T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

Eisenberg, Vasyl; Hoogi, Shiran; Shamul, Astar; Barliya, Tilda; Cohen, Cyrille J.

doi:10.1016/j.addr.2019.01.007

Cited by 22 publications

(26 citation statements)

References 365 publications

(432 reference statements)

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“…Unlike hematological malignancies, a major problem with solid tumors is the presence of an immunosuppressive TME [10,125]. In the TME, tumor cells activate immune checkpoint receptors (PD-1, CTLA-4, LAG3, TIGIT, VISTA) on T cells, through the expression of their ligands [3,126] and deliver immunosuppressive signals, which drive T cells into a state of exhaustion, tolerance, or dysfunction [127,128]. Therefore, blocking the co-suppression signal in CAR T cells may reverse the exhausted phenotype of CAR T cells and improve their antitumor function [129].…”

Section: Knocking Out Negative T Cell Regulators Immune Checkpoint Momentioning

confidence: 99%

Gene modification strategies for next-generation CAR T cells against solid cancers

et al. 2020

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Immunotherapies have become the backbone of cancer treatment. Among them, chimeric antigen receptor (CAR) T cells have demonstrated great success in the treatment of hematological malignancies. However, CAR T therapy against solid tumors is less effective. Antigen targeting; an immunosuppressive tumor microenvironment (TME); and the infiltration, proliferation, and persistence of CAR T cells are the predominant barriers preventing the extension of CAR T therapy to solid tumors. To circumvent these obstacles, the next-generation CAR T cells will require more potent antitumor properties, which can be achieved by gene-editing technology. In this review, we summarize innovative strategies to enhance CAR T cell function by improving target identification, persistence, trafficking, and overcoming the suppressive TME. The construction of multi-target CAR T cells improves antigen recognition and reduces immune escape. Enhancing CAR T cell proliferation and persistence can be achieved by optimizing costimulatory signals and overexpressing cytokines. CAR T cells equipped with chemokines or chemokine receptors help overcome their poor homing to tumor sites. Strategies like knocking out immune checkpoint molecules, incorporating dominant negative receptors, and chimeric switch receptors can favor the depletion or reversal of negative T cell regulators in the TME.

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Section: Knocking Out Negative T Cell Regulators Immune Checkpoint Momentioning

confidence: 99%

Gene modification strategies for next-generation CAR T cells against solid cancers

et al. 2020

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“…It may be crucial to combine siglec‐CAR along with other approaches, to regulate their function and minimize off‐target effects; for example, it will be possible to co‐express an inhibitory CARs that could modulate siglec‐CAR function 44,45 . Synthetic biology circuits (such as AND gates) or the use suicide genes 46 could also provide another layer of safety when using siglec‐CAR engineered T‐cells 17 …”

Section: Discussionmentioning

confidence: 99%

“…CARs targeting different glycosylated antigens have been developed in the past decade 17,23 . These were based scFv derived from mAbs often from murine origin.…”

Section: Discussionmentioning

confidence: 99%

“…The basic premise of cancer immunotherapy is to manipulate the immune system function to effectively fight the cancer 17 . Food and Drug Administration‐approved immunotherapies comprise two broad strategies which are checkpoint blockade to potentiate the immune system and the adoptive transfer of genetically engineered tumor‐specific lymphocytes 18,19 .…”

Section: Introductionmentioning

confidence: 99%

“…Food and Drug Administration‐approved immunotherapies comprise two broad strategies which are checkpoint blockade to potentiate the immune system and the adoptive transfer of genetically engineered tumor‐specific lymphocytes 18,19 . In the case of the latter, tumor specificity is achieved through the expression of chimeric antigen receptors (CARs) 20 which are composed of a targeting portion (generally a scFv specific for a defined antigen) and a signaling moiety (incorporating parts of FcRIIIγ or CD3ζ molecules) 17,21 . Still, these approaches are often limited to certain types of cancer, mainly hematological, due to the targeted antigen expression pattern.…”

Section: Introductionmentioning

confidence: 99%

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Targeting glycosylated antigens on cancer cells using siglec‐7/9‐based CAR T‐cells

Meril

Harush

Reboh

et al. 2020

Molecular Carcinogenesis

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Chimeric antigen receptor (CAR) T-cells treatment demonstrate the increasing and powerful potential of immunotherapeutic strategies, as seen mainly for hematological malignancies. Still, efficient CAR-T cell approaches for the treatment of a broader spectrum of tumors are needed. It has been shown that cancer cells can implement strategies to evade immune response that include the expression of inhibitory ligands, such as hypersialylated proteins (sialoglycans) on their surface. These may be recognized by sialic acid-binding immunoglobulin-type lectins (siglecs) which are surface receptors found primarily on immune cells. In this regard, siglec-7 and -9 are found on immune cells, such as natural killer cells, T-cells, and dendritic cells and they can promote immune suppression when binding to sialic acids expressed on target cells. In the present study, we hypothesized that it is possible to use genetically engineered T-cells expressing siglec-based CARs, enabling them to recognize and eliminate tumor cells, in a non-histocompatibility complex molecule restricted way. Thus, we genetically modified human T-cells with different chimeric receptors based on the exodomain of human siglec-7 and -9 molecules and selected optimal receptors. We then assessed their antitumor activity in vitro demonstrating the recognition of cell lines from different histologies. These results were confirmed in a tumor xenograft model exemplifying the potential of the present approach.Overall, this study demonstrates the benefit of targeting cancer-associated glycosylation patterns using CAR based on native immune receptors and expressed in human primary T-cells.

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Improving the Delivery of Drugs and Nucleic Acids to T Cells Using Nanotechnology

2021

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T cells play several roles in antitumor immunity, including mediating cytotoxicity, generating immune memory, and promoting humoral immunity. Given these critical roles, T cells are the therapeutic target of immunotherapies that have achieved clinical success, notably immune checkpoint inhibitors and chimeric antigen receptor T‐cell therapy. However, a fraction of patients benefits from these treatments due to intolerable toxicities and limited efficacy. These issues stem in part from inefficient and nonselective drug delivery to T cells. Nanotechnology may help resolve these delivery issues, as nanoparticles can serve as modular drug delivery vehicles with targeting abilities that can be applied for ex vivo and in vivo delivery. Herein, applications of nanotechnology in improving extracellular delivery of cytokines and small molecule drugs and intracellular delivery of siRNA to T cells are described. An overview of nanoparticle‐mediated delivery of nucleic acids for chimeric antigen receptor T‐cell therapy and CRISPR/Cas9 genome editing is provided. Finally, an outlook on the challenges and opportunities for the advancement of nanoparticle‐mediated drug delivery to T cells is shared.

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T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

Cited by 22 publications

References 365 publications

Gene modification strategies for next-generation CAR T cells against solid cancers

Gene modification strategies for next-generation CAR T cells against solid cancers

Targeting glycosylated antigens on cancer cells using siglec‐7/9‐based CAR T‐cells

Improving the Delivery of Drugs and Nucleic Acids to T Cells Using Nanotechnology

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