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Review
. 2018 Apr;189:43-51.
doi: 10.1016/j.clim.2017.07.006. Epub 2017 Jul 15.

Evolutionary Basis of a New Gene- And Immune-Therapeutic Approach for the Treatment of Malignant Brain Tumors: From Mice to Clinical Trials for Glioma Patients

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Free PMC article
Review

Evolutionary Basis of a New Gene- And Immune-Therapeutic Approach for the Treatment of Malignant Brain Tumors: From Mice to Clinical Trials for Glioma Patients

Pedro R Lowenstein et al. Clin Immunol. .
Free PMC article

Abstract

Glioma cells are one of the most aggressive and malignant tumors. Following initial surgery, and radio-chemotherapy they progress rapidly, so that patients' median survival remains under two years. They invade throughout the brain, which makes them difficult to treat, and are universally lethal. Though total resection is always attempted it is not curative. Standard of care in 2016 comprises surgical resection, radiotherapy and chemotherapy (temozolomide). Median survival is currently ~14-20months post-diagnosis though it can be higher in high complexity medical university centers, or during clinical trials. Why the immune system fails to recognize the growing brain tumor is not completely understood. We believe that one reason for this failure is that the brain lacks cells that perform the role that dendritic cells serve in other organs. The lack of functional dendritic cells from the brain causes the brain to be deficient in priming systemic immune responses to glioma antigens. To overcome this drawback we reconstituted the brain immune system for it to initiate and prime anti-glioma immune responses from within the brain. To achieve brain immune reconstitution adenoviral vectors are injected into the resection cavity or remaining tumor. One adenoviral vector expresses the HSV-1 derived thymidine kinase which converts ganciclovir into phospho-ganciclovir which becomes cytotoxic to dividing cells. The second adenovirus expresses the cytokine fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L differentiates precursors into dendritic cells and acts as a chemokine for dendritic cells. This results in HSV-1/ganciclovir killing of tumor cells, and the release of tumor antigens, which are then taken up by dendritic cells recruited to the brain tumor microenvironment by Flt3L. Concomitant release of HMGB1, a TLR2 agonist that activates dendritic cells, stimulates dendritic cells loaded with glioma antigens to migrate to the cervical lymph nodes to prime a systemic CD8+ T cytotoxic killing of brain tumor cells. This induced immune response causes glioma-specific cytotoxicity, induces immunological memory, and does not cause brain toxicity or autoimmunity. A Phase I Clinical Trial, to test our hypothesis in human patients, was opened in December 2013 (see: NCT01811992, Combined Cytotoxic and Immune-Stimulatory Therapy for Glioma, at ClinicalTrials.gov). This trial is a first in human trial to test whether the re-engineering of the brain immune system can serve to treat malignant brain tumors. The long and winding road from the laboratory to the clinical trial follows below.

Figures

FIGURE 1
FIGURE 1
This figure illustrates in schematic fashion the neuroimmune structure underlying the phenomenology known as the brain’s immune privilege. In this figure the antigen model used to explore the brain’s immune responses are non-replicating adenoviral vectors. (A) illustrates the condition in which adenoviral vectors are injected carefully only into the brain parenchyma proper. Under these conditions given the absence of afferent dendritic cells from the brain parenchyma, viral vectors have been shown to remain in the brain for 12 months and more. A systemic anti-adenoviral immune response will not be induced. (B) If however, the systemic immune system is primed, an immune response will be generated, brain inflammation will ensue, and the viral vectors will be eliminated. (C) Direct administration of vectors into the brain ventricles will induce a systemic anti-adenoviral immune response, as the ventricular immune system has all necessary cells and vessels to do so. Therefore, in our novel therapeutic strategy, we recruit dendritic cells to the brain to implement those essential aspects of immune function which are missing from the brain.
FIGURE 2
FIGURE 2
This figure exemplifies in practical fashion the neuroimmune structure underlying the phenomenology known as the brain’s immune privilege. Injection of an adenovirus expressing influenza hemagglutinin (HA) into the brain parenchyma does not cause a systemic anti-adenoviral, or anti-HA immune response. However, if the same virus is injected into the brain ventricles or subcutaneously a systemic immune response against HA can be detected. As a negative control, injection into the ventricles of a virus not expressing HA, does not cause systemic anti-HA immunity.
FIGURE 3
FIGURE 3
This figure illustrates the mechanism of action of our novel approach to re-design the brain immune system to allow it to recognize novel tumor antigens. Ad-TK+GCV kills tumor cells and releases HMGB1. Ad-Flt3L recruits dendritic cells to the brain. These take up tumor antigens, and upon stimulation of TLR2 by HMGB1, they induce a systemic anti brain tumor immune response.
FIGURE 4
FIGURE 4
This figure shows that the addition of RAd-Flt3L increases the efficiency of RAd-TK from 20% of long term animal survival to 75% of animals survival, demonstrating the efficiency of using both adenoviral vectors in a stringent model of glioblastoma.

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