Abstract
Simple SummaryThis 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.
Highlights
Sarcomas are rare cancers of the connective tissue that can arise anywhere in the body
We will discuss the Chimeric antigen receptor T (CAR T) cell therapies that are currently being tested in children with sarcoma, as well as new targets that are in pre-clinical development
We further discuss the strategies that are being investigated to overcome immunosuppression in the tumor microenvironment (TME), which we propose have the potential to significantly improve Chimeric antigen receptor (CAR) T cell therapy for children with sarcoma
Summary
Sarcomas are rare cancers of the connective tissue that can arise anywhere in the body. There are over 100 different histological subtypes that occur in children, with osteosarcomas, Ewing’s sarcomas, and rhabdomyosarcomas being the most prevalent [1,2]. Together, they account for over 10% of childhood cancers [3]. They account for over 10% of childhood cancers [3] This diversity of histology means that any one subtype of sarcoma is rare, and there has been little progress made towards new treatments in decades [4]. We will discuss the CAR T cell therapies that are currently being tested in children with sarcoma, as well as new targets that are in pre-clinical development. We further discuss the strategies that are being investigated to overcome immunosuppression in the TME, which we propose have the potential to significantly improve CAR T cell therapy for children with sarcoma
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