Immunotherapy for Malignant Glioma: Current Status and Future Directions

Malignant glioma is characterized by aggressive tumor growth, high heterogeneity, intricate oncogenic pathways, and intrinsic resistance to cell death, resulting in limited treatment options and low patient OS rates. By manipulating the immune system, immunotherapeutic approaches have shown promise in achieving long-lasting tumor remission with minimal adverse effects in diverse types of cancer, including melanoma and leukemia. Several trials utilizing checkpoint inhibitors, vaccines, chimeric antigen receptor (CAR) T cells, and oncolytic viruses for treating glioma reveal obstacles to achieving sustained responses, possibly due to a highly immunosuppressive tumor milieu, few and/or exhausted tumor-infiltrating lymphocytes, and a deficiency of specific and immunogenic tumor antigens. Various clinical factors, including corticosteroids, isocitrate dehydrogenase (IDH) mutations, age, gender, obesity, and gut microbiota, may have an important impact on the efficacy of immunotherapy in patients with glioma, enabling the optimal design of individualized treatment. The availability of data relating to the targeting of glioma stem cells, remodeling of the glioma microenvironment, CAR–natural killer cell interactions, shock and kill strategies, optogenetic immunomodulation, organoid use, and liquid biopsies of cerebrospinal fluid provide novel research directions for the development of glioma immunotherapy with optimal efficiency. Glioma is the most common intracranial primary malignancy, with limited treatment options and a poor overall survival (OS). Immunotherapy has been used successfully in various cancers, leading to the development of similar therapies that activate the patient’s immune system to eliminate glioma. In this review, we introduce the diverse immunotherapeutic approaches available for treating glioma, highlighting the successes and challenges resulting from current clinical trials. Additionally, we emphasize the effect of multiple clinical factors on immunotherapy to help optimize individualized treatment regimens. Finally, we also highlight several novel concepts and technologies that could be used to design new and/or improve existing immunotherapies. Such approaches will delineate a new blueprint for glioma treatment. Glioma is the most common intracranial primary malignancy, with limited treatment options and a poor overall survival (OS). Immunotherapy has been used successfully in various cancers, leading to the development of similar therapies that activate the patient’s immune system to eliminate glioma. In this review, we introduce the diverse immunotherapeutic approaches available for treating glioma, highlighting the successes and challenges resulting from current clinical trials. Additionally, we emphasize the effect of multiple clinical factors on immunotherapy to help optimize individualized treatment regimens. Finally, we also highlight several novel concepts and technologies that could be used to design new and/or improve existing immunotherapies. Such approaches will delineate a new blueprint for glioma treatment. a type of cancer treatment that manipulates the patient’s immune system to fight the cancer. Immunotherapy methods currently under investigation include checkpoint inhibitors, peptide vaccines, DC vaccines, CAR-T cells, and oncolytic viruses. T cells are genetically engineered to produce a particular surface receptor comprising an extracellular domain recognizing a specific TSA and an intracellular signaling domain activating the cytotoxic function of T cells. tumor cell-derived fragmented DNA that occurs in plasma, urine, and cerebrospinal fluid. cancers that have not been recognized by the immune system and are insensitive to current immunotherapy. also known as CD152; functions as an immune checkpoint that provides a negative signal to T cells when bound to CD80 or CD86 of APCs. a small population of cells within a glioma characterized by their ability to self-renew, proliferate indefinitely, and their multidifferentiation; are held responsible for tumor formation, progression, and therapeutic resistance. the presence of an IDH1 or IDH2 mutation is one of the most critical biomarkers for the molecular classification and prognostic prediction of adult diffuse gliomas. Patients with gliomas with a mutant IDH1 gene have a better outcome. regulators of the immune system with a critical role in maintaining self-tolerance and preventing autoimmunity through balancing co-stimulatory and inhibitory signals. administration of drugs before a main therapy; mainly refers to surgical operations. antigens encoded by tumor-specific mutated genes but that are entirely absent from the normal human genome. biological technique combining genetic manipulation and optics that controls cells expressing light-sensitive ion channels in living tissue. cluster of cells that grow as a miniaturized and simplified version of an organ produced in a dish in 3D. final resort therapy if the cancer has not responded to standard treatments. subpopulation of CD4+ T cells expressing the transcription factor Foxp3; have a negative role in regulating other cells in the immune system. native proteins shared by many patients with cancer and also expressed only limitedly in normal tissues. microglia are the resident macrophages of the CNS. TAMs account for most of the nonneoplastic cells in the tumor mass, and have a critical role in the creation of a TME that promotes tumor progression. measures the number of mutations within the genome carried by tumor cells and is a biomarker being studied in the prediction of response to immunotherapy. often the products of specific mutations; are exclusively expressed on cancer cells.