Development of CAR T Cells Expressing a Suicide Gene Plus a Chimeric Antigen Receptor Targeting Signaling Lymphocytic-Activation Molecule F7

Amatya, Christina; Pegues, Melissa A.; Lam, Norris; Vanasse, Danielle; Geldres, Claudia; Choi, Stephanie; Hewitt, Stephen M.; Feldman, Steven A.; Kochenderfer, James N.

doi:10.1016/j.ymthe.2020.10.008

Cited by 72 publications

(50 citation statements)

References 58 publications

(87 reference statements)

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“…Several studies found enhanced T-cell persistence in CAR constructs equipped with a 4-1BB domain rather than a CD28 domain [ 58 , 59 , 60 ]. However, other studies reported conflicting evidence in the difference in persistence between the two costimulatory domains, probably due to variability among patients and tumor types [ 6 , 61 , 62 , 63 , 64 , 65 ]. Other studies have reported that CAR T-cells containing 4-1BB display increased memory T-cell (TEM) phenotypic markers, which may delay CAR T-cell exhaustion [ 6 , 52 , 66 ].…”

Section: Factors Influencing T-cell Persistence In Clinical Settingsmentioning

confidence: 99%

Improving CAR T-Cell Persistence

Pietrobon

Todd

Goswami

et al. 2021

IJMS

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Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies.

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Section: Factors Influencing T-cell Persistence In Clinical Settingsmentioning

confidence: 99%

Improving CAR T-Cell Persistence

Pietrobon

Todd

Goswami

et al. 2021

IJMS

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“…For instance, the anti-SLAMF7 therapy against multiple myeloma (MM) included a dimerization domain fused to a caspase-9 domain suicide gene to mitigate the risk of off-target activation, as SLAMF7 is expressed on healthy leukocytes, including NK cells. The authors have shown efficacy in vitro and in vivo, and the modified cells could be eliminated by the addition of the dimerizing agent AP1903 (rimiducid) [ 93 ].…”

Section: Applications Of LV Vector Technologies For T Cell Engineeringmentioning

confidence: 99%

Lentiviral Vectors for T Cell Engineering: Clinical Applications, Bioprocessing and Future Perspectives

Labbé

Vessillier

Rafiq

2021

Viruses

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Lentiviral vectors have played a critical role in the emergence of gene-modified cell therapies, specifically T cell therapies. Tisagenlecleucel (Kymriah), axicabtagene ciloleucel (Yescarta) and most recently brexucabtagene autoleucel (Tecartus) are examples of T cell therapies which are now commercially available for distribution after successfully obtaining EMA and FDA approval for the treatment of blood cancers. All three therapies rely on retroviral vectors to transduce the therapeutic chimeric antigen receptor (CAR) into T lymphocytes. Although these innovations represent promising new therapeutic avenues, major obstacles remain in making them readily available tools for medical care. This article reviews the biological principles as well as the bioprocessing of lentiviral (LV) vectors and adoptive T cell therapy. Clinical and engineering successes, shortcomings and future opportunities are also discussed. The development of Good Manufacturing Practice (GMP)-compliant instruments, technologies and protocols will play an essential role in the development of LV-engineered T cell therapies.

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“…The use of affinity-tuned scFvs may empower wider use of CAR-T cells against validated targets. The insertion of suicide gene into CAR-T cells (e.g., dimerization domain fused to a caspase-9 domain) is also promising [ 124 ]. The use of effectors cells inducible by IL-12 are in evaluation in HCC [ 125 ].…”

Section: Main Obstacles and Possible Solutionsmentioning

confidence: 99%

Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials

Rochigneux

Chanez

Rauglaudre

et al. 2021

Cancers

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The mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. In unresectable HCC, the cornerstone of systemic treatments is switching from tyrosine kinase inhibitors to immune checkpoints inhibitors (ICI). Next to ICI, adoptive cell transfer represents another promising field of immunotherapy. Targeting tumor associated antigens such as alpha-fetoprotein (AFP), glypican-3 (GPC3), or New York esophageal squamous cell carcinoma-1 (NY-ESO-1), T cell receptor (TCR) engineered T cells and chimeric antigen receptors (CAR) engineered T cells are emerging as potentially effective therapies, with objective responses reported in early phase trials. In this review, we address the biological rationale of TCR/CAR engineered T cells in advanced HCC, their mechanisms of action, and results from recent clinical trials.

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Development of CAR T Cells Expressing a Suicide Gene Plus a Chimeric Antigen Receptor Targeting Signaling Lymphocytic-Activation Molecule F7

Cited by 72 publications

References 58 publications

Improving CAR T-Cell Persistence

Improving CAR T-Cell Persistence

Lentiviral Vectors for T Cell Engineering: Clinical Applications, Bioprocessing and Future Perspectives

Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials

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