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

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

Open access
Micklethwaite, Kenneth P., Gowrishankar, Kavitha, Gloss, Brian S., Li, Ziduo, Street, Janine A., Moezzi, Leili, Mach, Melanie A., Sutrave, Gaurav +12 more·2021·Blood
DOI 10.1182/blood.2021010858PMC PMC8532197
Open this paper in CoChat — free account

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1182/blood.2021010858

Cites

0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In a recent phase I trial, lymphoma arising from piggyBac transfected CAR T cells has been reported in two of nine patients with relapsed or refractory B-cell malignancies who achieved complete remission after product infusion.

    “Further, in a recent phase I trial, lymphoma arising from piggyBac transfected CAR T cells has been reported in two of nine patients with relapsed or refractory B-cell malignancies who achieved complete remission after product infusion.”

    From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [108]

    The Abstract and Introduction describe a phase 1 trial in patients with relapsed or persistent B-cell malignancy and report two lymphomas arising from piggyBac-modified CAR T cells. The introductory summary reports 2 of 10 patients, not 2 of 9, and says there was a high rate of complete remission rather than establishing that all nine patients achieved it. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 66

  1. [1]Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. [2]Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. [3]Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003; 302(5644):415-419. [DOI] [PubMed] [Google Scholar]
  4. [4]Howe SJ, Mansour MR, Schwarzwaelder K, et al. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest. 2008;118(9):3143-3150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. [6]Shah NN, Qin H, Yates B, et al. Clonal expansion of CAR T cells harboring lentivector integration in the CBL gene following anti-CD22 CAR T-cell therapy. Blood Adv. 2019;3(15):2317-2322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. [7]Newrzela S, Cornils K, Heinrich T, et al. Retroviral insertional mutagenesis can contribute to immortalization of mature T lymphocytes. Mol Med. 2011;17(11-12):1223-1232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. [8]Kebriaei P, Singh H, Huls MH, et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest. 2016;126(9):3363-3376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. [9]Manuri PV, Wilson MH, Maiti SN, et al. piggyBac transposon/transposase system to generate CD19-specific T cells for the treatment of B-lineage malignancies. Hum Gene Ther. 2010;21(4):427-437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. [10]Morita D, Nishio N, Saito S, et al. Enhanced expression of anti-CD19 chimeric antigen receptor in piggyBac transposon-engineered T cells. Mol Ther Methods Clin Dev. 2017;8:131-140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. [11]Saha S, Nakazawa Y, Huye LE, et al. piggyBac transposon system modification of primary human T cells. J Vis Exp. 2012; (69):e4235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. [12]Ramanayake S, Bilmon I, Bishop D, et al. Low-cost generation of Good Manufacturing Practice-grade CD19-specific chimeric antigen receptor-expressing T cells using piggyBac gene transfer and patient-derived materials. Cytotherapy. 2015;17(9):1251-1267. [DOI] [PubMed] [Google Scholar]
  12. [13]Bishop DC, Xu N, Tse B, et al. PiggyBac-engineered T cells expressing CD19-specific CARs that lack IgG1 Fc spacers have potent activity against B-ALL xenografts. Mol Ther. 2018;26(8):1883-1895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. [15]Singh H, Figliola MJ, Dawson MJ, et al. Manufacture of clinical-grade CD19-specific T cells stably expressing chimeric antigen receptor using Sleeping Beauty system and artificial antigen presenting cells. PLoS One. 2013;8(5):e64138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. [16]Ryland GL, Jones K, Chin M, et al. Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing. J Clin Pathol. 2018;71(10): 895-899. [DOI] [PubMed] [Google Scholar]
  15. [17]Markham JF, Yerneni S, Ryland GL, et al. CNspector: a web-based tool for visualisation and clinical diagnosis of copy number variation from next generation sequencing [published correction appears in Sci Rep. 2020;10(1):10400]. Sci Rep. 2019;9(1):6426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. [18]Brady T, Roth SL, Malani N, et al. A method to sequence and quantify DNA integration for monitoring outcome in gene therapy. Nucleic Acids Res. 2011;39(11):e72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. [19]Kamboj A, Hallwirth CV, Alexander IE, McCowage GB, Kramer B.. Ub-ISAP: a streamlined UNIX pipeline for mining unique viral vector integration sites from next generation sequencing data. BMC Bioinformatics. 2017;18(1):305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. [20]Freed D, Aldana R, Weber JA, Edwards JS.. The Sentieon Genomics Tools - a fast and accurate solution to variant calling from next-generation sequence data. bioRxiv. Preprint posted online 12 May 2017. doi: 10.1101/115717. [DOI] · DOI
