Abstract
T cell chimeric antigen receptor (CAR) technology has allowed for the introduction of a high degree of tumor selectivity into adoptive cell transfer therapies. Evolution of this technology has produced a robust antitumor immunotherapeutic strategy that has resulted in dramatic outcomes in liquid cancers. CAR-expressing T-cells (CARTs) targeting CD19 and CD20 have been successfully used in the treatment of hematologic malignancies, producing sustained tumor regressions in a majority of treated patients. These encouraging results have led to a historic and unprecedented FDA approval of CTL019, Novartis' CAR T-cell therapy for the treatment of children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). However, the translation of this technology to solid tumors, like malignant gliomas (MG), has thus far been unsuccessful. This review provides a timely analysis of the factors leading to the success of CART immunotherapy in the setting of hematologic malignancies, barriers limiting its success in the treatment of solid tumors, and approaches to overcome these challenges and allow the application of CART immunotherapy as a treatment modality for refractory tumors, like malignant gliomas, that are in desperate need of effective therapies.
Highlights
The field of oncology has been revolutionized by the emergence of cellular immunotherapies that harness and augment the natural capacity of the immune system to fight cancer
Due to a lack of known feasible tumorexclusive antigens, many tumorassociated antigens (TAAs) under current evaluation for CART immunotherapy are derived from overexpressed endogenous molecules, those that promote tumor proliferation and persistence
CARTs expressing a programmed cell death-1 (PD-1)-CD28 switch receptor were shown to be more resistant to tumor-induced immunosuppression, and in a solid tumor mouse model resulted in enhanced TIL infiltration and tumor regression as compared to treatment with CART therapy or PD-1 blockade alone [128]
Summary
The field of oncology has been revolutionized by the emergence of cellular immunotherapies that harness and augment the natural capacity of the immune system to fight cancer. The context of MHC molecules and not accessible to traditional CARs. Due to a lack of known feasible tumorexclusive antigens, many TAAs under current evaluation for CART immunotherapy are derived from overexpressed endogenous molecules, those that promote tumor proliferation and persistence (i.e., growth factor receptors). Due to a lack of known feasible tumorexclusive antigens, many TAAs under current evaluation for CART immunotherapy are derived from overexpressed endogenous molecules, those that promote tumor proliferation and persistence (i.e., growth factor receptors) Their disproportionately high degree of upregulation within tumors allows for preferential targeting of malignant cells. Depending on the location of off-target antigen expression, the resulting toxicities may have life-threatening consequences, as occurred in a patient receiving CART therapy for refractory HER2-overexpressing metastatic colorectal cancer This patient experienced fatal pulmonary toxicity shortly after CART infusion secondary to CAR recognition of low levels of HER2 on lung epithelium [60]. Modified T-cells in Treating Patients With Recurrent or Refractory Malignant Glioma
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