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Hochhalter et al. Association between HCMV and GBM

The main approach to anti-viral therapy revolves development of immunotherapy targets include
around the use of valganciclovir [64-68] and GTPases. [69] immediate early 1 (IE1), phosphoprotein 65 (pp65),
The rationale for using valganciclovir stems from the and glycoprotein B (gB). [74]
hypothesis that it will suppress HCMV replication in
HCMV-positive GBM cells leading to the suppression CLINICAL IMPLICATIONS
of virus-mediated tumor promoting mechanisms.
Recently, researchers at Vanderbilt University HCMV is a ubiquitous virus infecting nearly the entire
investigated the use of combination therapy using world population. With all the attention aimed at
bevacizumab and valganciclovir in treating recurrent targeting HCMV in GBM cells, the validity of HCMV
GBM, which demonstrated a trend toward improved as a clinical target is being explored. As of February
survival in those patients. [67] Finally, valganciclovir 2017, there are 13 clinical trials being conducted in
may target other viruses besides HCMV, which the United States evaluating anti-HCMV therapy for
have unclear roles in tumorigenesis. Despite GBM patients registered on clinicaltrials.gov [Table 2].
these advantages, valganciclovir suppresses viral Of these studies, two were terminated because of
replication, but does not eradicate the virus. Therefore, poor patient accrual. The first was a study sponsored
short-term treatment of valganciclovir would not be by Penn State University entitled, “A Phase I-II study
ideal in treating glioma patients as the benefits of tumor of allogeneic CMV specific cytotoxic T lymphocytes
suppression only last during treatment, necessitating (CTL) for patients with refractory glioblastoma
long-term treatment to maintain the suppressive multiforme (GBM). ” The goal of this study was to
[76]
effects. Further, this therapy would not be suitable for evaluate the safety and efficacy of the administration of
GBMs where there is no HCMV present as the tumor partially matched, allogenic HCMV specific cytotoxic T
cells would not be targeted. cells for patients with GBM who failed primary therapy.
The other study entitled, “Phase I/II administration of
The investigation of Rho GTPases and their CMV (cytomegalovirus)-specific cytotoxic T cells in
contribution to tumor progression is another area patients with glioblastoma multiforme (COGLI)” was
that is under investigation as a potential treatment sponsored by Baylor College of Medicine. The
[77]
option. [69] The rho GTPase family is known to play goal of this study was to determine the maximum
a crucial role in cytoskeleton organization, cell tolerated dose of HCMV-specific T cells administered
movement, and division. Three proteins within this in combination with temozolomide (TMZ) in patients
family that are frequently altered in tumors include with newly diagnosed GBM. Additional goals of this
RhoA & RhoC, which are typically overexpressed, study included identifying potential side effects and
while RhoB is usually downregulated. [70-72] Using assessing the efficacy of this therapy for the treatment
a naive GBM cell line, a GBM cell line that stably of GBM. Additionally, one study sponsored by the
expresses HCMV IE1, and shRNA technology to University of Florida entitled, “Peptide targets for
knockdown the Rho GTPases, it was determined glioblastoma against novel cytomegalovirus antigens,”
that HCMV infection and Rho isoform states affect was withdrawn prior to enrollment of participants by
cell morphology and influence proliferation rate and the principal investigator. The goal of this study was
[78]
motility of human GBM cells. [69] to identify the optimal and safe HCMV peptide specific
vaccine regimen in combination with TMZ for patients
The other approach to treating HCMV associated GBM with newly diagnosed GBM.
involves the use of HCMV directed immunotherapy.
The idea of HCMV in GBM has led to potential There are 8 studies currently active and/or recruiting
immunotherapy targets for treatment of GBM. [73,74] A patients. A phase I clinical trial sponsored by Baylor
study conducted by Nair et al. evaluated whether College of Medicine entitled “Administration of
[75]
T cells stimulated by HCMV pp65 RNA-transfected HER2 chimeric antigen receptor expressing CMV-
dendritic cells target and eliminate GBM tumor cells. specific cytotoxic T cells in patients with glioblastoma
The authors of this study concluded that HCMV- multiforme (HERT-GBM)” is being conducted to
specific T cells can effectively target GBM tumor determine the largest safe dose of HER2-CD28
cells and their results support the rationale for the CMV-T cells, to identify the potential side effects
development of HCMV-directed immunotherapy in of this therapy, and to evaluate its efficacy. As of
[84]
patients with GBM. As a result of this association September 2016, this study is listed as ongoing but
[75]
and the potential therapeutic options, several groups not recruiting participants. Another phase I/II clinical
are exploring novel approaches to developing GBM- trial entitled “A Phase I/II clinical trial of autologous
directed immunotherapy and vaccines. Potential cytomegalovirus (CMV)-specific cytotoxic T cells for
[74]
HCMV proteins that are being investigated for the glioblastoma (GBM) patients” is being sponsored by
102 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ June 16, 2017