Author(s): Heba Samaha aff1 , Shahenda El Naggar aff1 , Nabil Ahmed aff2 aff3
adoptive T-cell therapy; CARs; chimeric antigen receptors; GBM; glioblastoma; immunotherapy; TAA
Glioblastoma (GBM) is the most malignant primary brain cancer with an incidence around 3.19 per 100,000/year in the USA [1 ]. Poor prognosis is due to its infiltrative nature in the brain, genetic heterogeneity and the belligerent GBM stem cells. Despite the advance in new generation alkylating agents, such as temozolomide, along with radiation and tumor vasculature-targeting monoclonal antibodies, such as bevacuzimab, the overall survival has only accented by a few months above the natural history of the untreated tumor [2 ]. The Cancer Genome Atlas Research Network recently unraveled a genetic alteration which pinpointed potential antigenic targets in GBM [3 ]. Hence, targeted gene immunotherapy could be a vital hope for finding an efficient GBM cure.
Immunotherapy is an intriguing biologic which harnesses the power of the immune system to selectively kill tumor cells [4 ]. Active immunization with dendritic cell vaccines and immune recovery with cytokines, are encouraging approaches however, they are limited by their inability to expand tumor antigen-specific T cells, which are often anergized by the tumor hostile milieu [4 ]. One of the means to overcome this limitation is passive immunization with adoptively-transferred T cells [5 ]. Adoptively-transferred T cells are tumor-specific T cells prepared ex vivo, either de novo or by enriching a pre-existent tumor specific T-cell population, then retransferred back to patients, often after lymphodepletion [6 ]. Two tactics were scrutinized to generate tumor affinity-matured T cells by transducing T cells either with high-affinity tumor reactive T-cell receptor (TCR) genes or genes encoding chimeric antigen receptors (CARs) [7 ]. Broader adoptive therapy concept includes natural killer cells [ 8 ], lymphokine-activated killer cells [4 ]; as well as neural or mesenchymal stem-cells [9,10 ].
This review will highlight the use of T-cell adoptive therapy potential for GBM while embarking upon some challenges that need to be overcome to pave the way to an excelled GBM cure in the near future.
GBM: on the lam to escape the immune system
GBM patients often suffer from failed adaptive immunity because of the increased number of inhibitory cells, such as Tregs, Th17 cells and myeloid derived suppressor dendritic cells [11,12 ]. Additionally, the number of circulating cytotoxic cells is curtailed by apoptosis or anergy inducing signals [13 ]. Epigenetic alteration of GBM cells results in silencing HLA molecules, and antigenic genes while increasing the expression of immune checkpoint regulators, such as PD-L1 and Fas ligand. Moreover, the production of immunoinhibitory cytokines such as TGF-[beta], VEGF and IL-10 often offset a specific immune response, marred by a hypoxic and acidic GBM microenvironment [6,13 ]. Hence, to achieve effective tumor eradication, it is mandatory to powerfully target this GBM low immunogenic profile while optimizing the host to reverse the hostile GBM microenvironment.
T cells for adoptive transfer: harnessing the power of the cellular arm
T cells, the main effectors of the adaptive immune system, possess an innate avidity...