Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma

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 þ 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 þ 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 , TNFa þ , and CCL3 þ polyfunctional, CMV-specific CD8 þ T cells. These increases in polyfunctional CMV-specific CD8 þ 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. Cancer Res; 78(1); 256-64.Ó2017 AACR.

Cytomegalovirus promotes murine glioblastoma growth via pericyte recruitment and angiogenesis

“…Interestingly, HCMV proteins and nucleic acids have been identified in up to 90% of GBM specimens (6)(7)(8)(9)(10) as well as in some other cancers (11,12). Accumulating clinical data support the relevance of HCMV in GBM (13)(14)(15)(16)(17)(18)(19), with some encouraging responses reported with HCMV-targeted immunotherapies (14)(15)(16)(17)(18). Vaccination with DCs pulsed with tumor lysates led to expansion of mostly anti-CMV T cells in 1 responder (14), and CMV pp65 mRNApulsed autologous DCs showed promising long-term survival data in GBM (15)(16)(17).…”

The role of CMV in glioblastoma and implications for immunotherapeutic strategies

“…58 In a pilot study, 22 patients were randomized to receive adoptive transfer of pp65 specific T cells with CMV DC vaccine or saline. The patients who received the T cells and DC vaccine had a significant increase in CMV specific CD8 T cells that were positive for IFNγ, TNFα and CCL3 compared to patients who received the T cells and saline.…”

The impact of inflationary cytomegalovirus‐specific memory T cells on anti‐tumour immune responses in patients with cancer

“…The authors reported that patients given tetanus/diphtheria toxoid had enhanced DC migration, and significantly improved progression‐free and overall survival that exceeded 40 months (ClinicalTrials.gov identifier: NCT00639639) . Another recent clinical study showed that patients with GBM who received anti‐CMV adoptive cell transfer exhibited even better cellular immune responses further to an improved survival pattern following vaccination with a CMVpp65 RNA‐pulsed DC vaccine candidate . Prolonged treatment with valganciclovir as an adjunct to standard therapy has been shown to benefit patients with newly diagnosed or recurrent GBM, although randomized trials are warranted in the future .…”

“…124 Another recent clinical study showed that patients with GBM who received anti-CMV adoptive cell transfer exhibited even better cellular immune responses further to an improved survival pattern following vaccination with a CMVpp65 RNA-pulsed DC vaccine candidate. 125 Prolonged treatment with valganciclovir as an adjunct to standard therapy has been shown to benefit patients with newly diagnosed or recurrent GBM, although randomized trials are warranted in the future. [126][127][128] It is, however, worthwhile to examine in future studies whether antiviral therapy may also benefit patients with GBM through additional immune-related pathways, based on the clinical case of a patient with ependymoma, who after ganciclovir treatment showed enhanced innate immune and T-cell activation.…”