Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality

Sachdeva, Mohit; Busser, Brian W.; Temburni, Sonal; Jahangiri, Billal; Gautron, Anne-Sophie; Maréchal, Alan; Juillerat, Alexandre; Williams, Alan F.; Depil, Stéphane; Duchâteau, Philippe; Poirot, Laurent; Valton, Julien

doi:10.1038/s41467-019-13088-3

Cited by 52 publications

(80 citation statements)

References 70 publications

(111 reference statements)

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“…CRISPR tools can also be applied to engineer artificial T cell signaling circuits, to enhance anti-tumor T cell function by exploiting endogenous transcriptional regulation of specific responses ( Figure 3 f). For example, insertion of IL-12p70 into the IL-2Rα or PDCD1 gene locus produced T cells with antigen-dependent IL-12p70 production, resulting in enhanced anti-tumor function without significant toxicities [ 258 ]. Thus, hijacking the transcriptional regulatory system of defined loci can enable tight control of transgene expression, and could enhance the safety and specificity of functional T cell outputs.…”

Section: Therapeutic Genome Editingmentioning

confidence: 99%

Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy

Rath

Arber

2020

Cells

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T cell receptor (TCR)-based adoptive T cell therapies (ACT) hold great promise for the treatment of cancer, as TCRs can cover a broad range of target antigens. Here we summarize basic, translational and clinical results that provide insight into the challenges and opportunities of TCR-based ACT. We review the characteristics of target antigens and conventional αβ-TCRs, and provide a summary of published clinical trials with TCR-transgenic T cell therapies. We discuss how synthetic biology and innovative engineering strategies are poised to provide solutions for overcoming current limitations, that include functional avidity, MHC restriction, and most importantly, the tumor microenvironment. We also highlight the impact of precision genome editing on the next iteration of TCR-transgenic T cell therapies, and the discovery of novel immune engineering targets. We are convinced that some of these innovations will enable the field to move TCR gene therapy to the next level.

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Section: Therapeutic Genome Editingmentioning

confidence: 99%

Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy

Rath

Arber

2020

Cells

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“…Fourth-generation CARs, the so-called TRUCKs (CAR redirected T cells that deliver a transgenic product to the targeted tumor tissue) or armored CARs, present further enhancement in antitumoral potency, cytokine activity, and costimulatory ligands and enzymes that can degrade the extracellular matrix in solid tumors [9,10]. Further enhancement in the safety of CAR-T cell therapy can be obtained with the so-called smart T cells, which is under investigation [11,12,13].…”

Section: Four Generations Of Carsmentioning

confidence: 99%

A brief history of CAR-T cells: from laboratory to the bedside

Styczyński

2020

Acta Haematologica Polonica

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Chimeric antigen receptors (CARs) are genetically engineered receptors that provide specific properties to an immune effector cell and these receptors gain the specificity of a monoclonal antibody targeted against specific tumor cells. T cells with engineered CARs acquire potent immunological properties and redirect the immune system in order to eliminate malignant cells. First-engineered T cells with chimeric molecule (CAR-T cells) were developed in 1989–1993 by Israeli immunologists Zelig Eshhar and Gideon Gross. The first clinical application of CAR-T cells was done in the University of Pennsylvania and Children’s Hospital in Philadelphia by the immunologist Carl June and hematologist David Porter to patients with chronic lymphocytic leukemia in 2011 and together with the pediatrician Stephan Grupp to patients with acute lymphoblastic leukemia (ALL) in 2012. The US Food and Drug Administration Agency (FDA) in 2017 and the European Medicines Agency (EMA) in 2018 have licensed two products of CAR-T cells: tisagenlecleucel for the use in children and young adults up to 25 years of age with B-cell ALL who do not respond to treatment or have relapsed two or more times and tisagenlecleucel and axicabtagene ciloleucel for the use in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Current progress in CAR technology includes the use in other hematological malignancies, solid tumors, the use of dual CAR-T cells and chimeric antigen receptor natural killer cells (CAR-NK cells).

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“…One of those immune stimulating cytokines is IL-12P70, which was reported to increase CAR T cell activity [ 133 , 134 , 135 ]. Sachdeva et al [ 136 ] achieved using an elegant strategy two objectives at once by gene editing of CAR T cells, in which they placed the IL-12P70 expression into the PDCD1 locus coding for PD1. By this means the secretion of IL-12P70 is under the control of PDCD1 regulatory elements, thus will only be expressed when the CAR T cells encounters the tumor antigen.…”

Section: Preclinical Evaluation Of Car T and Car Nk Cell Therapiesmentioning

confidence: 99%

Humanized Mice Are Precious Tools for Preclinical Evaluation of CAR T and CAR NK Cell Therapies

Mhaidly

Verhoeyen

2020

Cancers

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Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary treatment for hematological malignancies. However, improvements in CAR T-cell therapies are urgently needed since CAR T cell application is associated with toxicities, exhaustion, immune suppression, lack of long-term persistence, and low CAR T-cell tumor infiltration. Major efforts to overcome these hurdles are currently on the way. Incrementally improved xenograft mouse models, supporting the engraftment and development of a human hemato-lymphoid system and tumor tissue, represent an important fundamental and preclinical research tool. We will focus here on several CAR T and CAR NK therapies that have benefited from evaluation in humanized mice. These models are of great value for the cancer therapy field as they provide a more reliable understanding of sometimes complicated therapeutic interventions. Additionally, they are considered the gold standard with regard to assessment of new CAR technologies in vivo for safety, efficacy, immune response, design, combination therapies, exhaustion, persistence, and mechanism of action prior to starting a clinical trial. They help to expedite the critical translation from proof-of-concept to clinical CAR T-cell application. In this review, we discuss innovative developments in the CAR T-cell therapy field that benefited from evaluation in humanized mice, illustrated by multiple examples.

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Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality

Cited by 52 publications

References 70 publications

Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy

Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy

A brief history of CAR-T cells: from laboratory to the bedside

Humanized Mice Are Precious Tools for Preclinical Evaluation of CAR T and CAR NK Cell Therapies

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