Faculty Collaboration Database

Detection of chromosomal alteration after infusion of gene-edited allogeneic CAR T cells. Mol Ther 2023 Mar 01;31(3):676-685

Date

12/16/2022

Pubmed ID

36518079

Pubmed Central ID

PMC10014221

DOI

10.1016/j.ymthe.2022.12.004

Scopus ID

2-s2.0-85145741279 (requires institutional sign-in at Scopus site)   4 Citations

Abstract

A chromosome 14 inversion was found in a patient who developed bone marrow aplasia following treatment with allogeneic chimeric antigen receptor (CAR) Tcells containing gene edits made with transcription activator-like effector nucleases (TALEN). TALEN editing sites were not involved at either breakpoint. Recombination signal sequences (RSSs) were found suggesting recombination-activating gene (RAG)-mediated activity. The inversion represented a dominant clone detected in the context of decreasing absolute CAR Tcell and overall lymphocyte counts. The inversion was not associated with clinical consequences and wasnot detected in the drug product administered to this patient or in any drug product used in this or other trials using the same manufacturing processes. Neither was the inversion detected in this patient at earlier time points or in any other patient enrolled in this or other trials treated with this or other product lots. This case illustrates that spontaneous, possibly RAG-mediated, recombination events unrelated to gene editing can occur in adoptive cell therapy studies, emphasizes the need for ruling out off-target gene editing sites, and illustrates that other processes, such as spontaneous V(D)J recombination, can lead to chromosomal alterations in infused cells independent of gene editing.

Author List

Sasu BJ, Opiteck GJ, Gopalakrishnan S, Kaimal V, Furmanak T, Huang D, Goswami A, He Y, Chen J, Nguyen A, Balakumaran A, Shah NN, Hamadani M, Bone KM, Prashad S, Bowen MA, Pertel T, Embree HD, Gidwani SG, Chang D, Moore A, Leonard M, Amado RG

Authors

Kathleen M. Bone PhD Associate Professor in the Pathology department at Medical College of Wisconsin
Mehdi H. Hamadani MD Professor in the Medicine department at Medical College of Wisconsin
Nirav N. Shah MD Associate Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Gene Editing
Hematopoietic Stem Cell Transplantation
Humans
Immunotherapy, Adoptive
T-Lymphocytes
Transcription Activator-Like Effector Nucleases