Immune and viral therapies for malignant primary brain tumors

ABSTRACT

Introduction: Glioblastoma multiforme (GBM) is a primary brain tumor with great lethality. Current standard of care with surgery, radiation therapy, and chemotherapy are ineffective in curing this disease. Recent advancements in biological therapies show promise in treating brain tumors.

Areas covered: This article provides a review of: the peripheral activation of antigen presenting cells such as dendritic cells to stimulate T cells to recognize and destroy tumor cells within the brain; the ex vivo expansion and transfer of dendritic cells, T cells, and engineered T cells expressing chimeric antigen receptors to target cells bearing specific tumor antigens as well as monoclonal antibodies as immune check point inhibitors. Gene therapy approaches have also been utilized to employ viral vectors in transducing cells to express cytokines for activating immune responses to brain tumors. Finally, the article reviews engineering of viruses for oncolytic targeting and destruction of malignant tumors within the brain.

Expert opinion: The ultimate goal of immune and viral approaches for treating malignant brain tumors is to cure this disease. Preclinical and clinical studies utilizing these biological therapeutic approaches for treating brain tumors have the potential to augment the current standard of care to provide potential curative therapies.

KEYWORDS:

• Glioblastoma multiforme
• GBM
• immunotherapy
• EGFRvIII
• dendritic cell vaccination
• adoptive T cell therapy
• gene therapy
• chimeric antigen receptor T cell
• monoclonal antibodies
• oncolytic virus

Article highlights

• Dendritic cells primed with autologous brain tumor lysate are effective in eliciting immune responses to tumors. A recent phase II clinical using DCs pulsed with tumor associated antigens that include HER2, TRP-2, gp100, MAGE-1, IL13Rα2 demonstrate median overall survival of 38 months.

• Adoptive cell transfer of γδT lymphokine - activated killer (LAK) cells resulted in median overall survival of 97 months in patients with malignant brain tumors.

• Chimeric antigen receptor (CAR) T cells have been engineered to target brain tumors expressing EGFRvIII, and is currently being evaluated in a clinical study. CAR T cells can be manufactured economically using Sleeping Beauty transposons.

• The poliovirus engineered to be an oncolytic virus, PVS-RIPO, has received breakthrough status by the U.S. Food and Drug Administration this year, thus accelerating it availability to patients with recurrent GBM.

• The third generation HSV-1 oncolytic virus, G47Δ, has been engineered to introduce mutations of the γ34.5 and α47 genes along with a third mutation consisting of an insertion of the LacZ gene to inactivate the ICP6 gene. The introduction of the ICP6 mutation provides greater specificity towards tumors in comparison to second generation iterations of HSV-1. The designation of G47Δ as a breakthrough technology in Japan in 2015 on the strength of a phase II study for treating residual or recurrent GBM bodes well for potential fast tracking in the U.S.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Additional information

Funding

The authors work is funded by the National Institutes of Health through grant no. R21 NS055738, the Masonic Cancer Center at the University of Minnesota, and Suzanne M Schwarz.