  19. [21]Jeffares DC, Jolly C, Hoti M, et al. Transient structural variations have strong effects on quantitative traits and reproductive isolation in fission yeast. Nat Commun. 2017;8:14061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. [22]Dennenmoser S, Sedlazeck FJ, Schatz MC, Altmüller J, Zytnicki M, Nolte AW.. Genome-wide patterns of transposon proliferation in an evolutionary young hybrid fish. Mol Ecol. 2019;28(6):1491-1505. [DOI] [PubMed] [Google Scholar]
  21. [23]Rausch T, Zichner T, Schlattl A, Stütz AM, Benes V, Korbel JO.. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012;28(18):i333-i339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. [24]Layer RM, Chiang C, Quinlan AR, Hall IM.. LUMPY: a probabilistic framework for structural variant discovery. Genome Biol. 2014;15(6):R84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. [25]Chen X, Schulz-Trieglaff O, Shaw R, et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016;32(8):1220-1222. [DOI] [PubMed] [Google Scholar]
  24. [26]Heinz S, Benner C, Spann N, et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010;38(4):576-589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. [27]Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15-21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. [28]Robinson JT, Thorvaldsdóttir H, Winckler W, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29(1):24-26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. [29]Lawrence M, Huber W, Pagès H, et al. Software for computing and annotating genomic ranges. PLOS Comput Biol. 2013; 9(8):e1003118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. [30]Lawrence M, Gentleman R, Carey V.. rtracklayer: an R package for interfacing with genome browsers. Bioinformatics. 2009; 25(14):1841-1842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. [31]Yu G, Wang LG, Han Y, He QY.. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16(5):284-287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. [33]Shugay M, Bagaev DV, Zvyagin IV, et al. VDJdb: a curated database of T-cell receptor sequences with known antigen specificity. Nucleic Acids Res. 2018;46(D1):D419-D427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. [34]Salter AI, Ivey RG, Kennedy JJ, et al. Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function. Sci Signal. 2018;11(544):eaat6753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. [35]Tate JG, Bamford S, Jubb HC, et al. COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 2019;47(D1):D941-D947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. [36]Galvan DL, Nakazawa Y, Kaja A, et al. Genome-wide mapping of PiggyBac transposon integrations in primary human T cells. J Immunother. 2009;32(8):837-844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. [37]Hamada M, Nishio N, Okuno Y, et al. Integration mapping of piggyBac-mediated CD19 chimeric antigen receptor T cells analyzed by novel tagmentation-assisted PCR. EBioMedicine. 2018;34:18-26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. [38]Li X, Ewis H, Hice RH, et al. A resurrected mammalian hAT transposable element and a closely related insect element are highly active in human cell culture. Proc Natl Acad Sci USA. 2013;110(6):E478-E487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. [40]Aganezov S, Goodwin S, Sherman RM, et al. Comprehensive analysis of structural variants in breast cancer genomes using single-molecule sequencing. Genome Res. 2020;30(9):1258-1273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. [41]Sedlazeck FJ, Rescheneder P, Smolka M, et al. Accurate detection of complex structural variations using single-molecule sequencing. Nat Methods. 2018;15(6):461-468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. [42]Chung JH, Bell AC, Felsenfeld G.. Characterization of the chicken beta-globin insulator. Proc Natl Acad Sci USA. 1997; 94(2):575-580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. [43]Sugie K, Jeon MS, Grey HM.. Activation of naïve CD4 T cells by anti-CD3 reveals an important role for Fyn in Lck-mediated signaling. Proc Natl Acad Sci USA. 2004; 101(41):14859-14864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. [44]Kataoka K, Nagata Y, Kitanaka A, et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet. 2015; 47(11):1304-1315. [DOI] [PubMed] [Google Scholar]
  41. [45]Muragaki Y, Mattei MG, Yamaguchi N, Olsen BR, Ninomiya Y.. The complete primary structure of the human alpha 1 (VIII) chain and assignment of its gene (COL8A1) to chromosome 3. Eur J Biochem. 1991; 197(3):615-622. [DOI] [PubMed] [Google Scholar]
