<i>In vivo</i> generated human CAR T cells eradicate tumor cells

Agarwal, Shiwani; Weidner, Tatjana; Thalheimer, Frederic B.; Buchholz, Christian J.

doi:10.1080/2162402x.2019.1671761

Cited by 61 publications

(41 citation statements)

References 20 publications

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“…Signs of CRS, the presence of tissue‐invading CAR-T cells and the complete elimination of the B‐lymphocyte‐rich zones in spleens were detected ( 98 ). More recently, efficient eradication of tumors in transplanted mice was demonstrated upon a single vector injection ( 99 ). Although further investigations are desirable, these promising results have demonstrated that the in vivo engineering of human CD8 + CAR-T cells could substantially simplify their manufacturing and the development of future cell-based immunotherapies.…”

Section: Optimizing the Delivery In Vivo Of Car-t mentioning

confidence: 99%

Proceedings From the First International Workshop at Sidra Medicine: “Engineered Immune Cells in Cancer Immunotherapy (EICCI): From Discovery to Off-the-Shelf Development”, 15th–16th February 2019, Doha, Qatar

et al. 2021

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The progress in the isolation and characterization of tumor antigen (TA)-specific T lymphocytes and in the genetic modification of immune cells allowed the clinical development of adoptive cell therapy (ACT). Several clinical studies highlighted the striking clinical activity of T cells engineered to express either Chimeric Antigen (CAR) or T Cell (TCR) Receptors to target molecularly defined antigens expressed on tumor cells. The breakthrough of immunotherapy is represented by the approval of CAR-T cells specific for advanced or refractory CD19+ B cell malignancies by both the Food and Drug Administration (FDA) and the European Medicinal Agency (EMA). Moreover, advances in the manufacturing and gene editing of engineered immune cells contributed to the selection of drug products with desired phenotype, refined specificity and decreased toxicity. An important step toward the optimization of CAR-T cell therapy is the development of “off-the shelf” T cell products that allow to reduce the complexity and the costs of the manufacturing and to render these drugs available for a broad number of cancer patients. The Engineered Immune Cells in Cancer Immunotherapy (EICCI) workshop hosted in Doha, Qatar, renowned experts, from both academia and industry, to present and discuss the progress on both pre-clinical and clinical development of genetically modified immune cells, including advances in the “off-the-shelf” manufacturing. These experts have addressed also organizational needs and hurdles for the clinical grade production and application of these biological drugs.

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Section: Optimizing the Delivery In Vivo Of Car-t mentioning

confidence: 99%

Proceedings From the First International Workshop at Sidra Medicine: “Engineered Immune Cells in Cancer Immunotherapy (EICCI): From Discovery to Off-the-Shelf Development”, 15th–16th February 2019, Doha, Qatar

et al. 2021

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“…The ankyrin domains have been selected from libraries to guaranty their high affinity. ScFvs and DARPins have been introduced successfully in MV [67] and in Nipah virus envelope glycoproteins [61,68,69] to target oncolytic domains and hematopoietic cells in vitro and in vivo [48,68,[70][71][72].…”

Section: Envelope Glycoproteins Retargeted To Specific Hematopoietic mentioning

confidence: 99%

Lentiviral Vector Pseudotypes: Precious Tools to Improve Gene Modification of Hematopoietic Cells for Research and Gene Therapy

Gutiérrez‐Guerrero

Cosset

Verhoeyen

2020

Viruses

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Viruses have been repurposed into tools for gene delivery by transforming them into viral vectors. The most frequently used vectors are lentiviral vectors (LVs), derived from the human immune deficiency virus allowing efficient gene transfer in mammalian cells. They represent one of the safest and most efficient treatments for monogenic diseases affecting the hematopoietic system. LVs are modified with different viral envelopes (pseudotyping) to alter and improve their tropism for different primary cell types. The vesicular stomatitis virus glycoprotein (VSV-G) is commonly used for pseudotyping as it enhances gene transfer into multiple hematopoietic cell types. However, VSV-G pseudotyped LVs are not able to confer efficient transduction in quiescent blood cells, such as hematopoietic stem cells (HSC), B and T cells. To solve this problem, VSV-G can be exchanged for other heterologous viral envelopes glycoproteins, such as those from the Measles virus, Baboon endogenous retrovirus, Cocal virus, Nipah virus or Sendai virus. Here, we provide an overview of how these LV pseudotypes improved transduction efficiency of HSC, B, T and natural killer (NK) cells, underlined by multiple in vitro and in vivo studies demonstrating how pseudotyped LVs deliver therapeutic genes or gene editing tools to treat different genetic diseases and efficiently generate CAR T cells for cancer treatment.

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“…More recently, this team evaluated the same CD8NiV-LV delivering the anti-CD19 CAR in an NSG mice engrafted with CD19 + Nalm-6 tumor cells, followed by injection with human PBMCs [ 164 ]. A single injection of this CD8 targeted LV was sufficient to eliminate CD19 + Nalm-6 tumor cells, whereas in control animals tumor cells expanded in a uncontrolled manner [ 164 ]. Surprisingly, they detected also anti-CD19 CAR expression at the surface of NKT cells in vivo, since these cells also express the CD8α chain, the target of the CD8NiV-LV particles.…”

Section: In Vivo Car T Cell Generation Using Lentiviral Vectors Tamentioning

confidence: 99%

Humanized Mice Are Precious Tools for Preclinical Evaluation of CAR T and CAR NK Cell Therapies

Mhaidly

Verhoeyen

2020

Cancers

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Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary treatment for hematological malignancies. However, improvements in CAR T-cell therapies are urgently needed since CAR T cell application is associated with toxicities, exhaustion, immune suppression, lack of long-term persistence, and low CAR T-cell tumor infiltration. Major efforts to overcome these hurdles are currently on the way. Incrementally improved xenograft mouse models, supporting the engraftment and development of a human hemato-lymphoid system and tumor tissue, represent an important fundamental and preclinical research tool. We will focus here on several CAR T and CAR NK therapies that have benefited from evaluation in humanized mice. These models are of great value for the cancer therapy field as they provide a more reliable understanding of sometimes complicated therapeutic interventions. Additionally, they are considered the gold standard with regard to assessment of new CAR technologies in vivo for safety, efficacy, immune response, design, combination therapies, exhaustion, persistence, and mechanism of action prior to starting a clinical trial. They help to expedite the critical translation from proof-of-concept to clinical CAR T-cell application. In this review, we discuss innovative developments in the CAR T-cell therapy field that benefited from evaluation in humanized mice, illustrated by multiple examples.

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In vivo generated human CAR T cells eradicate tumor cells

Cited by 61 publications

References 20 publications

Proceedings From the First International Workshop at Sidra Medicine: “Engineered Immune Cells in Cancer Immunotherapy (EICCI): From Discovery to Off-the-Shelf Development”, 15th–16th February 2019, Doha, Qatar

Proceedings From the First International Workshop at Sidra Medicine: “Engineered Immune Cells in Cancer Immunotherapy (EICCI): From Discovery to Off-the-Shelf Development”, 15th–16th February 2019, Doha, Qatar

Lentiviral Vector Pseudotypes: Precious Tools to Improve Gene Modification of Hematopoietic Cells for Research and Gene Therapy

Humanized Mice Are Precious Tools for Preclinical Evaluation of CAR T and CAR NK Cell Therapies

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