2021
DOI: 10.2147/btt.s252568
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How Can We Engineer CAR T Cells to Overcome Resistance?

Abstract: Chimeric antigen receptor (CAR) T cell therapy has achieved unrivalled success in the treatment of B cell and plasma cell malignancies, with five CAR T cell products now approved by the US Food and Drug Administration (FDA). However, CAR T cell therapies for solid tumours have not been nearly as successful, owing to several additional challenges. Here, we discuss mechanisms of tumour resistance in CAR T cell therapy and the emerging strategies that are under development to engineer CAR T cells to overcome resi… Show more

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Cited by 14 publications
(11 citation statements)
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References 245 publications
(427 reference statements)
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“…IL-15 maintains a naive and central memory phenotype with increased expression of anti-apoptotic proteins and reduced PD-1 expression [ 152 ]. Many other cytokines including IL-7, IL-18, IL-21, and IL-23 have now been tested for their ability to enhance CAR T cell antitumor responses and an overview can be consulted in the recent review of Glover and colleagues [ 153 ].…”
Section: Adoptive T Cell Transfer Therapy—a Focus On Car T Cellsmentioning
confidence: 99%
“…IL-15 maintains a naive and central memory phenotype with increased expression of anti-apoptotic proteins and reduced PD-1 expression [ 152 ]. Many other cytokines including IL-7, IL-18, IL-21, and IL-23 have now been tested for their ability to enhance CAR T cell antitumor responses and an overview can be consulted in the recent review of Glover and colleagues [ 153 ].…”
Section: Adoptive T Cell Transfer Therapy—a Focus On Car T Cellsmentioning
confidence: 99%
“…A summary of clinical trial activity in the solid tumour arena has recently been published (Adami and Maher 2021 ). Increasing efforts are being applied to address relevant obstacles in this quest, including target heterogeneity and lack of cancer selectivity, inadequate homing to and penetration of CAR-engineered cells within malignant lesions and the profoundly immunosuppressive nature of the tumour microenvironment (Glover et al 2021 ; Hull and Maher 2021 ). These efforts are likely to make an impact in the near future, as evidenced by recent successes in selected solid tumour types (Glover et al 2021 ; Hull and Maher 2021 ).…”
Section: Introductionmentioning
confidence: 99%
“…Increasing efforts are being applied to address relevant obstacles in this quest, including target heterogeneity and lack of cancer selectivity, inadequate homing to and penetration of CAR-engineered cells within malignant lesions and the profoundly immunosuppressive nature of the tumour microenvironment (Glover et al 2021 ; Hull and Maher 2021 ). These efforts are likely to make an impact in the near future, as evidenced by recent successes in selected solid tumour types (Glover et al 2021 ; Hull and Maher 2021 ). Given that over 90% of human cancers are solid tumours, the development of an effective CAR-based solution that can impact in this arena will prove profoundly disruptive, but will also impose an substantial drug delivery challenge which autologous solutions are unlikely to overcome.…”
Section: Introductionmentioning
confidence: 99%
“…proliferation. 1 Chimeric antigen receptor T-cell therapy (CART) directed against CD19 has shown remarkable efficacy in patients with relapsed acute lymphoblastic leukemia (ALL), and more recently, in patients with refractory diffuse large B-cell lymphoma (DLBCL). 2,3 Despite frequent durable remissions induced by CART in hematologic malignancies, about 60% of patients show a lack of response or eventually relapse, which is a major barrier to improve the outcome of the disease.…”
mentioning
confidence: 99%
“…Chimeric antigen receptor (CAR) T cells are genetically engineered T cells bearing a particular surface receptor composed of an extracellular single-chain variable fragment capable of direct recognition of a specific antigen 1. This immunotherapy represents a powerful weapon against various tumor cells since its action is independent of the major histocompatibility complex but instead relies on an intracellular CD3z domain eliciting the T-cell activation signal and a CD28 or 4-1BB domain triggering a costimulatory signal to allow CAR T-cell proliferation 1. Chimeric antigen receptor T-cell therapy (CART) directed against CD19 has shown remarkable efficacy in patients with relapsed acute lymphoblastic leukemia (ALL), and more recently, in patients with refractory diffuse large B-cell lymphoma (DLBCL) 2,3…”
mentioning
confidence: 99%