  42. [46]Liu X, Wu J, Zhang D, et al. Identification of potential key genes associated with the pathogenesis and prognosis of gastric cancer based on integrated bioinformatics analysis. Front Genet. 2018;9:265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. [47]Patsoukis N, Duke-Cohan JS, Chaudhri A, et al. Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation. Commun Biol. 2020;3(1):128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. [48]Richer MJ, Lang ML, Butler NS.. T cell fates zipped up: how the Bach2 basic leucine zipper transcriptional repressor directs T cell differentiation and function. J Immunol. 2016;197(4):1009-1015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. [49]Sakane-Ishikawa E, Nakatsuka S, Tomita Y, et al. ; Osaka Lymphoma Study Group . Prognostic significance of BACH2 expression in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group. J Clin Oncol. 2005;23(31):8012-8017. [DOI] [PubMed] [Google Scholar]
  46. [50]Ichikawa S, Fukuhara N, Katsushima H, et al. Association between BACH2 expression and clinical prognosis in diffuse large B-cell lymphoma. Cancer Sci. 2014;105(4):437-444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. [51]Liu J, Sørensen AB, Wang B, Wabl M, Nielsen AL, Pedersen FS.. Identification of novel Bach2 transcripts and protein isoforms through tagging analysis of retroviral integrations in B-cell lymphomas. BMC Mol Biol. 2009;10:2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. [52]Ikeda T, Shibata J, Yoshimura K, Koito A, Matsushita S.. Recurrent HIV-1 integration at the BACH2 locus in resting CD4+ T cell populations during effective highly active antiretroviral therapy. J Infect Dis. 2007; 195(5):716-725. [DOI] [PubMed] [Google Scholar]
  49. [53]Cesana D, Santoni de Sio FR, Rudilosso L, et al. HIV-1-mediated insertional activation of STAT5B and BACH2 trigger viral reservoir in T regulatory cells. Nat Commun. 2017; 8(1):498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. [54]Newrzela S, Al-Ghaili N, Heinrich T, et al. T-cell receptor diversity prevents T-cell lymphoma development. Leukemia. 2012; 26(12):2499-2507. [DOI] [PubMed] [Google Scholar]
  51. [55]Scholler J, Brady TL, Binder-Scholl G, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med. 2012;4(132):132ra53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. [56]Recchia A, Bonini C, Magnani Z, et al. Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells. Proc Natl Acad Sci USA. 2006;103(5):1457-1462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. [57]Sheih A, Voillet V, Hanafi LA, et al. Clonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy. Nat Commun. 2020;11(1):219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. [58]Nakazawa Y, Saha S, Galvan DL, et al. Evaluation of long-term transgene expression in piggyBac-modified human T lymphocytes. J Immunother. 2013;36(1):3-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. [59]Nakazawa Y, Huye LE, Salsman VS, et al. PiggyBac-mediated cancer immunotherapy using EBV-specific cytotoxic T-cells expressing HER2-specific chimeric antigen receptor. Mol Ther. 2011;19(12):2133-2143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. [60]Saito S, Nakazawa Y, Sueki A, et al. Anti-leukemic potency of piggyBac-mediated CD19-specific T cells against refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. Cytotherapy. 2014;16(9):1257-1269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. [61]Gregory T, Cohen AD, Costello CL, et al. Efficacy and safety of P-Bcma-101 CAR-T cells in patients with relapsed/refractory (r/r) multiple myeloma (MM) [abstract]. Blood. 2018;132(suppl 1):1012. [Google Scholar]
  58. [62]Costello CL, Gregory TK, Ali SA, et al. Phase 2 study of the response and safety of P-Bcma-101 CAR-T cells in patients with relapsed/refractory (r/r) multiple myeloma (MM) (PRIME) [abstract]. Blood. 2019; 134(suppl 1):3184. [Google Scholar]
  59. [63]Milone MC, Fish JD, Carpenito C, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 2009;17(8): 1453-1464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. [64]Porter DL, Levine BL, Kalos M, Bagg A, June CH.. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725-733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. [65]Ramezani A, Hawley TS, Hawley RG.. Performance- and safety-enhanced lentiviral vectors containing the human interferon-beta scaffold attachment region and the chicken beta-globin insulator. Blood. 2003;101(12):4717-4724. [DOI] [PubMed] [Google Scholar]
  62. [66]Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature. 2010;467(7313): 318-322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. [67]Arumugam PI, Higashimoto T, Urbinati F, et al. Genotoxic potential of lineage-specific lentivirus vectors carrying the beta-globin locus control region. Mol Ther. 2009;17(11):1929-1937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. [68]Grosso AR, Leite AP, Carvalho S, et al. Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma. eLife. 2015;4:e09214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. [69]Ambrosini G, Groux R, Bucher P.. PWMScan: a fast tool for scanning entire genomes with a position-specific weight matrix. Bioinformatics. 2018;34(14):2483-2484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. [70]Gu Z, Gu L, Eils R, Schlesner M, Brors B.. circlize implements and enhances circular visualization in R. Bioinformatics. 2014;30(19): 2811-2812. [DOI] [PubMed] [Google Scholar]

Cited by

Sorted by citations

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review