Resistance Mechanisms and Barriers to Successful Immunotherapy for Treating Glioblastoma

Adhikaree, Jason; Moreno-Vicente, Julia; Kaur, Aanchal Preet; Jackson, Andrew; Patel, Poulam M.

doi:10.3390/cells9020263

Cited by 49 publications

(55 citation statements)

References 138 publications

(166 reference statements)

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“…Despite several biological and clinical approaches, including the 2018 Nobel Prize for immune checkpoint blockade in cancer immunotherapy, no specific immune therapy treatment for GBM has been successful in phase III or randomized controlled trials due to either lack of positive response, or due to side-effects ( 173 ). Some of the clinical trials that did not show significant survival benefit include nivolumab (anti-PD-1) and ipilimubab (anti-CTLA-4) in recurrent GBM ( 174 ); nivolumab vs. TMZ and radiation therapy in newly-diagnosed GBM ( 175 ); and nivolumab in combination with TMZ and radiation therapy in newly-diagnosed GBM ( 176 ).…”

Section: Adaptive Immunity and T Reg Cellsmentioning

confidence: 99%

Molecular Heterogeneity and Immunosuppressive Microenvironment in Glioblastoma

et al. 2020

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Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a poor prognosis, despite surgical resection combined with radio- and chemotherapy. The major clinical obstacles contributing to poor GBM prognosis are late diagnosis, diffuse infiltration, pseudo-palisading necrosis, microvascular proliferation, and resistance to conventional therapy. These challenges are further compounded by extensive inter- and intra-tumor heterogeneity and the dynamic plasticity of GBM cells. The complex heterogeneous nature of GBM cells is facilitated by the local inflammatory tumor microenvironment, which mostly induces tumor aggressiveness and drug resistance. An immunosuppressive tumor microenvironment of GBM provides multiple pathways for tumor immune evasion. Infiltrating immune cells, mostly tumor-associated macrophages, comprise much of the non-neoplastic population in GBM. Further understanding of the immune microenvironment of GBM is essential to make advances in the development of immunotherapeutics. Recently, whole-genome sequencing, epigenomics and transcriptional profiling have significantly helped improve the prognostic and therapeutic outcomes of GBM patients. Here, we discuss recent genomic advances, the role of innate and adaptive immune mechanisms, and the presence of an established immunosuppressive GBM microenvironment that suppresses and/or prevents the anti-tumor host response.

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Section: Adaptive Immunity and T Reg Cellsmentioning

confidence: 99%

Molecular Heterogeneity and Immunosuppressive Microenvironment in Glioblastoma

et al. 2020

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“…Immunosuppression in GME undergoes numerous and complex mechanisms so that single-arm immunotherapy cannot break this tolerance. Besides local immune suppression, GBM can suppress systemic immunity in the patient [ 16 , 74 , 75 , 76 ]. The GME-infiltrated T cells are mainly differentiated to regulatory T cells (Tregs) due to the high levels of tumor growth factor (TGF)-β and indoleamine-2,3-dioxygenase (IDO) in the GME [ 77 , 78 ].…”

Section: Glioblastoma Immunotherapymentioning

confidence: 99%

Adenosinergic Pathway: A Hope in the Immunotherapy of Glioblastoma

Jin

Mao

Chen

et al. 2021

Cancers

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Brain tumors comprise different types of malignancies, most of which are originated from glial cells. Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor with a poor response to conventional therapies and dismal survival rates (15 months) despite multimodal therapies. The development of immunotherapeutic strategies seems to be necessary to enhance the overall survival of GBM patients. So far, the immunotherapies applied in GBM had promising results in the primary phases of clinical trials but failed to continue their beneficial effects in later phases. GBM-microenvironment (GME) is a heterogenic and rigorously immunosuppressive milieu wrapping by an impenetrable blood-brain barrier. Hence, in-depth knowledge about the dominant immunosuppressive mechanisms in the GME could foster GBM immunotherapy. Recently, the adenosinergic pathway (AP) is found to be a major player in the suppression of antitumor immune responses in the GME. Tumor cells evolve to metabolize pro-inflammatory ATP to anti-inflammatory adenosine. Adenosine can suppress immune responses through the signaling of adenosine receptors on immune cells. The preclinical results targeting AP in GBM showed promising results in reinvigorating antitumor responses, overriding chemoresistance, and increasing survival. We reviewed the current GBM immunotherapies and elaborated on the role of AP in the immunopathogenesis, treatment, and even prognosis of GBM. We suggest that future clinical studies should consider this pathway in their combination therapies along with other immunotherapeutic approaches.

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“…Terms like “cold” versus “hot” tumors, describing differences in lymphocyte infiltration in the tumor microenvironment, have become highly relevant [ 72 ]. The tumor mutational burden might be related to the presence of more or less tumor antigens on the surface [ 73 , 74 ]. Some genetic abnormalities, such as the p53 mutation, affect the extent of the expression of MHC molecules on the tumor cell surface [ 75 ].…”

Section: Immunotherapy For Gbmmentioning

confidence: 99%

Randomized Controlled Immunotherapy Clinical Trials for GBM Challenged

Gool

Makalowski

Fiore

et al. 2020

Cancers

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Immunotherapies represent a promising strategy for glioblastoma multiforme (GBM) treatment. Different immunotherapies include the use of checkpoint inhibitors, adoptive cell therapies such as chimeric antigen receptor (CAR) T cells, and vaccines such as dendritic cell vaccines. Antibodies have also been used as toxin or radioactive particle delivery vehicles to eliminate target cells in the treatment of GBM. Oncolytic viral therapy and other immunogenic cell death-inducing treatments bridge the antitumor strategy with immunization and installation of immune control over the disease. These strategies should be included in the standard treatment protocol for GBM. Some immunotherapies are individualized in terms of the medicinal product, the immune target, and the immune tumor–host contact. Current individualized immunotherapy strategies focus on combinations of approaches. Standardization appears to be impossible in the face of complex controlled trial designs. To define appropriate control groups, stratification according to the Recursive Partitioning Analysis classification, MGMT promotor methylation, epigenetic GBM sub-typing, tumor microenvironment, systemic immune functioning before and after radiochemotherapy, and the need for/type of symptom-relieving drugs is required. Moreover, maintenance of a fixed treatment protocol for a dynamic, deadly cancer disease in a permanently changing tumor–host immune context might be inappropriate. This complexity is illustrated using our own data on individualized multimodal immunotherapies for GBM. Individualized medicines, including multimodal immunotherapies, are a rational and optimal yet also flexible approach to induce long-term tumor control. However, innovative methods are needed to assess the efficacy of complex individualized treatments and implement them more quickly into the general health system.

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Resistance Mechanisms and Barriers to Successful Immunotherapy for Treating Glioblastoma

Cited by 49 publications

References 138 publications

Molecular Heterogeneity and Immunosuppressive Microenvironment in Glioblastoma

Molecular Heterogeneity and Immunosuppressive Microenvironment in Glioblastoma

Adenosinergic Pathway: A Hope in the Immunotherapy of Glioblastoma

Randomized Controlled Immunotherapy Clinical Trials for GBM Challenged

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