Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia

Paszkiewicz, Paulina J.; Fräßle, Simon P.; Srivastava, Shivani; Sommermeyer, Daniel; Hudecek, Michael; Drexler, Ingo; Sadelain, Michel; Liu, Lingfeng; Jensen, Michael C.; Riddell, Stanley R.; Busch, Dirk H.

doi:10.1172/jci84813

Cited by 253 publications

(222 citation statements)

References 30 publications

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“…Further, CD19-CAR_EGFRt T cells can be depleted through administration of an anti-EGFR antibody to mitigate toxicity or terminate the therapeutic effect after tumor clearance. We have recently shown in a pre-clinical model that depletion of CD19-CAR_EGFRt T cells after lymphoma eradication reverses B-cell aplasia as the major long-term side effect and adds another layer of safety to CD19-CAR T-cell therapy (Paszkiewicz et al, 2016).…”

Section: Clinical Trial With Car T Cells Engineered By Sleeping Beautmentioning

confidence: 99%

Going non-viral: theSleeping Beautytransposon system breaks on through to the clinical side

Hudecek

Izsvák

Johnen

et al. 2017

Critical Reviews in Biochemistry and Molecular Biology

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Molecular medicine has entered a high-tech age that provides curative treatments of complex genetic diseases through genetically engineered cellular medicinal products. Their clinical implementation requires the ability to stably integrate genetic information through gene transfer vectors in a safe, effective and economically viable manner. The latest generation of Sleeping Beauty (SB) transposon vectors fulfills these requirements, and may overcome limitations associated with viral gene transfer vectors and transient non-viral gene delivery approaches that are prevalent in ongoing pre-clinical and translational research. The SB system enables high-level stable gene transfer and sustained transgene expression in multiple primary human somatic cell types, thereby representing a highly attractive gene transfer strategy for clinical use. Here we review several recent refinements of the system, including the development of optimized transposons and hyperactive SB variants, the vectorization of transposase and transposon as mRNA and DNA minicircles (MCs) to enhance performance and facilitate vector production, as well as a detailed understanding of SB's genomic integration and biosafety features. This review also provides a perspective on the regulatory framework for clinical trials of gene delivery with SB, and illustrates the path to successful clinical implementation by using, as examples, gene therapy for age-related macular degeneration (AMD) and the engineering of chimeric antigen receptor (CAR)-modified T cells in cancer immunotherapy.

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Section: Clinical Trial With Car T Cells Engineered By Sleeping Beautmentioning

confidence: 99%

Going non-viral: theSleeping Beautytransposon system breaks on through to the clinical side

Hudecek

Izsvák

Johnen

et al. 2017

Critical Reviews in Biochemistry and Molecular Biology

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“…This system was used to eliminate 90% of T cells expressing iCasp9 within 30 minutes in patients receiving a hematopoietic stem cell transplant, and reversed graft-versus-host disease (GVHD) 70 . Alternative suicide genes include epitope tags that are recognized by FDA-approved mAb therapeutics such as cetuximab 71,72 or rituximab 73,74 , which induce T-cell death through endogenous antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. These epitope tags can also serve as handles for purification of transduced T-cell populations [11][12][13] .…”

Section: Review Articlementioning

confidence: 99%

Programming CAR-T cells to kill cancer

2018

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T cells engineered to express chimeric antigen receptors (CARs) that are specific for tumour antigens have led to high complete response rates in patients with haematologic malignancies. Despite this early success, major challenges to the broad application of CAR-T cells as cancer therapies remain, including treatment-associated toxicities and cancer relapse with antigen-negative tumours. Targeting solid tumours with CAR-T cells poses additional obstacles because of the paucity of tumourspecific antigens and the immunosuppressive effects of the tumour microenvironment. To overcome these challenges, T cells can be programmed with genetic modules that increase their therapeutic potency and specificity. In this Review Article, we survey major advances in the engineering of next-generation CAR-T therapies for haematologic cancers and solid cancers, with particular emphasis on strategies for the control of CAR specificity and activity and on approaches for improving CAR-T-cell persistence and overcoming immunosuppression. We also lay out a roadmap for the development of off-the-shelf CAR-T cells.

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“…Finally, it is possible to transduce T-cells to co-express both CAR and a truncated Epidermal Growth Factor Receptor (tEGFR). It was demonstrated in mice that targeting tEGFR with the monoclonal antibody cetuximab eliminated anti-CD19 CAR T-cells, leading to complete and permanent recovery of normal B-cells [52].…”

Section: Limiting the Toxicitymentioning

confidence: 99%

Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: Clinical data to date, current limitations and perspectives

Gauthier

Yakoub-Agha

2017

Current Research in Translational Medicine

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Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia

Cited by 253 publications

References 30 publications

Going non-viral: theSleeping Beautytransposon system breaks on through to the clinical side

Going non-viral: theSleeping Beautytransposon system breaks on through to the clinical side

Programming CAR-T cells to kill cancer

Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: Clinical data to date, current limitations and perspectives

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