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Simple Summary: This review explores the current trials using cellular immunotherapies in pediatric sarcoma and describes examples of promising new CAR T targets in sarcoma that are in preclinical development. We provide insights into the ways in which the immunosuppressive tumor immune microenvironment can impact on CAR T cell therapy, highlighting specific mechanisms by which the tumor microenvironment may limit CAR T efficacy. Appreciation of these mechanisms may lead to rational combinations of immunotherapies, for example, the combination of CAR T cells with checkpoint inhibitor drugs. We also describe innovations in CAR T cell generation and combination therapies that may pave the way to better clinical outcomes for these patients. Sarcomas are a diverse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or metastatic disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of adoptive cell therapy that potentially offers new hope for these children. In early trials, promising outcomes have been achieved in some pediatric patients with sarcoma. However, many children do not derive benefit despite significant expression of the targeted tumor antigen. The success of CAR T cell therapy in sarcomas and other solid tumors is limited by the immunosuppressive tumor microenvironment (TME). In this review, we provide an update of the CAR T cell therapies that are currently being tested in pediatric sarcoma clinical trials, including those targeting tumors that express HER2, NY-ESO, GD2, EGFR, GPC3, B7-H3, and MAGE-A4. We also outline promising new CAR T cells that are in pre-clinical development. Finally, we discuss strategies that are being used to overcome tumor-mediated immunosuppression in solid tumors; these strategies have the potential to improve clinical outcomes of CAR T cell therapy for children with sarcoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptors (CAR) are engineered molecules expressed on the cell surface that can recognise specific proteins and deliver an activation signal to the cells. Human T lymphocytes equipped with CAR, also called CAR-T cells, can target and kill tumour cells. This technology has been successfully used in treating some of the blood cancers in the last decade. Although the majority of research interest in CAR technology has been focused on CAR-T cells to date, the CAR design has also been used in other types of immune cells to fight against cancers. In this review, we discuss recent advances in CAR design beyond that used in conventional CAR-T cells and their novel indications to develop more potent CAR-based therapy for cancers. Chimeric antigen receptors (CAR) are genetically engineered receptors that can recognise specific antigens and subsequently activate downstream signalling. Human T cells engineered to express a CAR, also known as CAR-T cells, can target a specific tumour antigen on the cell surface to mediate a cytotoxic response against the tumour. CAR-T cell therapy has achieved remarkable success in treating hematologic malignancies, but not in solid tumours. Currently, extensive research is being carried out to make CAR-T cells a therapy for solid tumours. To date, most of the research interest in the field has focused on cytotoxic T lymphocytes as the carrier of CAR products. However, in addition to T cells, the CAR design can be introduced in other immune cells, such as natural killer (NK)/NKT cells, γδ T cells, mucosal-associated invariant T (MAIT) cells, dendritic cells (DC), macrophages, regulatory T cells (Treg), B cells, etc. Some of the CAR-engineered immune cells, such as CAR- γδ T and CAR-NK/NK-T cells, are directly involved in the anti-tumour response, demonstrated in preclinical studies and/or clinical trials. CAR-Tregs showed promising therapeutic potential in treating autoimmune diseases. In particular, B cells engineered with chimeric receptors can be used as a platform for long-term delivery of therapeutic proteins, such as recombinant antibodies or protein replacement, in an antigen-specific manner. CAR technology is one of the most powerful engineering platforms in immunotherapy, especially for the treatment of cancers. In this review, we will discuss the recent application of the CAR design in non-CAR-T cells and future opportunities in immunotherapy. [ABSTRACT FROM AUTHOR]