Table 1 Summary of published cases of genotoxic events in patients receiving haematopoietic stem cells gene therapy and CAR-T cell therapy.

From: Current landscape of vector safety and genotoxicity after hematopoietic stem or immune cell gene therapy

Haematopoietic Stem and Progenitor Cells

Disease

Vector platform/Genome editing

Genotoxic event

Patients reported

Suspected pathogenic mechanism

Refs.

X-SCID

γ-RV

ALL

6

Insertional mutagenesis: LMO2, CCND2, BMI1

[13]

CGD

γ-RV

MDS

5

Insertional mutagenesis: MDS-EVI1, PRDM16, SETBP1

[17, 111, 112]

WAS

γ-RV

ALL/AML

9

Insertional mutagenesis: LMO2, MDS1, MN1

[19]

ADA-SCID

γ-RV

ALL

1

Insertional mutagenesis: MDS-EVI1

Somatic variants

Chromosomal translocations

[21, 22]

X-ALD

LV

MDS

7

Insertional mutagenesis: MDS-EVI1

Somatic mutations: KRAS, NRAS, WT1, CDKN2A, CDKN2B, RUNX1

[43, 46]

SCD

LV

AML/MDS

2

Conditioning chemotherapy

Insertional mutagenesis: VAMP4

Somatic mutations: RUNX1, PTPN11

[35]

 

CRISPR-editing HDR

Bone marrow aplasia

1

Unknown

[108]

Somatic T cells

Multiple Myeloma

LV

BCMA-41BB-CD3z (Cilta-cel)

TCL

1

PBX2 vector integration.

Somatic mutations: TET2, PTPRB, NFKB2; Germline mutations: JAK3

[65, 66]

 

LV

BCMA-41BB-CD3z (Cilta-cel)

TCL

1

SSU72 gene vector integration; Multiple genomic changes

[72]

 

LV

BCMA-41BB-CD3z (Cilta-cel)

TCL

1

TANGO & TP53 vector integration

SOCS1 and DNMT3A mutations

[74]

 

LV

BCMA-41BB-CD3z (Cilta-cel)

TCL

1

ARID1A vector integration

Pre-infusion TET2 somatic mutation

[66]

NHL

γ-RV

CD19-CD28-CD3z (Axi-cel)

TCL

1

JAK3 variant in pre-infusion T cell clone

[69]

 

LV

CD19-41BB-CD3z (Tisa-cel)

TCL

1

Somatic TET2/DNMT3A mutations pre-infusion

[73]

 

γ-RV

CD19-CD28-CD3z (Axi-cel)

EBV+TCL

1

Pre-infusion TET2 mutated clone

[70]

 

γ-RV

CD19-CD28-CD3z (Axi-cel)

AITL

1

Somatic TET2/DNMT3A mutations

[71]

 

pb Transposon

CD19-41BB-CD3z

TCL

2

Abundant copy number variations in proto-oncogene and onco-suppressors; High VCN

[85]

 

LV

TALEN-editing

CD19-41BB-CD3z

Bone marrow aplasia

1

V(D)J recombination

[100]

  1. ADA-SCID adenosine-deaminase severe combined immunodeficiency, AITL angioimmunoblastic T-cell lymphoma, AML acute myeloid leukaemia, ALL acute lymphoblastic leukaemia, CGD chronic granulomatous disorder, EBV Epstein-Barr Virus, HDR homologous DNA repair, LV lentiviral vector, MDS myelodysplastic syndrome; pb piggyBac, RV retroviral vector, SCD sickle cell disease, TCL = T cell lymphoma, WAS Wiskott-Aldrich syndrome, X-ALD X-linked adrenoleukodystrophy, X-SCID X-linked severe combined immunodeficiency.
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