Driving CAR T cell translation forward

Schultz, Liora; Mackall, Crystal L.

doi:10.1126/scitranslmed.aaw2127

Cited by 66 publications

(70 citation statements)

References 10 publications

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“…Of all the tested constructs, CAR that incorporated the TM region of CD28 performed optimally (Figure 2). This strengthens the need to examine CAR function empirically 19,36‐38 . Closer examination of the critical Ig‐domains in the extracellular siglec‐7 moiety showed that the main functional domains for tumor recognition were 1 and 3.…”

Section: Discussionmentioning

confidence: 76%

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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Section: Discussionmentioning

confidence: 76%

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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“…Owing to emergence of relapse of ALL with cells that do not express CD19 in mechanisms of a phenomenon known as antigen escape, the Phase I study with the use of CAR-T cells with dual targeting of CD19/CD22 has demonstrated good efficacy, safety, and tolerability, thus opening possibility to trials studying bispecific targeting to circumvent CD19 down-regulation [17,23,24].…”

Section: Further Progress and Worldwide Distributionmentioning

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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“…52,53) Engineered CARs target many other antigens of blood cancers, including CD30 in Hodgkin's lymphoma as well as CD33, CD123, and FLT3 of acute myeloid leukemia. 54) Recent research has shown that Cas9-mediated PD-1 disruption in the CAR-T cells improved the anti-tumor effect observed in in-vitro and in-vivo experimental models, leading to the performance of a clinical trial. 55,56) All other ongoing clinical trials using genome-editing technologies are highlighted in Table 3.…”

Section: Applications Of Genome Editing Technologiesmentioning

confidence: 99%

Historic Overview of Genetic Engineering Technologies for Human Gene Therapy

Tamura

Toda

2020

Neurol. Med. Chir.(Tokyo)

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The concepts of gene therapy were initially introduced during the 1960s. Since the early 1990s, more than 1900 clinical trials have been conducted for the treatment of genetic diseases and cancers mainly using viral vectors. Although a variety of methods have also been performed for the treatment of malignant gliomas, it has been difficult to target invasive glioma cells. To overcome this problem, immortalized neural stem cell (NSC) and a nonlytic, amphotropic retroviral replicating vector (RRV) have attracted attention for gene delivery to invasive glioma. Recently, genome editing technology targeting insertions at site-specific locations has advanced; in particular, the clustered regularly interspaced palindromic repeats/CRISPR-associated-9 (CRISPR/ Cas9) has been developed. Since 2015, more than 30 clinical trials have been conducted using genome editing technologies, and the results have shown the potential to achieve positive patient outcomes. Gene therapy using CRISPR technologies for the treatment of a wide range of diseases is expected to continuously advance well into the future.

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Driving CAR T cell translation forward

Abstract: Successes in CAR T cell translation have propelled their commercial launch, but expanding the impact of cancer immunotherapies remains challenging.

Cited by 66 publications

References 10 publications

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

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

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

Historic Overview of Genetic Engineering Technologies for Human Gene Therapy

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