CD19 CAR antigen engagement mechanisms and affinity tuning

He, Changhao; Mansilla-Soto, Jorge; Khanra, Nandish; Hamieh, Mohamad; Bustos, Victor; Paquette, Alice J.; Angus, Andreina Garcia; Shore, Derek M.; Rice, William J.; Khelashvili, George; Sadelain, Michel; Meyerson, Joel R.

doi:10.1126/sciimmunol.adf1426

Cited by 20 publications

(27 citation statements)

References 76 publications

(109 reference statements)

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“…CAR antigen sensitivity may also be modulated through the CAR's binding affinity ( 41 ). Cryogenic electron microscopy structural studies performed on the FMC63 and SJ25C1 CD19-specific scFvs have pinpointed contact residues with CD19 and guided the rational design of 28ζ CARs with increased or decreased sensitivity to CD19 ( 42 ).…”

Section: Antigen Sensitivity and Car Designsmentioning

confidence: 99%

Programming CAR T Cell Tumor Recognition: Tuned Antigen Sensing and Logic Gating

et al. 2023

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The success of chimeric antigen receptor (CAR) T cells targeting B-cell malignancies propelled the field of synthetic immunology and raised hopes to treat solid tumors in a similar fashion. Antigen escape and the paucity of tumor-restricted CAR targets are recognized challenges to fulfilling this prospect. Recent advances in CAR T cell engineering extend the toolbox of chimeric receptors available to calibrate antigen sensitivity and combine receptors to create adapted tumor-sensing T cells. Emerging engineering strategies to lower the threshold for effective antigen recognition, when needed, and enable composite antigen recognition hold great promise for overcoming tumor heterogeneity and curbing off-tumor toxicities. Significance: Improving the clinical efficacy of CAR T cell therapies will require engineering T cells that overcome heterogeneous and low-abundance target expression while minimizing reactivity to normal tissues. Recent advances in CAR design and logic gating are poised to extend the success of CAR T cell therapies beyond B-cell malignancies.

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Section: Antigen Sensitivity and Car Designsmentioning

confidence: 99%

Programming CAR T Cell Tumor Recognition: Tuned Antigen Sensing and Logic Gating

et al. 2023

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“…Various intracellular signaling domains from immune receptors have been used as costimulatory domains in CARs. Similarly, numerous scFvs have been used to vary affinity or binding interface for a given antigen 10–13 . Unique hinge and transmembrane domain combinations have been used to improve CAR T‐cell function 14–16 .…”

Section: Modularity In Cell Therapymentioning

confidence: 99%

Harnessing the power of artificial intelligence to advance cell therapy

Capponi

Daniels

2023

Immunological Reviews

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SummaryCell therapies are powerful technologies in which human cells are reprogrammed for therapeutic applications such as killing cancer cells or replacing defective cells. The technologies underlying cell therapies are increasing in effectiveness and complexity, making rational engineering of cell therapies more difficult. Creating the next generation of cell therapies will require improved experimental approaches and predictive models. Artificial intelligence (AI) and machine learning (ML) methods have revolutionized several fields in biology including genome annotation, protein structure prediction, and enzyme design. In this review, we discuss the potential of combining experimental library screens and AI to build predictive models for the development of modular cell therapy technologies. Advances in DNA synthesis and high‐throughput screening techniques enable the construction and screening of libraries of modular cell therapy constructs. AI and ML models trained on this screening data can accelerate the development of cell therapies by generating predictive models, design rules, and improved designs.

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“…Generation of optimal low‐affinity binders derived from existing antibodies might facilitate the development of more functional and selective CAR binding domains 119 . The strategy was evaluated with anti‐CD19 CAR T‐cells for hematological diseases 19‐21 . The approach is better suitable for antigens whose expression on healthy tissues is low but upregulated on malignant tissues such as HER2/neu (ErbB2), EGFR, C4 folate receptor‐alpha (αFR), GD2, GPC2 and CD38 22‐28 .…”

Section: Strategies For Controlling Car T‐cell Activitymentioning

confidence: 99%

“…119 To avoid ON-target OFF-tumor toxicity, the CAR's binding domain affinity towards the target antigen can be reduced, leading to passive toxicity control (Table 1). [19][20][21][22][23][24][25][26][27][28] Tumor cells would still be targeted due to their high antigen expression; but nonmalignant cells with low antigen expression less frequently. Generation of optimal low-affinity binders derived from existing antibodies might facilitate the development of more functional and selective CAR binding domains.…”

Section: Prevention Of Treatment-associated Toxicitymentioning

confidence: 99%

“…CAR T-cells for hematological diseases. [19][20][21] The approach is better suitable for antigens whose expression on healthy tissues is low but upregulated on malignant tissues such as HER2/neu (ErbB2), EGFR, C4 folate receptor-alpha (αFR), GD2, GPC2 and CD38. [22][23][24][25][26][27][28] CAR T-cells toward tumor cells.…”

Section: Prevention Of Treatment-associated Toxicitymentioning

confidence: 99%

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Mechanisms and strategies for safe chimeric antigen receptor T‐cell activity control

Stock,

Klüver,

Fertig

et al. 2023

Intl Journal of Cancer

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The clinical application of chimeric antigen receptor (CAR) T‐cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood‐borne cancer types. However, CAR T‐cell therapy can lead to severe therapy‐associated toxicities including CAR‐related hematotoxicity, ON‐target OFF‐tumor toxicity, cytokine release syndrome (CRS) or immune effector cell‐associated neurotoxicity syndrome (ICANS). Just as CAR T‐cell therapy has evolved regarding receptor design, gene transfer systems and production protocols, the management of side effects has also improved. However, because of measures taken to abrogate adverse events, CAR T‐cell viability and persistence might be impaired before complete remission can be achieved. This has fueled efforts for the development of extrinsic and intrinsic strategies for better control of CAR T‐cell activity. These approaches can mediate a reversible resting state or irreversible T‐cell elimination, depending on the route chosen. Control can be passive or active. By combination of CAR T‐cells with T‐cell inhibiting compounds, pharmacologic control, mostly independent of the CAR construct design used, can be achieved. Other strategies involve the genetic modification of T‐cells or further development of the CAR construct by integration of molecular ON/OFF switches such as suicide genes. Alternatively, CAR T‐cell activity can be regulated intracellularly through a self‐regulation function or extracellularly through titration of a CAR adaptor or of a priming small molecule. In this work, we review the current strategies and mechanisms to control activity of CAR T‐cells reversibly or irreversibly for preventing and for managing therapy‐associated toxicities.

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CD19 CAR antigen engagement mechanisms and affinity tuning

Cited by 20 publications

References 76 publications

Programming CAR T Cell Tumor Recognition: Tuned Antigen Sensing and Logic Gating

Programming CAR T Cell Tumor Recognition: Tuned Antigen Sensing and Logic Gating

Harnessing the power of artificial intelligence to advance cell therapy

Mechanisms and strategies for safe chimeric antigen receptor T‐cell activity control

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