Remote Controlled CARs: Towards a Safer Therapy for Leukemia

June, Carl H.

doi:10.1158/2326-6066.cir-16-0132

Cited by 7 publications

(2 citation statements)

References 4 publications

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“…In addition, development of alternatives to doxycycline that have no antibiotic properties such as the doxycycline metabolite or the tetracycline agonist could be an ideal solution [ 25 ]. In addition to the inducer, the potential immunogenicity of the various prokaryotic and viral components in the rtTA fusion protein also raised safety concerns [ 26 ]. In a previous clinical study, HSV-TK-modified T cells provoked robust and durable CD8 + and CD4 + T-cell immune responses towards HSV-TK, resulting in the disappearance of the transferred cells [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Development of Inducible CD19-CAR T Cells with a Tet-On System for Controlled Activity and Enhanced Clinical Safety

He²,

Li³

et al. 2018

IJMS

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The tetracycline regulatory system has been widely used to control the transgene expression. With this powerful tool, it might be possible to effectively control the functional activity of chimeric antigen receptor (CAR) T cells and manage the severe side effects after infusion. In this study, we developed novel inducible CD19CAR (iCAR19) T cells by incorporating a one-vector Tet-on system into the CD19CAR construct. The iCAR19 T cells showed dox-dependent cell proliferation, cytokine production, CAR expression, and strong CD19-specific cytotoxicity. After 48 h of dox induction, the relative CAR expression of induced cells was five times greater than that of uninduced cells. Twenty-four hours after dox removal, CAR expression significantly decreased by more than 60%. In cytotoxicity assays, dox-treated cells induced significantly higher specific lysis against target cells. These results suggested that the activity of iCAR19 T cells was successfully controlled by our Tet-on system, offering an enhanced safety profile while maintaining a robust anti-tumor effect. Besides, all manufacture processes of the lentiviral vectors and the T cells were conducted according to the Good Manufacturing Practice (GMP) standards for subsequent clinical translation.

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Section: Discussionmentioning

confidence: 99%

Development of Inducible CD19-CAR T Cells with a Tet-On System for Controlled Activity and Enhanced Clinical Safety

He²,

Li³

et al. 2018

IJMS

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“…To improve the discriminatory nature of strategies used to reduce toxicity, design of CAR T cells equipped with tetracycline-inducible systems or AND/NOT Boolean logic gates permit enhanced control over effector responses and improved sensing of tumor targets. Sakemura and colleagues established a Tet-on inducible system for CD19 + malignancies, where administration of a tetracycline turns on CAR expression—useful for a period of heavy tumor burden—while withdrawal of the drug ceases CAR expression but permits survival of the cell—important for periods of off-tumor toxicity ( 92 , 93 ). Boolean logic gates aim to prevent toxicity while maintaining efficacy, rather than irreversibly deleting CAR T cells that are toxic against both tumor and host.…”

Section: Evolution Of the Car Designmentioning

confidence: 99%

CAR T Cells in Solid Tumors: Blueprints for Building Effective Therapies

et al. 2018

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Genetic redirection of T lymphocytes with chimeric antigen receptors (CARs) has soared from treating cancers preclinically to FDA approval for hematologic malignancies and commercial-grade production scale in under 30 years. To date, solid tumors are less susceptible to CAR therapies and instead have been treated more successfully with immune checkpoint blockade or tumor-infiltrating lymphocyte therapy. Here, we discuss the current challenges in treating solid tumors with CAR T cells, and the obstacles within the host and tumor microenvironment hindering their efficacy. We present a novel three-pronged approach for enhancing the efficacy of CAR T cells whereby a single infusion product can synergize the power of an optimal CAR construct, a highly potent T cell subset, and rejuvenate the endogenous immune response to conquer therapeutically-resistant solid tumors.

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Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice

Luskin

DeAngelo

2017

Curr Hematol Malig Rep

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Over half of patients diagnosed with B-cell acute lymphoblastic leukemia (ALL) develop relapsed or refractory disease. Traditional chemotherapy salvage is inadequate, and new therapies are needed. Chimeric antigen receptor (CAR) T cell therapy is a novel, immunologic approach where T cells are genetically engineered to express a CAR conferring specificity against a target cell surface antigen, most commonly the pan-B-cell marker CD19. After infusion, CAR T cells expand and persist, allowing ongoing tumor surveillance. Several anti-CD19 CAR T cell constructs have induced high response rates in heavily pre-treated populations, although durability of response varied. Severe toxicity (cytokine release syndrome and neurotoxicity) is the primary constraint to broad implementation of CAR T cell therapy. Here, we review the experience of CAR T cell therapy for ALL and ongoing efforts to modify existing technology to improve efficacy and decrease toxicity. As an anti-CD19 CAR T cell construct may be FDA approved soon, we focus on issues relevant to practicing clinicians.

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Remote Controlled CARs: Towards a Safer Therapy for Leukemia

Cited by 7 publications

References 4 publications

Development of Inducible CD19-CAR T Cells with a Tet-On System for Controlled Activity and Enhanced Clinical Safety

Development of Inducible CD19-CAR T Cells with a Tet-On System for Controlled Activity and Enhanced Clinical Safety

CAR T Cells in Solid Tumors: Blueprints for Building Effective Therapies

Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice

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