Increased antitumor efficacy of PD-1-deficient melanoma-specific human lymphocytes

Marotte, Lucine; Simon, Sylvain; Vignard, Virginie; Dupré, Émilie; Gantier, Malika; Cruard, Jonathan; Alberge, Jean-Baptiste; Hussong, Melanie; Deleine, Cécile; Heslan, Jean‐Marie; Shaffer, James; Beauvais, Tiffany; Gaschet, Joëlle; Scotet, Emmanuel; Fradin, Delphine; Jarry, Anne; Nguyen, Tuan Huy; Labarrière, Nathalie

doi:10.1136/jitc-2019-000311

Cited by 22 publications

(28 citation statements)

References 48 publications

(50 reference statements)

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“…These modified CAR T-cells also induced a decline in the TGF-β-induced conversion of regulatory T (Treg) cells [ 128 ]. In addition to CAR T-cells, using CRISPR-modified tumor-specific effector memory T-cells can be considered as an appropriate alternative for immunotherapy of solid tumors [ 129 ].…”

Section: The Deluxe Zone Of Cancer Therapy Where Crispr Meets Immunomentioning

confidence: 99%

CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy

et al. 2020

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Cancer immunotherapy has been emerged as a promising strategy for treatment of a broad spectrum of malignancies ranging from hematological to solid tumors. One of the principal approaches of cancer immunotherapy is transfer of natural or engineered tumor-specific T-cells into patients, a so called “adoptive cell transfer”, or ACT, process. Construction of allogeneic T-cells is dependent on the employment of a gene-editing tool to modify donor-extracted T-cells and prepare them to specifically act against tumor cells with enhanced function and durability and least side-effects. In this context, CRISPR technology can be used to produce universal T-cells, equipped with recombinant T cell receptor (TCR) or chimeric antigen receptor (CAR), through multiplex genome engineering using Cas nucleases. The robust potential of CRISPR-Cas in preparing the building blocks of ACT immunotherapy has broaden the application of such therapies and some of them have gotten FDA approvals. Here, we have collected the last investigations in the field of immuno-oncology conducted in partnership with CRISPR technology. In addition, studies that have addressed the challenges in the path of CRISPR-mediated cancer immunotherapy, as well as pre-treatment applications of CRISPR-Cas have been mentioned in detail.

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Section: The Deluxe Zone Of Cancer Therapy Where Crispr Meets Immunomentioning

confidence: 99%

CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy

et al. 2020

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“…As TILs are already a viable treatment option in solid cancers, particularly melanoma, it is feasible to try to improve responses in treatment resistant patient. It is possible, for example, to use CRISPR to knockout T-cell exhaustion markers that may be regulating the activity of adoptively transferred T-cells; examples of which include PD-1 knockout [ 78 , 79 ], DGK) knockout to increase TCR activation [ 80 ], or pooled gene knock-ins to improve in vivo T-cell fitness [ 81 ]. Finally, there is recent evidence of the development of universal CAR-T-cells, where CD52 was knocked out in CAR-T cells, to prevent graft-versus-host disease by preventing CAR-T-cell loss upon anti-CD52 mediated depletion of immune cells during therapy [ 82 ].…”

Section: Discussionmentioning

confidence: 99%

T-Cell Gene Therapy in Cancer Immunotherapy: Why It Is No Longer Just CARs on The Road

Crowther

Svane

Met

2020

Cells

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T-cells have a natural ability to fight cancer cells in the tumour microenvironment. Due to thymic selection and tissue-driven immunomodulation, these cancer-fighting T-cells are generally low in number and exhausted. One way to overcome these issues is to genetically alter T-cells to improve their effectiveness. This process can involve introducing a receptor that has high affinity for a tumour antigen, with two promising candidates known as chimeric-antigen receptors (CARs), or T-cell receptors (TCRs) with high tumour specificity. This review focuses on the editing of immune cells to introduce such novel receptors to improve immune responses to cancer. These new receptors redirect T-cells innate killing abilities to the appropriate target on cancer cells. CARs are modified receptors that recognise whole proteins on the surface of cancer cells. They have been shown to be very effective in haematological malignancies but have limited documented efficacy in solid cancers. TCRs recognise internal antigens and therefore enable targeting of a much wider range of antigens. TCRs require major histocompatibility complex (MHC) restriction but novel TCRs may have broader antigen recognition. Moreover, there are multiple cell types which can be used as targets to improve the “off-the-shelf” capabilities of these genetic engineering methods.

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“…Thus, intervention of PDL1/PD1 pathway emerges as a promising approach for reinvigorating CAR T cells in certain clinical application. Strategies for intervention of PDL1/PD1 axis developed recently involving CAR T cells modified to secrete PD1 blocking scFv [ 127 ], disruption of PD1 by gene editing [ 128 , 129 ], and the application of monoclonal antibodies targeting PDL1 or PD1. Of note, compared to 4-1BB/CAR T cells, CD28/CAR T cells are more susceptible to exhaustion that PD-1/PD-L1 blockade confers a priority [ 130 , 131 ].…”

Section: Car T Cells Differentiation and Exhaustionmentioning

confidence: 99%

Engineering better chimeric antigen receptor T cells

2020

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CD19-targeted CAR T cells therapy has shown remarkable efficacy in treatment of B cell malignancies. However, relapse of primary disease remains a major obstacle after CAR T cells therapy, and the majority of relapses present a tumor phenotype with retention of target antigen (antigen-positive relapse), which highly correlate with poor CAR T cells persistence. Therefore, study on factors and mechanisms that limit the in vivo persistence of CAR T cells is crucial for developing strategies to overcome these limitations. In this review, we summarize the rapidly developing knowledge regarding the factors that influence CAR T cells in vivo persistence and the underlying mechanisms. The factors involve the CAR constructs (extracellular structures, transmembrane and intracellular signaling domains, as well as the accessory structures), activation signaling (CAR signaling and TCR engagement), methods for in vitro culture (T cells collection, purification, activation, gene transduction and cells expansion), epigenetic regulations, tumor environment, CD4/CD8 subsets, CAR T cells differentiation and exhaustion. Of note, among these influence factors, CAR T cells differentiation and exhaustion are identified as the central part due to the fact that almost all factors eventually alter the state of cells differentiation and exhaustion. Moreover, we review the potential coping strategies aiming at these limitations throughout this study.

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Increased antitumor efficacy of PD-1-deficient melanoma-specific human lymphocytes

Cited by 22 publications

References 48 publications

CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy

CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy

T-Cell Gene Therapy in Cancer Immunotherapy: Why It Is No Longer Just CARs on The Road

Engineering better chimeric antigen receptor T cells

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