To go or not to go? Biological logic gating engineered T cells

Abbott, Rebecca C; Hughes‐Parry, Hannah E; Jenkins, Misty R.

doi:10.1136/jitc-2021-004185

Cited by 32 publications

(22 citation statements)

References 84 publications

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“…The combination of AI/ML with some of these more advanced target discovery approaches may improve the selection of specific tumor targets [3,78]. A higher-order strategy to improve cancer specificity is the simultaneous targeting of multiple antigens combined with the use of logic gates for regulating CAR T cell activation [87]. In addition to safer targeting, challenges relating to the immune suppressive tumor microenvironment and delivery still need to be addressed.…”

Section: Discussionmentioning

confidence: 99%

Target selection and clinical chimeric antigen receptor T cell activity against solid tumors

Hofe

Yang

Jin

2023

iLABMED

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Chimeric antigen receptor (CAR) T cell therapy is a relatively new form of targeted therapy that has demonstrated impressive success in treating hematological malignancies. It has been challenging to translate this success to solid tumors. Reasons for this include barriers to delivery, tumor heterogeneity, cancer cells' ability to evade the immune system as well as identifying the optimal target. Most CAR T clinical trials have targeted well‐characterized cancer targets with significant preclinical and in some cases clinical validation. Published results from some of these trials show signs of anti‐cancer activity that warrant encouragement, but also caution, given instances of unacceptable toxicity. The narrow therapeutic window is complicated by the ability of CAR T cells to expand in patients regardless of dose. Here, we review those trials showing encouraging results in the context of target selection. It is clear that more specific tumor targeting is required, either by affinity tuning to avoid low‐level target expression in healthy cells, logic gating, or the identification of new targets that are more cancer specific.

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Section: Discussionmentioning

confidence: 99%

Target selection and clinical chimeric antigen receptor T cell activity against solid tumors

Hofe

Yang

Jin

2023

iLABMED

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“…Many variations have been made to the structure or composition of CARs and CAR T cells to improve their efficacy in solid tumors, the extent of which is beyond this review (see cited reviews for extensive detail on many different CAR varieties and applications) [ 5 , 113 , 114 , 115 ]. These modifications range from multi-specific CARs which bind multiple antigens to logic gated CAR T cells to cytokine secreting CAR T cells and CARs engineered into other cell types besides T cells [ 5 ].…”

Section: Car T-cell Advancements and Co-treatments To Overcome Immuno...mentioning

confidence: 99%

Tumor Microenvironment Immunosuppression: A Roadblock to CAR T-Cell Advancement in Solid Tumors

Johnson

Townsend

O’Neill

2022

Cells

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Chimeric antigen receptor (CAR) T cells are an exciting advancement in cancer immunotherapy, with striking success in hematological cancers. However, in solid tumors, the unique immunosuppressive elements of the tumor microenvironment (TME) contribute to the failure of CAR T cells. This review discusses the cell populations, cytokine/chemokine profile, and metabolic immunosuppressive elements of the TME. This immunosuppressive TME causes CAR T-cell exhaustion and influences failure of CAR T cells to successfully infiltrate solid tumors. Recent advances in CAR T-cell development, which seek to overcome aspects of the TME immunosuppression, are also reviewed. Novel discoveries overcoming immunosuppressive limitations of the TME may lead to the success of CAR T cells in solid tumors.

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“…The administration of CAR-T cells whose scFv will have low affinity, and thus whose activation requires a high density of Ag on the surface of target cells, may prevent the destruction of normal tissues with low Ag expression [10,41,42].…”

Section: On-target/off-tumor Effectmentioning

confidence: 99%

“…Some patients treated with anti-CD19 CAR-T cells may relapse with CD19-tumor cells due to mutations or alternative gene splicing. Research is currently in progress to develop CAR-T cells that have CARs directed against several different Ags, including CD20 and CD22, to delay or avoid the difficulties associated with Ag loss [1,10,42].…”

Section: Antigen Lossmentioning

confidence: 99%

A living drug: application of CAR-T therapy for lymphoid malignancies and beyond

et al. 2022

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The ongoing development of novel personalized cancer therapies has resulted in the implementation of T-cells enriched with synthetic chimeric antigen receptors, known as chimeric antigen receptors T-cell (CAR-T) cells, into clinical practice. CAR-T cells are able to recognize and bind specific antigens present on the surface of target cellsso-called tumor-associated antigens. This innovative method has been approved for the treatment of hematological malignancies and may also serve as a bridge to hematopoietic stem cell transplantation. The production of the drug containing modified T-cells consists of several steps -leukapheresis, T-cell activation, transduction and expansion of the final CAR-T cells. Activation of CAR-T cells occurs through a pathway independent of the major histocompatibility complex, which is often associated with uncontrolled responses from the immune system and adverse reactions such as cytokine release syndrome. CAR-T therapy can only be performed in certified centers, and requires close cooperation between experienced specialists of different medical disciplines. This is what determines its effectiveness. Every step from collection and cryopreservation, through transport and modification, to thawing and infusion is strictly controlled because it has a critical impact on the quality and efficiency of the drug. Despite its proven benefits, CAR-T therapy remains available only to patients who meet well-defined criteria. These however are liable to change with the emergence of new indications.

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To go or not to go? Biological logic gating engineered T cells

Cited by 32 publications

References 84 publications

Target selection and clinical chimeric antigen receptor T cell activity against solid tumors

Target selection and clinical chimeric antigen receptor T cell activity against solid tumors

Tumor Microenvironment Immunosuppression: A Roadblock to CAR T-Cell Advancement in Solid Tumors

A living drug: application of CAR-T therapy for lymphoid malignancies and beyond

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