Chimeric NKG2D CAR-Expressing T Cell-Mediated Attack of Human Ovarian Cancer Is Enhanced by Histone Deacetylase Inhibition

Song, De-Gang; Ye, Qunrui; Santoro, Stephen P.; Fang, Chongyun; Best, Andrew; Powell, Daniel J.

doi:10.1089/hum.2012.143

Cited by 85 publications

(67 citation statements)

References 45 publications

(48 reference statements)

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“…Pretreatment with valproic acid enhanced the adoptive transfer of T cells expressing a CAR containing the extracellular domain of the NKG2D receptor and the intracellular domains of CD137 and CD3ζ in ovarian cancer cells [81]. Valproic acid selectively sensitized cancer cells to T-cell attack by inducing NKG2D ligand surface expression and improving antigen-specific recognition of NKG2D CAR-expressing T cells.…”

Section: Tcr-t Cells Require a Specific Hla Subtype While Hla Restricmentioning

confidence: 96%

Epigenetic Modulation with Histone Deacetylase Inhibitors in Combination with Immunotherapy

2015

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Understanding the contribution of dysregulated gene silencing to epigenomic alterations in cancer development provides the rationale for the use of epigenetic modulators, such as histone deacetylase (HDAC) inhibitors, in cancer therapy. HDAC inhibitors have been approved as single agents for cutaneous and peripheral T-cell lymphoma and have shown promising activity in reversing therapy resistance in other tumor types. The effects of HDAC inhibitors on immune modulation have created a recent interest in their potential role in immunotherapy. This review describes the current understanding on integrating HDAC inhibitors into various immunotherapeutic approaches, such as cancer vaccines, adoptive T-cell transfer and immune checkpoint inhibitors. Furthermore, it summarizes promising treatment strategies in epigenetic immune priming from clinical trials that are currently underway.

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Section: Tcr-t Cells Require a Specific Hla Subtype While Hla Restricmentioning

confidence: 96%

Epigenetic Modulation with Histone Deacetylase Inhibitors in Combination with Immunotherapy

2015

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“…The NKz10-CAR, which demonstrated the most severe toxicity in our studies, has only been previously tested on human NK cells using immunodeficient animals, which precludes the ability to assess toxicity due to a lack of cross-reactivity 40,41 . Likewise, CARs composed of the NKG2D extracellular domain fused to a conventional CAR scaffold have thus far only been tested using in vitro assays, and so possible toxicities were not yet evaluated 42,43 . The results of this work conclude that NKG2D-CAR-T cells can be highly toxic and that the toxicity is influenced by both the host and the conditioning regimen.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

T Cells Engineered With Chimeric Antigen Receptors Targeting NKG2D Ligands Display Lethal Toxicity in Mice

et al. 2015

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Ligands for the NKG2D receptor are overexpressed on tumors, making them interesting immunotherapy targets. To assess the tumoricidal properties of T cells directed to attack NKG2D ligands, we engineered murine T cells with two distinct NKG2D-based chimeric antigen receptors (CARs): (i) a fusion between the NKG2D receptor and the CD3ζ chain and (ii) a conventional second-generation CAR, where the extracellular domain of NKG2D was fused to CD28 and CD3ζ. To enhance the CAR surface expression, we also engineered T cells to coexpress DAP10. In vitro functionality and surface expression levels of all three CARs was greater in BALB/c T cells than C57BL/6 T cells, indicating strain-specific differences. Upon adoptive transfer of NKG2D-CAR-T cells into syngeneic animals, we observed significant clinical toxicity resulting in morbidity and mortality. The severity of these toxicities varied between the CAR configurations and paralleled their in vitro NKG2D surface expression. BALB/c mice were more sensitive to these toxicities than C57BL/6 mice, consistent with the higher in vitro functionality of BALB/c T cells. Treatment with cyclophosphamide prior to adoptive transfer exacerbated the toxicity. We conclude that while NKG2D ligands may be useful targets for immunotherapy, the pursuit of NKG2D-based CAR-T cell therapies should be undertaken with caution.

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“…NKG2D CARs are one such example [20,31,123,124,125,126]. These CARs can target a variety of tumor types [127,128,129,130].…”

Section: Receptor-ligandmentioning

confidence: 99%

Practical considerations for chimeric antigen receptor design and delivery

Oldham

Medin

2017

Expert Opinion on Biological Therapy

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The development of chimeric antigen receptor (CAR)-modified immune cells has become a highly active field of research since the introduction of this approach in 1989. New ideas are constantly being proposed and tested, resulting in CARs that are more effective and specialized. Areas covered: Many aspects of CAR design and administration can be varied in order to achieve the best possible outcomes; optimization of this therapeutic schema is an active area of research. Here, the authors summarize the work that has been carried out thus far to assess different adaptations for each portion of the CAR itself. They also discuss the various methods used for CAR transgene transfer into effector cells. Expert opinion: While the field has made significant advancements in terms of expansion and testing of the variations available for CAR therapy, it remains difficult to ascertain which options are truly superior and under what conditions. Continued research in this area, as well as in aspects such as improving the safety profile and the anti-tumor potency of CARs, will be required to bring this therapy from early-phase clinical trials to standard of care as an effective treatment for a broad range of tumor types.

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Chimeric NKG2D CAR-Expressing T Cell-Mediated Attack of Human Ovarian Cancer Is Enhanced by Histone Deacetylase Inhibition

Cited by 85 publications

References 45 publications

Epigenetic Modulation with Histone Deacetylase Inhibitors in Combination with Immunotherapy

Epigenetic Modulation with Histone Deacetylase Inhibitors in Combination with Immunotherapy

T Cells Engineered With Chimeric Antigen Receptors Targeting NKG2D Ligands Display Lethal Toxicity in Mice

Practical considerations for chimeric antigen receptor design and delivery

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