Abstract
With recent advances, chimeric antigen receptor (CAR) immunotherapy has become a promising modality for patients with refractory cancer diseases. The successful results of CAR T cell therapy in relapsed and refractory B-cell malignancies shifted the paradigm of cancer immunotherapy by awakening the scientific, clinical, and commercial interest in translating this technology for the treatment of solid cancers. This review elaborates on fundamental principles of CAR T cell therapy (development of CAR construct, challenges of CAR T cell therapy) and its application on solid tumors as well as CAR T cell therapy potential in the field of neuro-oncology. Glioblastoma (GBM) is identified as one of the most challenging solid tumors with a permissive immunological milieu and dismal prognosis. Standard multimodal treatment using maximal safe resection, radiochemotherapy, and maintenance chemotherapy extends the overall survival beyond a year. Recurrence is, however, inevitable. GBM holds several unique features including its vast intratumoral heterogeneity, immunosuppressive environment, and a partially permissive anatomic blood–brain barrier, which offers a unique opportunity to investigate new treatment approaches. Tremendous efforts have been made in recent years to investigate novel CAR targets and target combinations with standard modalities for solid tumors and GBM to improve treatment efficacy. In this review, we outline the history of CAR immunotherapy development, relevant CAR target antigens validated with CAR T cells as well as preclinical approaches in combination with adjunct approaches via checkpoint inhibition, bispecific antibodies, and second-line systemic therapies that enhance anticancer efficacy of the CAR-based cancer immunotherapy.
Highlights
In the 1980s, a new chapter of cellular immunotherapy was established for cancer patients, as the initial successful clinical applications of adoptive cell transfer in patients with metastatic melanoma and relapsed leukemia revealed the potential of a therapeutic approach with tumor-specific T cells [1,2,3,4]
Most chimeric antigen receptor (CAR) T cell-based approaches consist of autologous enriched T cells, whereas CAR natural killer (NK) cell-based gene therapy products can be generated from allogeneic donors, so that they possibly reduce the tremendous costs and the limited availability of an autologous therapy caused by logistics and the low cell numbers of heavily pretreated patients [147,148,149]
CAR T cells expressing receptors 100/January 2021 specific for EGFRvIII, IL13Rα2, Her2, CD133, ephrin type A receptor 2 (EphA2), or GD2 with or without anti-PDL-1 monoclonal antibody (mAb) and intratumor heterogeneities of molecular, genetic, and cellular signatures result in tumor diversity, making GBM more challenging to target with a single antigen
Summary
Chimeric antigen receptors (CARs) are synthetic receptors which recognize and target cells expressing a cognate target ligand and as a result redirect the killing activity of CAR T cells against a specific tumor cell antigen [44]. CAR constructs consist of four main components: the single-chain variable fragment (scFv), the hinge, the transmembrane (TM) domain, and the intracellular signaling domain [45] (Fig. 1A). The first-generation CARs only contained an activating domain, namely, CD3ζ, without a costimulatory domain. They showed limited cytokine production, insufficient T cell proliferation, and expansion, and rapidly became anergic [35, 45, 66, 67]. By combining the advantageous aspects of costimulatory domains, the third generation CARs emerged with greater intracellular signaling activity as well as superior persistence and proliferation properties [79, 80]. Kinetic and quantitative differences in CARs with different signaling domains have been demonstrated, highlighting that the choice of costimulatory signal has proven to be a critical element of CAR design [81]
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