The Landscape of CAR T Cells Beyond Acute Lymphoblastic Leukemia for Pediatric Solid Tumors

Immunotherapy for pediatric malignancies holds the promises of improving outcomes and reducing treatment-related complications. Among different forms of immunotherapy that are actively being pursued, the adoptive transfer of T cells that express chimeric antigen receptors (CARs) has garnered great excitement because of the success of CAR T-cell therapy for CD19-positive malignancies.1-11 CARs are synthetic molecules that combine the specificity of monoclonal antibodies with the effector function of T cells.12-14 The prototypic CAR consists of an antigen binding domain encoded by a single-chain variable fragment derived from a monoclonal antibody, a hinge and transmembrane domain, and signaling domains derived from the CD3.ζ chain as well as costimulatory molecules, such as CD28 and/or 41BB (Fig. 1A). The majority of CAR T-cell products are generated by viral transduction that uses replication incompetent retroviral or lentiviral vectors (Fig. 1B). FIGURE 1. Scheme of CAR T-Cell Generation (A) CARs consist of an ectodomain, hinge and transmembrane domain, and endodomain. CARs have been designed with or without costimulatory (costim) signaling domains. As examples, first- and second- generation (Gen) CARs are shown. (B) CAR T cells are produced by activating T cells in the presence of cytokines. When T cells proliferate, they are transduced with viral vectors that encode CARs. CAR T cells subsequently are expanded with cytokines, and sufficient CAR T cells for preclinical or clinical studies are generated within 9 to 10 days of culture initiation. Since the submission of the first investigational new drug application for CD19–CAR T cells, the field has moved rapidly and culminated in 2017 with approval by the U.S. Food and Drug Administration (FDA) of two CD19–CAR T-cell products.15 The interested reader is referred to recent reviews, which summarize the clinical results of CD19–CAR T cells in detail.1,2 Here, we highlight only the key findings, which must be considered as we develop and improve current CAR T-cell therapy approaches for pediatric solid tumors. First, lymphodepleting chemotherapy with cyclophosphamide and fludarabine is critical to allow engraftment and expansion of adoptively transferred CD19–CAR T cells. Second, CD19–CAR T cells can eradicate B-cell malignancies regardless of their underlying genetic alteration. Third, CD19–CAR T cells, can eradicate B-cell malignancies, which are refractory to chemotherapy and/or radiation, highlighting that T cells kill their target cells through different cytotoxic mechanisms than conventional