Researchers at the University of Pennsylvania School of Medicine and Adaptimmune Limited today announced the approval of an Investigational New Drug (IND) application from the US Food and Drug Administration (FDA) and opening for enrollment 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 recognize 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 recognize 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 recognize 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 while 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 with Pablo Tebas, MD, Director of the adult AIDS Clinical Trials Unit (ACTU), Department of Infectious Diseases Division at the University of Pennsylvania.

“We are treating patients for the first time with an enhanced version of a natural T cell receptor designed to recognize and clear HIV. This is the first time an engineered T cell receptor will be given to patients with HIV infection,” said June. “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 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.

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.

The SL9 HA-GAG-TCR Trial:

The study is an open label, exploratory Phase I multiple arm study to evaluate the safety, tolerability and antiviral effects of escalating doses of a single administration of autologous T cells modified using lentiviral vectors expressing high affinity gag-specific TCRs in patients who are positive for the tissue type HLA A02. The specific target of the TCR is the HIV-1 gag epitope SL9 (SLYNVATL) detectable in 75% of HIV-infected patients with this tissue type.

The process to make the autologous cells at the University of Penn will involve isolating and converting a portion of the patient’s T cells to a single population of killer (CD8+) T cells containing the engineered TCRs. Two TCRs will be compared: the natural wild type TCR for the SL9 epitope (WT-GAG-TCR) and a higher affinity version (HA-GAG-TCR). The trial will enroll a total of twenty-four patients who are currently well-controlled on anti-retroviral medications (HAART) in four equal cohorts. In the first cohort, patients will be infused with WT-GAG-TCR T cells and then start an analytical structured treatment interruption (STI) to their HAART for a maximum of 16 weeks unless criteria for reinstatement of HAART are invoked. After initial dosing, patients will enroll in the second cohort evaluating HA-GAG-TCR T cells. Once a safe dose is established in these two cohorts, the third and fourth cohorts will enroll in which eligible patients will begin an STI and then receive T cell infusions 6 weeks in to their STI of initially WT-GAG-TCR (cohort 3) and then HA-GAG-TCR (cohort 4), unless criteria for HAART reinstatement are invoked. All patients will be followed for 9 months following study treatment. The primary objective of the study is to evaluate the safety and feasibility of treating patients with HA-GAG-TCR modified T cells.

Preclinical data

Preclinical data on SL9 HA-GAG-TCR were published in the journal Nature Medicine (Varela-Rohena, A. et al. Control of HIV-1 immune escape by CD8 T-cells expressing enhanced T-cell receptor. Nature Medicine, 2008 Dec;14(12):1390-5.) and presented at the European AIDS Conference in Vilnius in April 2009. Phage display was used 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.

About HIV/AIDS

Since the discovery of the human immunodeficiency virus (HIV) in 1984 and its role in the cause acquired immunodeficiency syndrome (AIDS) the HIV pandemic has become one of the most serious challenges to human health in the 21st Century. UNAIDS estimates indicate that over 33 million people are now living with HIV rising by approximately 1 million per year. Whilst combinations of highly active anti-retroviral therapy (HAART) have been relatively successful in crippling the virus and delaying by years the onset of AIDS, crucially such therapy does not represent a cure and the combined problems of drug resistance mutations, toxicity and patient adherence raise questions about the long-term efficacy of treatment as well as the cost and availability of such drugs in poorer parts of the world where the pandemic is most acute. More recently, hopes that vaccines could be used to control the disease by provoking an immune response to the virus have also begun to fade as it has become apparent that HIV’s phenomenal capacity for variation enables it to out-run, and eventually over-run, the human immune system . New approaches are needed that reach beyond these existing efforts, barrier methods and behavioral changes which can truly prevent or cure HIV infection.

About the University of Pennsylvania (PENN)

PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System.

Penn’s School of Medicine is currently ranked #3 in the nation in U.S.News & World Report’s survey of top research-oriented medical schools; and, according to the National Institutes of Health, received over $366 million in NIH grants (excluding contracts) in the 2008 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s top ten “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation’s first hospital; and Penn Presbyterian Medical Center, named one of the nation’s “100 Top Hospitals” for cardiovascular care by Thomson Reuters. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.

