Detection of chromosomal alteration after infusion of gene-edited allogeneic CAR T cells

A chromosome 14 inversion was found in a patient who devel-oped 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) -medi-ated activity. The inversion represented a dominant clone de-tected 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 pro-cesses. 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 il-lustrates that spontaneous, possibly RAG-mediated, recombi-nation 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 chromo-somal alterations in infused cells independent of gene editing.