Seattle -- Researchers at the Fred Hutchinson Cancer Research Center (FHCRC), the University of Washington (UW) and Targeted Genetics Corp. (Nasdaq:TGEN) announce the publication of data from a Phase I study evaluating a new concept in the therapy of HIV-1 infection. The paper ,titled "In vivo Migration and Function of Transferred HIV-1 Specific Cytotoxic T Cells," appears in the current issue of the journal Nature Medicine.
The study, a collaborative effort by Stanley Riddell, M.D., Philip Greenberg, M.D., Lawrence Corey, M.D., Scott Brodie, Ph.D., and Debra Lewinsohn, M.D., researchers at FHCRC and UW, Bruce Patterson, Ph.D., of Northwestern University, and Targeted Genetics used the immune system, specifically cytotoxic T cells, to destroy HIV-infected cells.
"This is a first step in developing an approach that uses the patient's own immune system to combat HIV infection," said Riddell. "Remarkably, a few CTLs can be expanded to more than a billion in culture and still retain the ability to function and home normally in the body. The results are encouraging, but it will be essential to develop approaches to improve the survival and the duration of the antiviral activity."
Cytotoxic, or killer, T cells (CTLs) that function to eliminate virally infected or malignant cells are part of the normal, healthy immune system. For those infected with HIV these CTLs are present, but are insufficient to control HIV replication. For the study, researchers hypothesized that infusing larger numbers of these cells would help control HIV replication. In addition, since each patient has unique cytotoxic T cells specific to HIV-1, it was important to isolate and expand cells from each patient treated.
In this study CTLs capable of recognizing the HIV-1 Gag protein (Gag-specific CTLs) were isolated from HIV positive patients and grown in culture to produce billions of CTLs capable of attacking HIV-infected cells. These enlarged pool of cells were then infused back into the patients. Patients received three escalating doses of CTLs at two-week intervals and then received two additional infusions at one-week intervals of CTLs that had been modified to contain a marker gene that would allow the persistence and location of the cells to be identified. Following each treatment with Gag-specific CTLs there was a decrease in the number of infected CD4 T cells present. Additionally, the transferred Gag-specific CTLs traveled to and localized within lymph nodes, the major reservoir of HIV infection. However, the antiviral effects were temporary due to the gradual decline of the transferred CTLs.
The demonstration that infused cytotoxic T cells can migrate to lymph nodes, the major site of HIV-1 replication - and that this is associated with greater cytotoxic activity against HIV-1 in the lymph nodes -- provides hope that this form of therapy may benefit HIV-1 infected persons. The patients treated on this study were receiving one to two antiretroviral drugs. Future studies are planned for patients on antiviral cocktails with the hope that the cells will last longer in such persons. In addition, cytokines such as IL-2 may allow these cells to persist.
"One advantage to adoptive immunotherapy is that the infusions are nontoxic," said Corey, study collaborator and head of FHCRC's Infectious Disease Program. "If we can provide levels of CTLs that control viral replication for a period of weeks to months, this may markedly extend the ability of antiviral drugs to HIV-1 to control viral replication long term."
Part of the research team's effort was the development of techniques to measure whether the infused CTLs reduced the number of HIV-1 infected cells. Brodie and Patterson developed a method to measure the number of HIV-1 infected CD4 and T cells circulating in the blood and showed that when high numbers of CTLs were present the number of HIV-1 expressing cells in the blood markedly decreased. These techniques confirm that CD8+ CTLs directed at HIV-1 can kill HIV-1 infected cells in vivo. This lays the groundwork that techniques to sustain the CD8+ CTL at high levels for extended time periods can be useful therapeutic options.
"It has been found that patients with high levels of HIV-specific CTLs are less likely to progress to AIDS," said Brodie. "If one can make HIV-specific CTLs last for a prolonged time then it may cause clinical benefit."
The proprietary process used to expand cells in culture is known as the Rapid Expansion Method (REM). REM technology enables the rapid and reproducible expansion of antigen-specific CTLs that retain their function in vivo. REM technology has broad potential to make adoptive immunotherapy, as described in this paper, a clinical reality. FHCRC was issued a patent for the REM technology in October 1998 by the U. S. Patent and Trademark Office. This broad patent was licensed exclusively to Targeted Genetics Corporation and forms the foundation of the company's cellular therapy platform.
"Adoptive immunotherapy represents a potentially powerful tool in the treatment of infectious diseases such as HIV as well as cancer," said H. Stewart Parker, president and chief executive officer of Targeted Genetics. "Previous studies have demonstrated that antigen-specific or 'targeted' T cells normally play a crucial role in eliminating virally infected or cancerous cells from the body. However, clinical development of adoptive immunotherapy has been hampered by the inability to expand targeted CTLs. The REM technology overcomes this hurdle and, as described in the publication, rapidly expands antigen-specific cells to numbers greater than one billion, which can then be administered to the patient.
The data in this publication demonstrate the ability of these cells to target and eliminate diseased cells and highlight the potential utility of the REM technology in adoptive immunotherapy." Targeted Genetics plans to commercialize the REM technology for adoptive immunothe! rapy, antigen discovery, immune system modulation, genomics and other therapeutic and research uses.
The Fred Hutchinson Cancer Research Center is an independent, non-profit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Recognized internationally for its pioneering work in bone marrow transplantation, the Center has four scientific divisions collaborating to form a unique environment for conducting basic and applied science. One of 35 National Cancer Institute-designated comprehensive cancer centers in the country, it is the only one in the Northwest.
Targeted Genetics Corp. develops gene and cell therapy products for the treatment of certain acquired and inherited diseases. The company has three lead development programs targeting cystic fibrosis, cancer, and infectious diseases as well as an extensive gene delivery and cellular therapy technology platform.
The study was funded by the National Institute of Allergy and Infectious Disease's Special Program for Innovative Research in AIDS Therapies (SPIRAT) grant; the retroviral vector was provided by Targeted Genetics Corp.
Journal
Nature Medicine