Source: University of Pennsylvania School of Medicine

AIDS Healthcare Foundation (AHF) hailed the news that four million people from low and middle income countries living with HIV/AIDS were on lifesaving antiretroviral treatment in 2008, a 36% increase over 2007. The news came in a new report, ‘Towards Universal Access: Scaling Up Priority HIV/AIDS Interventions in the Health Sector’ (September 2009) released by the World Health Organization (WHO), the United Nations Children’s Fund (UNICEF) and the Joint United Nations Programme on HIV/AIDS (UNAIDS). The numbers also represent a tenfold increase of those on treatment over the past five years; however, AHF officials note that of the 33 million people living with HIV/AIDS worldwide, millions more still lack access to lifesaving treatment, and countless numbers of those do not even know their HIV status, as they have never been tested for the virus.

“Four million lives are being saved today because many more people in resource-poor countries around the globe now have access to medical care and lifesaving antiretroviral medications-an accomplishment we should all take a moment to celebrate and cheer,” said Michael Weinstein, President of AIDS Healthcare Foundation which currently provides medical care and services to more than 110,000 individuals in 21 countries worldwide. “However, there are 33 million people living with HIV/AIDS worldwide, and millions still lack access to this rising lifeboat of AIDS care and treatment. The vast majority of people infected with HIV worldwide don’t know it, as they have never had a chance to get tested for the virus. While the treatment numbers reported today are welcome progress in the global battle against AIDS, we should take heed of the fact that this report also shows the need for dramatically stepped up HIV testing services as a means to break the chain of new infections and identify and link people in need to care and treatment.”

Source
AIDS Healthcare Foundation

Responding to today’s news that the Food and Drug Administration (FDA) Antiviral Advisory Committee has approved Pfizer Inc.’s AIDS therapy, Selzentry (maraviroc), for use in therapy-naïve patients, AIDS Healthcare Foundation (AHF) strongly criticized Pfizer for its current pricing of the drug at an Average Wholesale Price (AWP) of $13,767 per-patient per-year-which, if this price remains when use is expanded, would make it the most expensive first-line AIDS drug on the market.

Selzentry was originally approved by the FDA in August 2007 as a salvage drug-utilized in patients who do not respond favorably, or have developed resistance, to other AIDS drugs-and priced at $12,528 per-patient per-year. In just two years, the price for Selzentry-which must be taken with at least two other AIDS drugs-has increased by nearly 10%. Pfizer reported $46 million in sales for Selzentry in 2008, according to the Associated Press.

“In this time of growing national concern over ballooning healthcare costs, it is simply criminal for Pfizer to continue to price Selzentry at the salvage therapy rate, especially now that the market for the drug will be vastly expanded by the FDA’s likely upcoming approval of the drug for first-line use,” said Michael Weinstein, President of AIDS Healthcare Foundation. “Government programs such as AIDS Drug Assistance Programs and Medicaid are likely to be the largest purchaser of Selzentry. Where exactly does the burden of Pfizer’s price-gouging fall? On the taxpayers. And for what reason? So that the largest pharmaceutical company in the world, Pfizer, can make just a little more profit-while bankrupting government programs already hurting for funds as they work to ensure that Americans living with HIV/AIDS receive the lifesaving treatment they need.”

“While any new HIV/AIDS drug on the market is welcome, we urge Pfizer to use restraint and to lower the price of Selzentry immediately upon FDA approval for this expanded use,” said Michael Weinstein, President of AIDS Healthcare Foundation.

An estimated 1.2 million people in the U.S. are living with HIV/AIDS. As a result of antiretroviral treatment, many more people are living longer with HIV/AIDS, and a greater burden has been put on the health care system, including several of the federally funded, state-run AIDS Drug Assistance Programs (ADAP) nationwide. State ADAPs are funded by the federal Ryan White CARE Act and are the primary source of HIV/AIDS medications for uninsured and underinsured Americans. Funding for AIDS care has been largely flat-funded or saw only minor funding in recent years-increases which are not proportional to the need, nor able to support inflated pharmaceutical prices.

Source
AIDS Healthcare Foundation

View drug information on Selzentry.