Two cases of T cell lymphoma following Piggybac-mediated CAR T cell therapy

Abstract

Recently, Micklethwaite et al. 1 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. et al. Investigation of product derived lymphoma following infusion of piggyBac modified CD19 chimeric antigen receptor T-cells. Blood. 2021; (Published online May 11, 2021)https://doi.org/10.1182/blood.2021010858 Crossref Scopus (28) Google Scholar and Bishop et al. 2 Bishop D.C. Clancy L.E. Simms R. Burgess J. Mathew G. Moezzi L. Street, J.A., Sutrave, G., Atkins, E., McGuire, H.M. et al. Development of CAR T-cell lymphoma in two of ten patients effectively treated with piggyBac modified CD19 CAR T-cells. Blood. 2021; (Published online May 19, 2021)https://doi.org/10.1182/blood.2021010813 Crossref Scopus (25) Google Scholar reported results of a phase I first-in-human clinical trial of CD19-directed allogeneic chimeric antigen receptor (CAR)-T cells in 10 patients with relapsed or persistent B cell malignancies after matched-related allogeneic hematopoietic stem cell transplantation (HSCT). CAR-T cells were produced via electroporation with a Piggybac (PB) transposon vector, encoding a CD19 CAR (second generation, with a 4-1BB co-stimulatory domain) driven by a human elongation factor-1 alpha (EF1a) promoter, terminated by an SV40 polyadenylation signal, and flanked by chicken hypersensitivity site 4 (cHS4) β-globin insulator sequences. Clinical responses (five patients with continuous complete remission at median follow-up of 18 months) were promising and comparable to those seen with retroviral CD19-CAR vectors. Surprisingly, two patients developed donor-derived T cell lymphoma. While the exact causes are still under investigation, clinical trials with PB-based CAR-T cells were voluntarily suspended at the investigators’ research centers. The authors discuss a number of mechanisms that may have contributed to T cell transformation and have performed work to address potential underlying causes, which we put into perspective here regarding lessons learned in gene therapy trials with integrating retroviral vectors.