J Korean Neurosurg Soc.  2023 Jul;66(4):356-381. 10.3340/jkns.2022.0267.

Advanced T and Natural Killer Cell Therapy for Glioblastoma

• Yoon WS
• Chung DS

• KMID: 2543528
• DOI: http://doi.org/10.3340/jkns.2022.0267

Abstract

Although immunotherapy has been broadly successful in the treatment of hematologic malignancies and a subset of solid tumors, its clinical outcomes for glioblastoma are still inadequate. The results could be due to neuroanatomical structures such as the bloodbrain- barrier, antigenic heterogeneity, and the highly immunosuppressive microenvironment of glioblastomas. The antitumor efficacy of endogenously activated effector cells induced by peptide or dendritic cell vaccines in particular has been insufficient to control tumors. Effector cells, such as T cells and natural killer (NK) cells can be expanded rapidly ex vivo and transferred to patients. The identification of neoantigens derived from tumor-specific mutations is expanding the list of tumor-specific antigens for glioblastoma. Moreover, recent advances in gene-editing technologies enable the effector cells to not only have multiple biological functionalities, such as cytokine production, multiple antigen recognition, and increased cell trafficking, but also relieve the immunosuppressive nature of the glioblastoma microenvironment by blocking immune inhibitory molecules, which together improve their cytotoxicity, persistence, and safety. Allogeneic chimeric antigen receptor (CAR) T cells edited to reduce graft-versushost disease and allorejection, or induced pluripotent stem cell-derived NK cells expressing CARs that use NK-specific signaling domain can be a good candidate for off-the-shelf products of glioblastoma immunotherapy. We here discuss current progress and future directions for T cell and NK cell therapy in glioblastoma.

Keyword

Glioblastoma; T-lymphocytes; Killer cells, natural; Immunotherapy

Figure

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  Fig. 1. Advances in chimeric antigen receptor (CAR) generation. CARs are composed of an extracellular domain of a tumor antigen recognition molecule that contains the single-chain variable fragment (scFv) of a monoclonal antibody, intracellular domains with a T cell receptor signaling domain and an additional costimulatory domain that lead to T cell activation, and a transmembrane domain as a spacer. The intracelluar domain has been optimized in successive generations of CAR T cells to enhance its signaling capacity. First-generation CARs utilized CD3ζ chain only as an intracellular activation domain. Second- and third-generation CARs were developed by combining CD3ζ with one (second-generation) or more (third-generation) costimulatory domains such as CD28 and OX40 or 4-1BB. Fourth-generation CARs incorporated a cytokine signaling domain such as interleukin-15 receptor alpha (IL-15Rα) or Janus kinase-signal transducers and activators of transcription (JAK-STAT) into the intracellular domain of third-generation CARs.

Reference

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