Chimeric antigen receptor (CAR) immunotherapy: basic principles, current advances, and future prospects in neuro-oncology

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.

Updates in IDH-Wildtype Glioblastoma

“…CAR T cells are engineered T cells that express antigen-binding receptors that lead to target cell killing of tumor cells. There are a number of current efforts in GBM to exploit this immunotherapy strategy [ 205 , 239 ], including targeting multiple neoantigens, in combination with ICI or through direct intratumoral delivery.…”

Natural killer cell awakening: unleash cancer-immunity cycle against glioblastoma

“…It is especially critical for GBM, a highly heterogeneous tumor with a complex tumor microenvironment. Presently, initial clinical experiences of CAR-T therapy for GBM have only three target antigens (EGFRvIII, HER2 and IL-13Rα2, which are short for epidermal growth factor receptor variant III, human epidermal growth factor receptor 2, and interleukin-13 receptor alpha 2 respectively) [ 9 ]. Their effects restrictively depend on the exclusive expression of antigen on cancer cells and vary a lot among several phases I clinical trials [ 10 , 11 ].…”

Immune Cell Metabolic Fitness for Life

“…In both cases, the hope is that the CAR T is more damaging to the tumor than to healthy tissue. For the patient, several adverse effects may present such as fever, hypoxia, hypotension, tachycardia, etc., many of these resulting from cytokine release syndrome, commonly referred to as cytokine storm [ 84 , 85 , 86 ]. It is not fully clear how cytokine release syndrome is initiated, although there is evidence that engineered CAR T cells may stimulate neighboring cells to induce cytokine release and signaling [ 87 ].…”