Immune Cells Modified by Gene Therapy Survive After a Decade in HIV+ PeopleNelson Vergel
What an amazing study!
They have followed HIV+ people that have had T cells modified by genetic engineering and given by transfusion once during the past 11 years of study . 41 of the 43 people were still healthy 11 years later. Their modified T cells could still be found in their bodies.
Modified 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 studied to date. Their inserted transgene retained expression and function to resist HIV infection. The modified (CD4z )T cells had stable levels of incorporation into the body’s tissues, with decay half-lives that exceeded 16 years, in marked contrast to previous trials testing engineered T cell trials.
The sample size was small but this study provides the first data of long term safety of this approach. The HIV cure research field is moving fast!
www.ScienceTranslationalMedicine.org 2 May 2012 Vol 4 Issue 132
Decade-Long Safety and Function of Retroviral-Modified
Chimeric Antigen Receptor T Cells
John Scholler,1* Troy L. Brady,2* Gwendolyn Binder-Scholl,1 Wei-Ting Hwang,3 Gabriela Plesa,1 Kristen M. Hege,4 Ashley N. Vogel,1 Michael Kalos,1 James L. Riley,2 Steven G. Deeks,5 Ronald T. Mitsuyasu,6 Wendy B. Bernstein,7 Naomi E. Aronson,7,8 Bruce L. Levine,1 Frederic D. Bushman,2† Carl H. June1†
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 CD3z signaling chain (CD4z). 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 CD4z 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 CD4z 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.
These results provide a framework to guide the therapy of a wide spectrum of human diseases.
1Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104–6076, USA. 2Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104–6076, USA. 3Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104–6076, USA. 4Celgene Corporation, 1500 Owens Street, Suite 600, San Francisco, CA 94158, USA. 5Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. 6Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90035, USA. 7Walter Reed National Military Medical Center, Bethesda, MD 20889, USA. 8Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.