World’s first engineered T cell receptor trial opens with new cellular therapy for HIV

Oct 11 2009

Researchers at Adaptimmune Limited and the University of Pennsylvania School of Medicine, have announced the approval of an Investigational New Drug (IND) application from the US Food and Drug Administration (FDA) and opening for enrolment of the first ever study using patients’ cells carrying an engineered T cell receptor to treat HIV (SL9 HA-GAG-TCR). The trial may have important implications in the development of new treatments for HIV potentially slowing – or even preventing – the onset of AIDS.

The trial makes use of the body’s natural ability to recognise infected cells by enhancing the power of the T cell receptor (TCR) on killer T cells. When a virus infects cells, it hijacks the host cell machinery in order to replicate and spread infection. These infected cells then expose or “present” small parts of the virus proteins 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. However, HIV not only replicates itself quickly on infection but also has the ability to mutate rapidly, swiftly disguising its fingerprints to allow it to hide from killer T-cells.

Researchers at the Oxford University spin-out Adaptimmune have spent a decade working on ways to improve the natural ability of the TCR to recognise infected and cancerous cells; a process which has involved remaking the natural TCR protein and then modifying its ability to bind to the molecular fingerprints of the affected cells.

Last year, with colleagues at the University of Pennsylvania, they engineered and tested a killer T-cell receptor that can recognise all the different disguises HIV is known to have used to evade detection. The researchers transferred this receptor to the killer T-cells to create genetically engineered "bionic assassins" able to destroy HIV-infected cells in culture. Now, less than a year later, they are taking their unique technology into the clinic.

“The immune system uses T cell receptors to find and trigger the elimination of infected cells”, says Dr Bent Jakobsen, Chief Scientific Officer at Adaptimmune Ltd. “HIV, however, poses an intractable challenge because it has a phenomenal ability to escape detection through mutation whilst the immune system is not able to adapt its T cell receptors. Together with our colleagues at the University of Pennsylvania, we have previously shown that it is possible to engineer a T cell receptor that detects the known spectrum of HIV escape mutants for this particular fingerprint and triggers a more potent immune response when transferred into a patient’s cells. Today sees that important research result move into the clinic – for the first time allowing us to test the power of super potent immune cells against HIV in reality.”

The trial will be led by Carl June, MD of the Abramson Family Cancer Research Institute and the Department of Pathology and Laboratory Medicine alongside Pablo Tebas, MD, Director of the adult AIDS Clinical Trials Unit (ACTU), Department of Infectious Diseases Division at the University of Pennsylvania.

Professor June said: “We are treating patients for the first time with an enhanced version of a natural T cell receptor designed to recognise and clear HIV. This is the first time an engineered T cell receptor will be given to patients with HIV infection. We will be treating patients currently well-controlled on HAART therapies in order to establish whether the engineered killer T cells containing the receptor are safe, and to identify a range of doses of the cells that can be safely administered. It is a truly an important day for T cell immunotherapy.”

“Using monoclonal antibodies revolutionized the treatment of many rheumatologic and lympho proliferative diseases”, added Dr Pablo Tebas, Principal Investigator on the new trial. “These engineered T cells are the equivalent of monoclonal antibodies in the other big branch of the immune system: the cellular branch. We hope to target cells infected with the HIV virus and eliminate them. This first study will evaluate safety and the right dose of these cells needed to be effective.”

According to UNAIDS/WHO figures, over 2.7 million people were infected with HIV in 2007 with over 33 million people estimated to be living with HIV worldwide. No cure or effective vaccine yet exists. Current treatment regimens are based on combinations of different classed of anti-retroviral drugs which although successful in delaying the onset of AIDS for several years, have serious side effects and must be taken daily for life. Drug resistance is also increasingly a problem. New, effective ways to control the disease therefore remain a priority.

If the trial confirms the safety and preliminary effectiveness of the engineered T cell treatment for HIV, Adaptimmune plans to conduct a follow-on Phase II trial to confirm efficacy in a larger group of patients. In partnership with its colleagues at the University of Pennsylvania it is also planning a first safety study of engineered T cells targeted to cancer to commence in 2010.

Note: The Penn investigators in this study have no financial interest or other relationship with Adaptimmune LTD, apart from their scientific collaboration in developing the engineered killer T cell, conducting laboratory experiments and planning human clinical trials.

http://www.adaptimmune.com/