Immunotherapy for Glioblastoma

Vaccine Against Brain Cancer
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Picture from http://www.columbianeurosurgery.org/

Glioblastoma multiforme (GBM) is a lethal disease that has no known cure with the median survival of less than 15 months [1]. Common treatments such as surgery, radiotherapy, and chemotherapy are not much effective in treating glioblastomas. Immunotherapy is a promising approach to treatment of glioblastoma multiforme as it targets only the tumour cells while leaving other healthy cells alone. Tumour resistance has been associated with angiogenesis, immune suppression of cytokines, B cells and T cells, as well as other reduced immune responses. Based on these aspects, different immuno-therapeutic approaches have been studied and showed promising results such as angiogenic inhibitors, vaccine therapy, and cell-based therapy [1]. In fact, the first cell-based therapy was authorized to be used in treating prostate cancer in 2011 [1], promoting new immunotherapeutic approaches for treatment of cancer. Currently, some immunotherapies have shown some promising results for treatment of GBM. Some potential examples are peptide-based vaccines, dendritic cell (DC) vaccines, and induced adoptive immunity. These studies are currently in phase III clinical trial.

1. Passive Immunotherapy

Immunotherapy Fights Cancer
Video from The Cancer Immunotherapy Channel

Anti-angiogenic Mechanism of Bevacizumad
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Cancer cells produce VEGF to promote vascular proliferation (top).
Bevacizumad binds to VEGF, thus preventing blood vessel
formation and minimizing tumour growth (bottom) [1]

Passive immunotherapy involves immune cells or antibodies that are already primed to target the tumour cell. It does not require to activate the immune system of the patient as the immune cells have already made active in vitro before injecting into the patient [1].

1.1 Monoclonal Antibodies

Antibodies that target specific antigen that is associated with the cancer cell are collected from patients. Antibodies then are directly cloned from B cell mRNA [2]. Bevacizumad is a IgG1 monoclonal antibody that inhibits the formation of new blood vessels to the tumour (i.e. tumour angiogenesis) by binding to vascular endothelial growth factor (VEGF) ligand [1]. Bevacizumad gives a high response rate of 46% 6-month survival in recurrent GBM [3].

1.2 Cytokine Stimulation

The increase number of regulatory T cells is a hallmark of GBM which contributes to the immune suppression in the CNS. Local administration of cytokines to the GB mouse model has shown IL-12 to have the ability to restore the immunity [4]. In progressive model of GB, a combination of IL-12 and systemic blockade of the co-inhibitory receptor CTLA-4 on T cells shows elimination of tumour while treatment with either IL-2 or CTLA-4 was not effective [4]. This conbination acts on decreasing regulatory T¬ cells and increasing effector T cells, thus reversing the dampening of the immune system.

1.3 Adoptive Immune Effector Cells

This immunotherapy involves the establishment of the adoptive immunity which boosts the immune response of T cells against the tumour by antigen-presenting cells (APCs) [5]. First, lymphocytes are collected from periperal blood mononuclear cells or lymph nodes. These immune cells are activated in ex-vivo by tumour-associated antigens and then injected to patient [1].

1.3a Lymphocyte Activated Killer (LAK) Cell

LAK cells are obtained from peripheral lymphocytes with IL-2 and other cytokines being present. LAK cells produce T cells and NK cells in a non-specific fashion [1-5]. LAK cells were the first attempt using non-specific approach which showed only small effectiveness. Currently, specific cellular approaches are more focused in the majority of immunotherapy studies.

1.3b Cytotoxic T Lymphocytes (CTL)

Similar to LAK cells, CTLs are collected from peripheral blood mononuclear cells and stimulated with antigens in ex vivo, thus producing activated CTLs that have tumour specificity [1]. In the presence of IL-2, CTLS can be derived from tumour infiltrating lymphocytes (TILs). Administration of CTLs or TILs shows more effective response compared to LAK cells.

2. Active Immunotherapy

Active immunotherapy focuses on enhancing patient's immune system by priming it with antigens obtained from their tumour cells. These antigens are specific to the tumour and can be used in vaccine development.

2.1 Peptide-Based Therapy

Gp96-Peptide Complex
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Mechanism of HSP Gp96-Peptide Complex in Active
Immunization against cancer cells [6]

This approach uses peptide that is associated with tumour-specific antigen which binds to MHC class I molecule, therefore activating CTLs [1]. Glioma stem cells (GSC) are a promising target of this therapy to improve the outcomes of the treatment.

