Decade-Long Safety and Function of Retroviral-Modified Chimeric Antigen Receptor T-cells
By J. Scholler, Troy L. Brady, G. Binder-Scholl, Wei-Ting Hwang, G. Plesa, K. Hege, Ashley N. Vogel, M. Kalos, J. Riley, Steven G. Deeks and 6 more. Science Translational Medicine, 2012
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Adoptively transferred chimeric antigen receptor T cells have stable stem cell–like persistence for at least a decade and more than 500 years of patient safety. Standing the Test of Time Retroviral vectors were once the mainstay of gene transfer because they could stably integrate into the host genome. However, some patients in early trials developed leukemia because of insertional mutagenesis. Now, Scholler et al. report that retroviral vector–mediated gene transfer in T cells may not have the same safety concerns, and that these cells may persist over a decade in patients. The authors followed patients from three clinical trials who received T cells transduced with gammaretroviruses carrying a chimeric antigen receptor. They found that these cells were present in recipients over a decade after infusion at levels higher than those induced by standard vaccines. These cells were still functional, had stable levels of engraftment, and did not require host immunosuppression before transplant. Moreover, the authors found no evidence of integration-induced immortalization, with no observable enrichment of integration sites near genes involved in growth control or transformation. Thus, the safety of retroviral vectors may be cell type–specific, opening up engineered T cells as a delivery platform for therapeutics. 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.
Subfields: Genetics, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/a49462fbedb774d96d433d692ac004a842fa9aed
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Citations in the corpus
- Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses (2018, neutral): “Despite these encouraging results, safety and efficacy continue to be major hurdles that hinder CAR T cell therapy development (Brentjens et al., 2013; Kochenderfer et al., 2012; Morgan et al., 2010; Scholler et al., 2012).”
- STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade (2015, background): “The efferent arm of the immune system has been a principal target in the development of cancer immunotherapies (1, 2), but the innate immune system plays a pivotal role inmodulating the potency and specificity of these active vaccination strategies (3, 4).”
- The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “Incorporation of Costimulatory Domains CAR T cells expressing a zeta chain in the absence of a costimulatory domain have been shown to persist for more than a decade without adverse effects after adoptive transfer in patients with acquired immunodeficiency (Mitsuyasu et al., 2000; Scholler et al., 2”