piggyBac-transposon-mediated CAR-T cells for the treatment of hematological and solid malignancies

Yagyu, Shigeki; Nakazawa, Yozo

doi:10.1007/s10147-023-02319-9

Cited by 5 publications

(5 citation statements)

References 68 publications

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“…Finally, novel production pipelines of CAR-T cells like piggyBac -transposon-based technologies offer the possibility of cost reduction and shortening of production cycles ( 202 ). Approaches combining such transposon-based delivery systems with CRISPR technologies have the potential to facilitate allogeneic CAR-T-cell therapy through depletion of HLA-I and the TCR on donor cells ( 203 ).…”

Section: Discussionmentioning

confidence: 99%

Broadening the horizon: potential applications of CAR-T cells beyond current indications

Karsten,

Matrisch,

Cichutek

et al. 2023

Front. Immunol.

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Engineering immune cells to treat hematological malignancies has been a major focus of research since the first resounding successes of CAR-T-cell therapies in B-ALL. Several diseases can now be treated in highly therapy-refractory or relapsed conditions. Currently, a number of CD19- or BCMA-specific CAR-T-cell therapies are approved for acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma (MM), and follicular lymphoma (FL). The implementation of these therapies has significantly improved patient outcome and survival even in cases with previously very poor prognosis. In this comprehensive review, we present the current state of research, recent innovations, and the applications of CAR-T-cell therapy in a selected group of hematologic malignancies. We focus on B- and T-cell malignancies, including the entities of cutaneous and peripheral T-cell lymphoma (T-ALL, PTCL, CTCL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), classical Hodgkin-Lymphoma (HL), Burkitt-Lymphoma (BL), hairy cell leukemia (HCL), and Waldenström’s macroglobulinemia (WM). While these diseases are highly heterogenous, we highlight several similarly used approaches (combination with established therapeutics, target depletion on healthy cells), targets used in multiple diseases (CD30, CD38, TRBC1/2), and unique features that require individualized approaches. Furthermore, we focus on current limitations of CAR-T-cell therapy in individual diseases and entities such as immunocompromising tumor microenvironment (TME), risk of on-target-off-tumor effects, and differences in the occurrence of adverse events. Finally, we present an outlook into novel innovations in CAR-T-cell engineering like the use of artificial intelligence and the future role of CAR-T cells in therapy regimens in everyday clinical practice.

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Section: Discussionmentioning

confidence: 99%

Broadening the horizon: potential applications of CAR-T cells beyond current indications

Karsten,

Matrisch,

Cichutek

et al. 2023

Front. Immunol.

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“…A recent study demonstrated the presence in the human genome of a homologous protein, PGBD5, derived from domesticated PB transposons [ 209 ], suggesting possible cross-reactivity between the PB endogenous human transposon and a risk of cross-reactivity of exogenous sequences. The applications of PB and the related clinical progress in CAR-T cell therapies for solid malignancies in recent years are worthy of note [ 210 ].…”

Section: Tcr-t Design and Manufacturingmentioning

confidence: 99%

Novel insights into TCR-T cell therapy in solid neoplasms: optimizing adoptive immunotherapy

Shao,

Yao,

Yang

et al. 2024

Exp Hematol Oncol

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Adoptive immunotherapy in the T cell landscape exhibits efficacy in cancer treatment. Over the past few decades, genetically modified T cells, particularly chimeric antigen receptor T cells, have enabled remarkable strides in the treatment of hematological malignancies. Besides, extensive exploration of multiple antigens for the treatment of solid tumors has led to clinical interest in the potential of T cells expressing the engineered T cell receptor (TCR). TCR-T cells possess the capacity to recognize intracellular antigen families and maintain the intrinsic properties of TCRs in terms of affinity to target epitopes and signal transduction. Recent research has provided critical insight into their capability and therapeutic targets for multiple refractory solid tumors, but also exposes some challenges for durable efficacy. In this review, we describe the screening and identification of available tumor antigens, and the acquisition and optimization of TCRs for TCR-T cell therapy. Furthermore, we summarize the complete flow from laboratory to clinical applications of TCR-T cells. Last, we emerge future prospects for improving therapeutic efficacy in cancer world with combination therapies or TCR-T derived products. In conclusion, this review depicts our current understanding of TCR-T cell therapy in solid neoplasms, and provides new perspectives for expanding its clinical applications and improving therapeutic efficacy.

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“…To date, nearly two dozen phase I or I/II clinical trials have been registered using either the SB or PB transposons to modify cells of the immune system for the expression of chimeric antigen receptors (CARs) (see Section 8 ), mostly covering the field of adoptive immunotherapy for hematological malignancies, metastatic breast, prostate and lung cancers, as well as metastatic solid tumors. In addition, SB transposon-engineered plasmablasts expressing α-I-iduronidase are currently evaluated to treat patients suffering from Hurler syndrome [ 145 , 146 ]. The first phase I clinical trial using the TcBuster transposon is currently under development at the stage of patient recruitment (# NCT05312801) for Non-Hodgkin Lymphoma.…”

Section: Transgene Chromosomal Integration Using Non-viral Techniquesmentioning

confidence: 99%

Antibiotic-Free Gene Vectors: A 25-Year Journey to Clinical Trials

Marie,

Scherman

2024

Genes

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Until very recently, the major use, for gene therapy, specifically of linear or circular DNA, such as plasmids, was as ancillary products for viral vectors’ production or as a genetic template for mRNA production. Thanks to targeted and more efficient physical or chemical delivery techniques and to the refinement of their structure, non-viral plasmid DNA are now under intensive consideration as pharmaceutical drugs. Plasmids traditionally carry an antibiotic resistance gene for providing the selection pressure necessary for maintenance in a bacterial host. Nearly a dozen different antibiotic-free gene vectors have now been developed and are currently assessed in preclinical assays and phase I/II clinical trials. Their reduced size leads to increased transfection efficiency and prolonged transgene expression. In addition, associating non-viral gene vectors and DNA transposons, which mediate transgene integration into the host genome, circumvents plasmid dilution in dividing eukaryotic cells which generate a loss of the therapeutic gene. Combining these novel molecular tools allowed a significantly higher yield of genetically engineered T and Natural Killer cells for adoptive immunotherapies due to a reduced cytotoxicity and increased transposition rate. This review describes the main progresses accomplished for safer, more efficient and cost-effective gene and cell therapies using non-viral approaches and antibiotic-free gene vectors.

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piggyBac-transposon-mediated CAR-T cells for the treatment of hematological and solid malignancies

Cited by 5 publications

References 68 publications

Broadening the horizon: potential applications of CAR-T cells beyond current indications

Broadening the horizon: potential applications of CAR-T cells beyond current indications

Novel insights into TCR-T cell therapy in solid neoplasms: optimizing adoptive immunotherapy

Antibiotic-Free Gene Vectors: A 25-Year Journey to Clinical Trials

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