Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells.
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.
Published In/Presented At
Scholler, J., Brady, T. L., Binder-Scholl, G., Hwang, W. T., Plesa, G., Hege, K. M., Vogel, A. N., Kalos, M., Riley, J. L., Deeks, S. G., Mitsuyasu, R. T., Bernstein, W. B., Aronson, N. E., Levine, B. L., Bushman, F. D., & June, C. H. (2012). Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Science translational medicine, 4(132), 132ra53. https://doi.org/10.1126/scitranslmed.3003761
Medicine and Health Sciences
Department of Pathology and Laboratory Medicine