Targeting CD33 in Chemoresistant AML Patient-Derived Xenografts by CAR-CIK Cells Modified with an Improved SB Transposon System

Rotiroti, Maria Caterina; Buracchi, Chiara; Arcangeli, Silvia; Galimberti, Stefania; Valsecchi, Maria Grazia; Perriello, Vincenzo Maria; Raskó, Tamás; Alberti, Gaia; Magnani, Chiara F.; Cappuzzello, Claudia; Lundberg, Felix; Pande, Amit; Dastoli, Giuseppe; Introna, Martino; Serafini, Marta; Biagi, Ettore; Izsvák, Zsuzsanna; Biondi, Andrea; Tettamanti, Sarah

doi:10.1016/j.ymthe.2020.05.021

Cited by 37 publications

(36 citation statements)

References 54 publications

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“…A description of CIK cells is out of the scope of this review. However, it is notable that in the AML setting CD33 has been recently tested as target for preclinical validation of a novel strategy with CAR engineered CIK cells as a means of adoptive immunotherapy ( 97 ).CIK cells have been transduced with a CD33.CAR by using a non-viral system, which offers improved transfection efficiency. CD33.CAR-CIK cells showed significant antileukemic activity in vitro and, when used in patient-derived AML xenograft models, were capable of contrasting AML development both as early treatment and in mice with established disease.…”

Section: Adoptive T Cell Therapiesmentioning

confidence: 99%

Immunotherapy in Acute Myeloid Leukemia: Where We Stand

Isidori¹,

Cerchione

Daver

et al. 2021

Front. Oncol.

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In the past few years, our improved knowledge of acute myeloid leukemia (AML) pathogenesis has led to the accelerated discovery of new drugs and the development of innovative therapeutic approaches. The role of the immune system in AML development, growth and recurrence has gained increasing interest. A better understanding of immunological escape and systemic tolerance induced by AML blasts has been achieved. The extraordinary successes of immune therapies that harness the power of T cells in solid tumors and certain hematological malignancies have provided new stimuli in this area of research. Accordingly, major efforts have been made to develop immune therapies for the treatment of AML patients. The persistence of leukemia stem cells, representing the most relevant cause of relapse, even after allogeneic stem cell transplant (allo-SCT), remains a major hurdle in the path to cure for AML patients. Several clinical trials with immune-based therapies are currently ongoing in the frontline, relapsed/refractory, post-allo-SCT and minimal residual disease/maintenance setting, with the aim to improve survival of AML patients. This review summarizes the available data with immune-based therapeutic modalities such as monoclonal antibodies (naked and conjugated), T cell engagers, adoptive T-cell therapy, adoptive-NK therapy, checkpoint blockade via PD-1/PD-L1, CTLA4, TIM3 and macrophage checkpoint blockade via the CD47/SIRPa axis, and leukemia vaccines. Combining clinical results with biological immunological findings, possibly coupled with the discovery of biomarkers predictive for response, will hopefully allow us to determine the best approaches to immunotherapy in AML.

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Section: Adoptive T Cell Therapiesmentioning

confidence: 99%

Immunotherapy in Acute Myeloid Leukemia: Where We Stand

Isidori¹,

Cerchione

Daver

et al. 2021

Front. Oncol.

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“…Additionally, SB and PB have been used to generate allogenic “off-the-shelf” CAR-natural killer (NK) cells that have shown encouraging results against solid tumors [ 214 , 215 ]. Cytokine-induced killer (CIK) cells, effector lymphocytes displaying a mixed T and NK phenotype with non-HLA-restricted cytotoxicity and minimal alloreactivity, have also been generated with SB to target CD19, CD123, and CD33 [ 216 , 217 ]. Finally, SB was shown successful for T cell receptor (TCR)-T cell engineering [ 24 , 218 ], a strategy that enables to broaden the spectrum of targets as the MHC-TCR interaction also permits recognition of epitopes from intracellular proteins.…”

Section: Preclinical Applicationsmentioning

confidence: 99%

Contemporary Transposon Tools: A Review and Guide through Mechanisms and Applications of Sleeping Beauty, piggyBac and Tol2 for Genome Engineering

Sandoval-Villegas

Nurieva

Amberger

et al. 2021

IJMS

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Transposons are mobile genetic elements evolved to execute highly efficient integration of their genes into the genomes of their host cells. These natural DNA transfer vehicles have been harnessed as experimental tools for stably introducing a wide variety of foreign DNA sequences, including selectable marker genes, reporters, shRNA expression cassettes, mutagenic gene trap cassettes, and therapeutic gene constructs into the genomes of target cells in a regulated and highly efficient manner. Given that transposon components are typically supplied as naked nucleic acids (DNA and RNA) or recombinant protein, their use is simple, safe, and economically competitive. Thus, transposons enable several avenues for genome manipulations in vertebrates, including transgenesis for the generation of transgenic cells in tissue culture comprising the generation of pluripotent stem cells, the production of germline-transgenic animals for basic and applied research, forward genetic screens for functional gene annotation in model species and therapy of genetic disorders in humans. This review describes the molecular mechanisms involved in transposition reactions of the three most widely used transposon systems currently available (Sleeping Beauty, piggyBac, and Tol2), and discusses the various parameters and considerations pertinent to their experimental use, highlighting the state-of-the-art in transposon technology in diverse genetic applications.

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“…The use of SB100X in mRNA format and a transposon as MC to engineer CAR T-cells targeting the myeloma antigen SLAMF7 [ 88 ] will be investigated in the context of a European multicenter clinical trial [ 89 ]. In collaboration with the Max-Delbrück Center for Molecular Medicine (MDC, Berlin, Germany), we are currently exploring the use of the hyperactive SB100X transposase and pT4 transposon for the generation of anti-CD33 CARCIK cells (Rotiroti MC et al, in press, Molecular Therapy 2020 [ 90 ]).…”

Section: Early Clinical Experiencesmentioning

confidence: 99%

Transposon-Based CAR T Cells in Acute Leukemias: Where Are We Going?

Magnani

Tettamanti

Alberti

et al. 2020

Cells

Self Cite

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Chimeric Antigen Receptor (CAR) T-cell therapy has become a new therapeutic reality for refractory and relapsed leukemia patients and is also emerging as a potential therapeutic option in solid tumors. Viral vector-based CAR T-cells initially drove these successful efforts; however, high costs and cumbersome manufacturing processes have limited the widespread clinical implementation of CAR T-cell therapy. Here we will discuss the state of the art of the transposon-based gene transfer and its application in CAR T immunotherapy, specifically focusing on the Sleeping Beauty (SB) transposon system, as a valid cost-effective and safe option as compared to the viral vector-based systems. A general overview of SB transposon system applications will be provided, with an update of major developments, current clinical trials achievements and future perspectives exploiting SB for CAR T-cell engineering. After the first clinical successes achieved in the context of B-cell neoplasms, we are now facing a new era and it is paramount to advance gene transfer technology to fully exploit the potential of CAR T-cells towards next-generation immunotherapy.

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Targeting CD33 in Chemoresistant AML Patient-Derived Xenografts by CAR-CIK Cells Modified with an Improved SB Transposon System

Cited by 37 publications

References 54 publications

Immunotherapy in Acute Myeloid Leukemia: Where We Stand

Immunotherapy in Acute Myeloid Leukemia: Where We Stand

Contemporary Transposon Tools: A Review and Guide through Mechanisms and Applications of Sleeping Beauty, piggyBac and Tol2 for Genome Engineering

Transposon-Based CAR T Cells in Acute Leukemias: Where Are We Going?

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