2.1a Heat Shock Protein

Gp96 is a type of heat shock proteins (HSP) or chaperones that help protein folding and prevent misfolding. Gp96 collected from the tumour can be used as an autologous vaccine that specifically activates cytolytic and helper T cells. Vitespen is a commercial HSp-peptide complex vaccine that contains tumour-specific Gp96. Even though Vitespen still has limited effectiveness, it improves the survival rate to 1.7 year compared to 4-month survival of other immunologic drugs. Furthermore, Vitespen does not have any severe side effects associated with it [6].
Gp96-peptide collected from tumour is made into vaccine which is inject intradermally. Gp96 can bind to different HSP receptors on APCs, therefore activating APCs such as macrophages and DCs. Consequently, this activation leads to the upregulation of MHC class I and II and the release of various chemokines and cytokines. As the result, the tumour-specific activation of cytolytic and helper T cells is established to recognize and target tumour that carries that specific antigen [6].

2.1b Armed Oncolytic HSV (oHSV)

oHSV
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Armed oHSV used in specific targeting cancer cell.
As associated with cytokines such as IL-12, oHSV can have
multiple effects on tumour microenviroment, angiogenesis, T cell activity [7]

Oncolytic virus provides advantages in targetting cancer cells as it contains engineered tumour specificity and is able to replicate and spread across the tumour. Oncolytic herpes simplex virus (oHSV) is commonly used as it can rapidly induce immunity against tumour. Moreover, it has a large genome which makes it easier to engineer transgenes [4]. In a study by Cheema, et al, mouse 005 GSC were derived and induced into the brains of syngeneic C57B1/6 mice in order to create human-like glioblastoma. G47Δ , an armed oHSV that selectively targets the GSCs. In order to target the tumour microenvironment, IL-12 transgene is also engineered into the virus to express IL-12 which can link the innate and adaptive immunity together as it stimulate the proliferation of T cell and NK cells and enhance the release of IFN- γ. These multiple effects of IL-12 promote the killing mediated by T cell and inhibition of angiogenesis in the tumour. The results show that G47Δ-mIL12 directly target GSCs and bulk tumour cells by decreasing the numner of regulatory T cells and activate the immunity mediated by T cells. Even this immunovirotherapy is very promising, there are areas of improvements needed to be addressed as G47Δ-mIL12 only gives long-term survival rate of 10 - 20%. [7]

2.2 Dendritic Cell Based Therapy

Dendritic Cell Vaccination
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Dendritic Cell is primed to a tumour-associated antigen,
thus being able to regulte helper T cells and CTLs to kill the cancer [5]

The CNS only allows some immune cells to selectively pass through the blood brain barrier [1]. There are low numbers of T cells and no APCs in the CNS, however, under specific conditions such as inflammation, microgial cells travel to the CNS and consequently release cytokines and chemokines which recruit immune cells such as macrophages and dendritic cells (DCs). Those immune cells are APCs, thus vaccine therapy based on DC is the most common approach. Only the activated T cells can get into the CNS. In glioblastoma, there is a systemic suppression of the immune system as well as a rich population of immunosupressive factors produced by the tumour cells such as transforming growth factor beta (TGF-Beta) and vascular endothelial growth factor (VEGF) [1-5]. Those factors suppress the development of T cells. VEGEF also prevents DCs from becoming mature [1].
Cell-based therapy uses APCs that are already activated by tumour antigens to prime the immune cells such as DCs against the cancer cells. DCs is more suitable to be used in this therapy as it is considered as professional APC which takes important parts in monitoring and maintaining T cell response [8-9]. DCs are obtained by growing autologous peripheral blood mononuclear cells with growth factors such as GM-CSF and IL-4. DCs are activated by antigens derived from tumour cells, then administered intradermally in the tumour or lymph nodes [1]. DC vaccination can use various antigens associated with cancer cells such as A2B5 monoclonal antibody [10]. In addition, IFNα-induced DCs can also promote the apoptotic pathway of the tumour cells [11].

Bibliography
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7. Cheema, T.A., Wakimoto, H., Fecci, P.E., Ning, J., Kuroda, T., Jevaretna, D.S., Martuza, R.L., and Rabkin, S.D. Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell mode. Pro. Natl Acad. Sci. USA. 110(29):12006-11 (2013).
8. Banchereau, J., Briere, I., Caux, C. Immunobiology of dendritic cells. Annual Review of Immunology. 18:767–811 (2000).
9. Steinman, R. M., Banchereau, J. Taking dendritic cells intomedicine. Nature. 449(7161):419–426 (2007).
10. Xu, M., Yu, Y., Hua, W., Wu, Z., Zhong, P., Mao, Y., Zhou, L., Luo F., Chu, Y. Mouse glioma immunotherapy mediated by A2B5+ GL261 cell lysate-pulsed dendritic cells. J Neurooncol. 116:497-504 (2014).
11. Tyrinova, T.V., et al. Cytotoxic activity of ex-vivo generated IFNa-induced monocyte-derived dendritic cells in brain glioma patients. Cellular Immunology. 284:146-153 (2013).

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