Dendritic cells enhance polyfunctionality of adoptively transferred T cells that target cytomegalovirus in glioblastoma

Elizabeth A. Reap, Carter M. Suryadevara, Kristen A. Batich, Luis Sanchez-Perez, Gary E. Archer, Robert J. Schmittling, Pamela K. Norberg, James E. Herndon, Patrick Healy, Kendra L. Congdon, Patrick C. Gedeon, Olivia C. Campbell, Adam M. Swartz, Katherine A. Riccione, John S. Yi, Mohammed K. Hossain-Ibrahim, Anirudh Saraswathula, Smita K. Nair, Anastasie M. Dunn-Pirio, Taylor M. BroomeKent J. Weinhold, Annick Desjardins, Gordana Vlahovic, Roger E. McLendon, Allan H. Friedman, Henry S. Friedman, Darell D. Bigner, Peter E. Fecci, Duane A. Mitchell, John H. Sampson

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

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 CD8þ 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 CD8þ 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 IFNg þ, TNFaþ, and CCL3þ polyfunctional, CMV-specific CD8þ T cells. These increases in polyfunctional CMV-specific CD8þ T cells correlated (R ¼ 0.7371, P ¼ 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.

Original languageEnglish
Pages (from-to)256-264
Number of pages9
JournalCancer Research
Volume78
Issue number1
DOIs
StatePublished - 1 Jan 2018
Externally publishedYes

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