ADAPTIMMUNE LTD
PRESS RELEASE
Embargoed until 18.00 hrs (London) on 9 November 2008
HIV'S disguises no match for ‘Bionic Assassins’
Adaptimmune engineers immune cells able to clear HIV – clinical trials planned
HIV is a master of disguise, able to rapidly change its identity and hide undetected in infected cells. But now, in a long-standing collaborative research effort partially-funded by the Wellcome Trust, scientists from Oxford-based Adaptimmune Limited, in partnership with the Universities of Cardiff and Pennsylvania, have engineered immune cells to act as "bionic assassins" that see through HIV’s many disguises.
The findings of the study, published online today in the journal Nature Medicine, may have important implications for developing new treatments for HIV and slowing – or even preventing – the onset of AIDS. Over 33 million people were estimated to be living with HIV worldwide in 2007. Although anti-retroviral drugs have been successful in delaying the onset of AIDS for several years, the drugs are expensive, have serious side effects and must be taken for life. No vaccine or cure yet exists and drug resistance is increasingly a problem.
When viruses enter our bodies, they hijack the machinery of host cells in order to replicate and spread infection. When our body’s cells are infected with a virus they expose small parts of the virus on their surface, offering a "molecular fingerprint" called an epitope for killer T-cells from the immune system to identify. This triggers an immune response, eliminating the virus and any cells involved in its production.
As with other viruses, HIV enters the body and replicates itself rapidly. However, it also has the ability to mutate quickly, swiftly disguising its fingerprints to allow it to hide from killer T-cells.
Professor Andy Sewell of Cardiff University, co-lead author of the study and long-term collaborator with Adaptimmune, said: "When the body mounts a new killer T-cell response to HIV, the virus can alter the molecular fingerprint that these cells are searching for in just a few days. It’s impossible to track and destroy something that can disguise itself so readily. As soon as we saw over a decade ago how quickly the virus can evade the immune system we knew there would never be a conventional vaccine for HIV."
Now, Professor Sewell and colleagues from Adaptimmune Ltd and the University of Pennsylvania School of Medicine have engineered and tested a killer T-cell receptor that can recognise all of the different disguises that HIV is known to have used to evade detection. The researchers attached this receptor to the killer T-cells to create genetically engineered "bionic assassins" able to destroy HIV-infected cells in culture.
Dr Bent Jakobsen, co-lead author and Chief Scientific Officer at Adaptimmune Ltd, the company which owns the technology, said: "The T-cell receptor is nature’s way of scanning and removing infected cells – it is uniquely designed for the job but probably fails in HIV because of the tremendous capability of the virus to mutate. Now we have managed to engineer a receptor that is able to detect HIV’s key fingerprints and is able to clear HIV infection in the laboratory. If we can translate those results in the clinic, we could at last have a very powerful therapy on our hands."
The researchers believe that HIV's chameleon-like ability may still prevent the virus from being completely flushed out of the body. It could mutate and change its fingerprint further, hiding behind these new disguises and evading detection. However, each time the virus is forced to mutate to avoid detection by killer T-cells, it appears to become less powerful.
"In the face of our engineered assassin cells, the virus will either die or be forced to change its disguises again, weakening itself along the way," says Professor Sewell. "We’d prefer the first option but I suspect we’ll see the latter. Even if we do only cripple the virus, this will still be a good outcome as it is likely to become a much slower target and be easier to pick off. Forcing the virus to a weaker state would likely reduce its capacity to transmit within the population and may help slow or even prevent the onset of AIDS in individuals."
Pending regulatory approval, Professor Carl June and Dr James Riley from the University of Pennsylvania in Philadelphia will shortly begin clinical trials using the engineered killer T-cells.
Professor June said: "We hope to begin testing the treatment on patients with advanced HIV infection next year. If the therapy in that group proves successful, we will treat patients with early stage well-controlled HIV infection. The goal of these studies is to establish whether the engineered killer T cells are safe, and to identify a range of doses of the cells that can be safely administered."
"The AIDS virus evades human immunity in all it infects," said Professor Rodney Phillips, from the University of Oxford, where the collaborative research effort first began in 2003. "Until now no-one has been able to clear the virus naturally. Immune cells modified in the laboratory in this way provide a test as to whether we can enhance the natural response in a useful and safe way to clear infected cells. If successful the technology could be applied to other infectious agents."
The researchers are now exploring using engineered receptors on killer T-cells as a way of improving immune responses to cancer.
Nature Medicine ?Published online: 9 November 2008 | doi:10.1038/nm.1779
Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor
Angel Varela-Rohena1, Peter E Molloy2, Steven M Dunn2, Yi Li2, Megan M Suhoski1, Richard G Carroll1, Anita Milicic3, Tara Mahon2, Deborah H Sutton2, Bruno Laugel3, Ruth Moysey2, Brian J Cameron2, Annelise Vuidepot2, Marco A Purbhoo2, David K Cole4, Rodney E Phillips3, Carl H June1, Bent K Jakobsen5, Andrew K Sewell3,4,6 & James L Riley1,6
Abstract
HIV's considerable capacity to vary its HLA-I-restricted peptide antigens allows it to escape from host cytotoxic T lymphocytes (CTLs). Nevertheless, therapeutics able to target HLA-I-associated antigens, with specificity for the spectrum of preferred CTL escape mutants, could prove effective. Here we use phage display to isolate and enhance a T-cell antigen receptor (TCR) originating from a CTL line derived from an infected person and specific for the immunodominant HLA-A*02-restricted, HIVgag-specific peptide SLYNTVATL (SL9). High-affinity (KD < 400 pM) TCRs were produced that bound with a half-life in excess of 2.5 h, retained specificity, targeted HIV-infected cells and recognized all common escape variants of this epitope. CD8 T cells transduced with this supraphysiologic TCR produced a greater range of soluble factors and more interleukin-2 than those transduced with natural SL9-specific TCR, and they effectively controlled wild-type and mutant strains of HIV at effector-to-target ratios that could be achieved by T-cell therapy.
1. Abramson Family Cancer Research Institute and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 556 BRB II/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6160, USA.
2. Immunocore Ltd., 57c Milton Park, Abingdon, Oxon OX14 4RX, UK.
3. The Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford OX1 3SY, UK.
4. Department of Medical Biochemistry and Immunology, Henry Wellcome Building, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
5. Adaptimmune Ltd., 57c Milton Park, Abingdon, Oxon OX14 4RX, UK.
6. These authors contributed equally to this work.
Correspondence to: Bent K Jakobsen5 e-mail: bent.jakobsen@adaptimmune.com
Correspondence to: James L Riley1,6 e-mail: rileyj@exchange.upenn.edu |
