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Cited by 226CAR-T cell therapy researchVirus-based gene therapy researchCRISPR and Genetic Engineering

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Investigation of product-derived lymphoma following infusion of piggyBac-modified CD19 chimeric antigen receptor T cells

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Micklethwaite, Kenneth P., Gowrishankar, Kavitha, Gloss, Brian S., Li, Ziduo, Street, Janine A., Moezzi, Leili, Mach, Melanie A., Sutrave, Gaurav, Clancy, Leighton E., Bishop, David C., Louie, Raymond H. Y., Cai, Curtis, Foox, Jonathan, MacKay, Matthew, Sedlazeck, Fritz J., Blombery, Piers, Mason, Christopher E., Luciani, Fabio, Gottlieb, David J., Blyth, Emily·2021·Blood
DOI 10.1182/blood.2021010858PMC PMC8532197
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Abstract

We performed a phase 1 clinical trial to evaluate outcomes in patients receiving donor-derived CD19-specific chimeric antigen receptor (CAR) T cells for B-cell malignancy that relapsed or persisted after matched related allogeneic hemopoietic stem cell transplant. To overcome the cost and transgene-capacity limitations of traditional viral vectors, CAR T cells were produced using the piggyBac transposon system of genetic modification. Following CAR T-cell infusion, 1 patient developed a gradually enlarging retroperitoneal tumor due to a CAR-expressing CD4+ T-cell lymphoma. Screening of other patients led to the detection, in an asymptomatic patient, of a second CAR T-cell tumor in thoracic para-aortic lymph nodes. Analysis of the first lymphoma showed a high transgene copy number, but no insertion into typical oncogenes. There were also structural changes such as altered genomic copy number and point mutations unrelated to the insertion sites. Transcriptome analysis showed transgene promoter–driven upregulation of transcription of surrounding regions despite insulator sequences surrounding the transgene. However, marked global changes in transcription predominantly correlated with gene copy number rather than insertion sites. In both patients, the CAR T-cell–derived lymphoma progressed and 1 patient died. We describe the first 2 cases of malignant lymphoma derived from CAR gene–modified T cells. Although CAR T cells have an enviable record of safety to date, our results emphasize the need for caution and regular follow-up of CAR T recipients, especially when novel methods of gene transfer are used to create genetically modified immune therapies. This trial was registered at www.anzctr.org.au as ACTRN12617001579381.

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Metadata

Authors
Micklethwaite, K. P., Gowrishankar, K., Gloss, B. S., Li, Z., Street, J. A., Moezzi, L., Mach, M. A., Sutrave, G., Clancy, L. E., Bishop, D. C., Louie, R. H. Y., Cai, C., Foox, J., MacKay, M., Sedlazeck, F. J., Blombery, P., Mason, C. E., Luciani, F., Gottlieb, D. J., & Blyth, E.
Affiliations
  • The University of Sydney (AU)
  • Westmead Institute for Medical Research (AU)
  • UNSW Sydney (AU)
  • Weill Cornell Medicine (US)
  • Baylor University (US)
  • The Royal Melbourne Hospital (AU)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2021-10-21
Volume
138
Issue
16
Pages
1391-1405
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2021010858
PMC
PMC8532197
OpenAlex
W3163947612
Cited by
226
References
0
Citations by year
2026: 32 · 2025: 54 · 2024: 63 · 2023: 30 · 2022: 33 · 2021: 14
FWCI
12.75
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (R01CA249054, P01CA214274)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Keywords
piggyBac transposon, CD19 chimeric antigen receptor, retroperitoneal lymphoma, para-aortic lymph nodes, B-cell malignancies, transgene copy number, gene expression profiling, CAR T cell safety
MeSH terms
Aged, DNA Transposable Elements, Humans, Lymphoma, Male, Receptors, Antigen, T-Cell, T-Lymphocytes, Leukemia, B-Cell, Gene Expression Regulation, Neoplastic, Immunotherapy, Adoptive, Lymphoma, B-Cell, Clinical Trials, Phase I as Topic, Gene Transfer Techniques, Transgenes, Transcriptome

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