Chimeric antigen receptors: driving immunology towards synthetic biology

Sadelain, Michel

doi:10.1016/j.coi.2016.06.004

Cited by 81 publications

(58 citation statements)

References 99 publications

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“…Highly potent CTL for adoptive immunotherapy may be most effectively stimulated in vitro on relevant pMHC molecule arrays using piconewton shear forces to train and expand CTL for subsequent in vivo use. Chimeric antigen receptor T cells (CAR-Ts) consisting of an antibody antigen binding fragment of predefined specificity as an ectodomain linked to an intracellular T-cell activation domain originally proposed by Eshhar and coworkers in 1989 (80) have shown great clinical promise recently (81). Molecular features of TCR mechanobiology revealed here should be exploited to optimize the synthetic biology of CAR-T design to confer heightened potency as well as intrinsic regulation features.…”

Section: Discussionmentioning

confidence: 99%

Mechanosensing drives acuity of αβ T-cell recognition

Feng

Brazin

Kobayashi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

162

197

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T lymphocytes use surface αβ T-cell receptors (TCRs) to recognize peptides bound to MHC molecules (pMHCs) on antigen-presenting cells (APCs). How the exquisite specificity of high-avidity T cells is achieved is unknown but essential, given the paucity of foreign pMHC ligands relative to the ubiquitous self-pMHC array on an APC. Using optical traps, we determine physicochemical triggering thresholds based on load and force direction. Strikingly, chemical thresholds in the absence of external load require orders of magnitude higher pMHC numbers than observed physiologically. In contrast, force applied in the shear direction (∼10 pN per TCR molecule) triggers T-cell Ca 2+ flux with as few as two pMHC molecules at the interacting surface interface with rapid positional relaxation associated with similarly directed motor-dependent transport via ∼8-nm steps, behaviors inconsistent with serial engagement during initial TCR triggering. These synergistic directional forces generated during cell motility are essential for adaptive T-cell immunity against infectious pathogens and cancers.mechanosensor | T-cell receptor | T-cell activation | optical tweezers | cellular force relaxation T he T-cell receptor (TCR) expressed on T lymphocytes of the adaptive immune system is a stout and squat (12-nm wide × 8-nm tall) multisubunit surface complex with a ligand binding moiety that is an αβ disulfide-linked heterodimer buttressed by the associated invariant CD3 subunits (1-3). The αβ chains are each encoded by V and J gene segments and in the case of the β, a D segment as well (4). The clone-specific TCR unique to each T lymphocyte endows mammals with the capacity to detect perturbations in host cellular function resulting from myriad infectious pathogens, physical damage (thermal, irradiation, etc.), or premalignant or malignant cellular transformations while averting strong self-reactivities that could induce autoimmunity (5).Signaling is initiated through ligation of the clonotype by its cognate antigenic peptide bound to an MHC molecule (pMHC) and displayed on the surface of antigen-presenting cells (APCs) (6, 7). Ligation impacts disposition and function of the associated CD3 dimers (CD3 γ, CD3 δ, and CD3ζζ) as well as the transmembrane domains of the TCR heterodimer and CD3 subunits that interdigitate in the membrane to signal into the cytoplasm (8, 9). A cascade of intracellular events involving phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3 cytoplasmic domains with subsequent ZAP70 activation and downstream signaling follows (10, 11). Membrane-associated CD8 and CD4 coreceptors, marking cytotoxic T lymphocytes (CTLs) and helper T cells, respectively, function to bring the membrane-anchored Src family tyrosine kinase Lck to the TCR-pMHC complex for the initiation of ITAM phosphorylation. Signaling, in turn, leads to a transient rise of cytosolic Ca 2+ and other biochemical events resulting in transcriptional activation, ultimately resulting in developmental decisions or effector functi...

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Section: Discussionmentioning

confidence: 99%

Mechanosensing drives acuity of αβ T-cell recognition

Feng

Brazin

Kobayashi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

162

197

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“…Conventional T cells expressing surface CARs have been directed to specific selected antigens expressed by neoplastic cells, inducing antigen-mediated immune responses, such as tumor regression and elimination (3,4). Using this approach, CAR T cells have emerged as a new therapy for several hematologic cancers and have ushered in a new era for CAR-based cancer immunotherapy (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

T cells expressing chimeric antigen receptor promote immune tolerance

Pierini¹,

Iliopoulou²,

Peiris³

et al. 2017

JCI Insight

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“…66,67 CARs are composed of an extracellular antigen-binding domain, typically the single-chain variable fragment (scFv) derived from a monoclonal antibody, and an intracellular signaling domain, usually the CD3z chain of the TCR. 68 While CARs have been used extensively to redirect the specificity of T cells for clinical use, studies of CAR-modified NK cells have been largely preclinical to date. However, the dramatic clinical responses and prolonged remissions observed after the infusion of CD19 CAR-T cells in patients with lymphoid malignancies, particularly ALL, 1-5 have rekindled the enthusiasm to further study and optimize CAR-modified NK cells for clinical use.…”

Section: Advantages and Challenges Of Car-nk Cell Therapymentioning

confidence: 99%

Engineering Natural Killer Cells for Cancer Immunotherapy

et al. 2017

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The past several years have seen tremendous advances in the engineering of immune effector cells as therapy for cancer. While chimeric antigen receptors (CARs) have been used extensively to redirect the specificity of autologous T cells against hematological malignancies with striking clinical results, studies of CAR-modified natural killer (NK) cells have been largely preclinical. In this review, we focus on recent advances in NK cell engineering, particularly on preclinical evidence suggesting that NK cells may be as effective as T cells in recognizing and killing targets after genetic modification. We will discuss strategies to introduce CARs into both primary NK cells and NK cell lines in an effort to provide antigen specificity, the challenges of manufacturing engineered NK cells, and evidence supporting the effectiveness of this approach from preclinical and early-phase clinical studies using CAR-engineered NK cells. CAR-NK cells hold great promise as a novel cellular immunotherapy against refractory malignancies. Notably, NK cells can provide an "off-the-shelf" product, eliminating the need for a personalized and patient-specific product that plagues current CAR-T cell therapies. The ability to more potently direct NK cell-mediated cytotoxicity against refractory tumors through the expression of CAR is likely to contribute to the recent paradigm shift in cancer treatment.

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Chimeric antigen receptors: driving immunology towards synthetic biology

Cited by 81 publications

References 99 publications

Mechanosensing drives acuity of αβ T-cell recognition

Mechanosensing drives acuity of αβ T-cell recognition

T cells expressing chimeric antigen receptor promote immune tolerance

Engineering Natural Killer Cells for Cancer Immunotherapy

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