Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells

John Scholler, Troy L. Brady, Gwendolyn Binder-Scholl, Wei Ting Hwang, Gabriela Plesa, Kristen M. Hege, Ashley N. Vogel, Michael Kalos, James L. Riley, Steven G. Deeks, Ronald T. Mitsuyasu, Wendy B. Bernstein, Naomi E. Aronson, Bruce L. Levine, Frederic D. Bushman*, Carl H. June

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

525 Scopus citations

Abstract

The success of adoptive T cell gene transfer for treatment of cancer and HIV is predicated on generating a response that is both durable and safe. We report long-term results from three clinical trials to evaluate gammaretroviral vector-engineered T cells for HIV. The vector encoded a chimeric antigen receptor (CAR) composed of CD4 linked to the CD3ζ signaling chain (CD4ζ). CAR T cells were detected in 98% of samples tested for at least 11 years after infusion at frequencies that exceeded average T cell levels after most vaccine approaches. The CD4ζ transgene retained expression and function. There was no evidence of vector-induced immortalization of cells; integration site distributions showed no evidence of persistent clonal expansion or enrichment for integration sites near genes implicated in growth control or transformation. The CD4ζ T cells had stable levels of engraftment, with decay half-lives that exceeded 16 years, in marked contrast to previous trials testing engineered T cells. These findings indicate that host immunosuppression before T cell transfer is not required to achieve long-term persistence of gene-modified T cells. Further, our results emphasize the safety of T cells modified by retroviral gene transfer in clinical application, as measured in >500 patient-years of follow-up. Thus, previous safety issues with integrating viral vectors are hematopoietic stem cell or transgene intrinsic, and not a general feature of retroviral vectors. Engineered T cells are a promising form of synthetic biology for long-term delivery of protein-based therapeutics. These results provide a framework to guide the therapy of a wide spectrum of human diseases.

Original languageEnglish
Article number132ra53
JournalScience Translational Medicine
Volume4
Issue number132
DOIs
StatePublished - 2 May 2012
Externally publishedYes

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