DC vaccination experienced a significant increase in the overall frequencies of IFNγ+, TNFα+, and CCL3+ polyfunctional, CMV-specific CD8+ T cells. These increases in polyfunctional CMV-specific CD8+ T cells correlated (R = 0.7371, P = 0.0369) with overall survival, although we cannot conclude this was causally related. Our data implicate polyfunctional T-cell responses as a potential biomarker for effective antitumor immunotherapy and support a formal assessment of this combination approach in a larger randomized study.Significance: A randomized pilot trial in patients with GBM implicates polyfunctional T-cell responses as a biomarker for effective antitumor immunotherapy. Cancer Res; 78(1); 256-64. ©2017 AACR. ©2017 American Association for Cancer Research.Entities:
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Year: 2017 PMID： 29093005 PMCID： PMC5754236 DOI： 10.1158/0008-5472.CAN-17-0469
Source DB: PubMed Journal: Cancer Res ISSN： 0008-5472 Impact factor: 12.701