12/24/2020 4:16:07 PM
Has immunotherapy been an effective weapon against glioblastoma?
GBM is the most aggressive form of brain cancer with a very low survival despite different therapies because of its immune suppressive microenvironment(1). In this issue, we will discuss the immunotherapy options of glioblastoma (GBM).
One of these therapies is the neoantigen vaccine that could elicit T-helper cells and provide active immunity. Vaccine therapy must be combined with radiotherapy, surgery, and Temozolomide (an oral chemotherapy drug) to have an efficient effect. Must of these vaccines like BEV(EGFRvIII targeted peptide vaccine ) and IMA 950( 11 tumor-associated peptide vaccine ) could promote dendritic cells and T-cells against GBM and reduce T-reg and tumor suppression cytokines(2–5). But due to GBM, slow mutational activity, this therapy can't be much effective.
Another strategy against GBM is immune checkpoint blockade(6). Anti-CTLA4 and Anti-PD-1/PD-L1 are some examples of CBI (checkpoint blockade immunotherapy); researches show that combination therapy with vaccines must be more effective and increase the neoantigen immunotherapy. But this therapy is failed in most cases because of the lack of these receptors on the tumor's surface.
Another strategy is the monoclonal Antibodies(7). These antibodies can block some tumor's transmembrane proteins like CD-47 (a "don't eat me") protein. But this therapy can be efficient with Temozolomide and stimulates the phagocytosis of glioma cells.
The other immunotherapy is CAR-T cells (chimeric antibody receptor). These are synthetic molecules designed to redirect T-cells to specific antigens. Although this therapy is effective enough in hematologic tumors, it is still a challenge to treat GBM via this therapy due to the lack of appropriate surface antigens and also an immunosuppressive environment(2,8). Likewise, CAR-T therapy in children with solid tumors brings edema and death. CAR-T therapy requires extensive laboratory validation to avoid cross-reactivity. (8)
CAR-T cells are engineered with SFCV so they can bypass the tumor's low MHC presentation. (9)
CAR-T cell therapy combination with checkpoint inhibition and virus therapy could overcome tumor heterogeneity and tumor scape caused by target antigen loss.(2,10)
Despite these immunotherapies, GBM is still a dangerous tumor that patients couldn't live on more than 15 months after treatment because of its high resistance and low antigen-presenting levels. (11)
The most important cause of resistance is the GBM heterogeneity and its low neoantigen presenting activity (1). So, after all, more researches are needed to find a novel therapy against neoantigens and also tumor microenvironment.
BY: Fatemeh Jalali
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