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Hochhalter et al. Association between HCMV and GBM

on overall survival. A phase I clinical trial entitled Karolinska University Hospital in Sweden and has a
“AVeRT: Anti-PD-1 monoclonal antibody (Nivolumab) current status that is listed as “unknown”. Despite
[88]
in combination with DC vaccines for the treatment of the status on clinicaltrials.gov, results from this study
recurrent Grade III and Grade IV brain tumors” is being have been published in the International Journal of
conducted to assess the safety of giving DC vaccines Cancer and will be presented in more detail below.
with nivolumab, an anti-PD-1 monoclonal antibody, to
patients with high grade gliomas. Overall survival While we await the results of these studies, there have
[83]
and progression-free survival will also be evaluated. been two published clinical trials reporting differences
This study is currently recruiting participants as of in clinical efficacy. The first study was conducted by
[65]
December 2016. Two additional studies sponsored Stragliotto et al. in Sweden and consisted of 42
by Duke University Medical Center are both ongoing patients randomized 1:1 to valganciclovir or placebo
but are not currently recruiting participants as of July in addition to standard therapy. The primary endpoint
2016. One of these studies, entitled “Regulatory T-cell of the study was tumor volume at 3 and 6 months
inhibition with Basiliximab (Simulect ) during recovery assessed by neuroimaging. Secondary endpoints
®
from therapeutic temozolomide-induced lymphopenia included progression free survival and overall survival
during antitumor immunotherapy targeted against at 6, 12, 18, and 24 months. Authors of this study
cytomegalovirus in patients with newly-diagnosed concluded that valganciclovir is safe and well tolerated
glioblastoma multiforme”, is a phase I clinical trial in patients receiving both temozolomide and radiation
and will evaluate whether basiliximab, a monoclonal therapy. However, primary and secondary endpoints
antibody to the IL-2 receptor of T cells. In addition, were similar between the two groups, with trends
the study in determine whether basiliximab inhibits but no significant differences observed. Despite
the functionality and numeric recovery of T-regulatory demonstrating no significant differences, the authors,
cells in GBM patients with TMZ-induced lymphopenia in a retrospective analysis of the same cohort with
who are undergoing targeted immunotherapy using inclusion of additional patients on valganciclovir for
CMV pp65-LAMP mRNA-loaded dendritic cells and compassionate reasons, found that the rate of survival
GM-CSF. The other study from Duke is also a of valganciclovir treated patients at 2 years was 62%
[85]
phase I clinical trial. The study entitled “Anti-tumor compared to 18% in historical controls with similar
immunotherapy targeted against cytomegalovirus demographics. The interpretation of this data has
[64]
in patients with newly-diagnosed glioblastoma called into question whether the quoted survival rate
multiforme during recovery from therapeutic is misleading. [89]
temozolomide-induced lymphopenia” is to determine
[90]
the feasibility and safety of vaccinating with HCMV Another study conducted by Mitchell et al. at Duke
pp65-LAMP mRNA-loaded dendritic cells, with or University consisted of 12 patients randomized to pre-
without autologous lymphocyte transfer, in patients treatment with mature dendritic cells (DC) or tetanus
with newly diagnosed GBM who previously had TMZ- toxoid (Td), to help stimulate the immune system,
induced lymphopenia. [86] with HCMV-specific dendritic cell vaccine in addition
to standard therapy. The main objective of this study
A few additional studies investigating the use of HCMV was not to test the validity of HCMV as a tumor
as a novel target for GBM therapy have recently been specific target since the authors have previous shown
completed. The phase I clinical trial entitled “Evaluation the presence of HCMV antigens in GBM. As such,
of recovery from drug-induced lymphopenia using the authors surmise that HCMV is a viable target for
cytomegalovirus-specific T-cell adoptive transfer” immunotherapy. Therefore, the authors of this study
sponsored by Duke University Medical Center is listed wanted to evaluate methods for enhancing the efficacy
as completed on clinicaltrials.gov. In this study, of HCMV-specific dendritic cell vaccines. In so doing,
[87]
the investigators assessed if administering HCMV- six patients were pretreated with mature dendritic cells,
specific DCs to adult patients with newly diagnosed while the other 6 patients were pretreated with tetanus
GBM with TMZ-induced lymphopenia enhanced the toxoid. Primary endpoint was DC accumulation and
T-cell response and whether this therapy was safe migration. Secondary endpoints included progression
for patients. Another study entitled “A randomized free and overall survival. The authors demonstrated
double blind controlled proof of concept study of the that there was greater DC migration in Td-pretreated
efficacy and safety of Valcyte as an add-on therapy in patients than in those treated with mature DCs.
®
patients with malignant glioblastoma with successful Also, Td-pretreated patients showed a significant
surgical resection of at least 90% of the initial tumor increase in both progression-free survival and overall
and CMV infection demonstrated histologically survival compared to DC-pretreated patients. The
and immunohistochemically,” was sponsored by authors concluded that pre-conditioning with Td may
104 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ June 16, 2017