The T cell is at the heart of a great deal of research at UCLA. Investigators from a variety of disciplines, notably oncology, immunology and virology, are studying ways to turn these white blood cells into medical weapons that can attack some forms of cancer, and find and eliminate persistent infections such as HIV.
T cells are the body’s natural-seek-and-destroy missiles. They are groomed to detect non-self cells, and attack the invaders while calling in the rest of the immune system troops. Researchers say the future of immunotherapy is to train the T cells to “see” the cancer, the HIV microbes, and a myriad of other abnormal cells that have been hiding, and to fully arm the T cells’ response.
Much progress has recently been made in T cell research and therapy, and researchers say there is so much hope for more.
According to Dr. Irvin S. Chen, professor of microbiology, immunology and molecular genetics at UCLA, the immune response to chronic viral infection is very similar to cancer as the viruses manage to evade the immune system. Therefore, the key to understanding the immune system’s strengths and weaknesses is multidisciplinary collaboration.
That’s why the mission shared with some 200 UCLA investigators from different departments working on HIV is “cure” research. Theirs is an effort to completely eliminate the virus from infected individuals. As it stands now, antiretroviral drugs keep people who are infected stable, but the virus is still in their bodies while the drugs themselves have a number of side effects.
One approach tested at UCLA, gene therapy, received a $15 million grant last year from the National Institutes of Health. This is just the latest federal support of research that has been ongoing for 15 years. Called “defend and attack” by Dr. Chen, the goal of this work is to engineer cells with genes that can protect the body against HIV infection while also fighting the virus.
The project began in the early 1990s with the observation that some people never become infected with HIV despite high-risk sexual exposure to HIV-infected individuals. It was discovered that these people do not have a gene called C-C chemokine receptor type 5 (CCR5), a receptor protein on the surface of T cells.
HIV infects T cells through the CCR5 receptor so people without this portal remain uninfected. Researchers have found that only about 1 percent of the Caucasian population does not have this gene, the lack of which does not negatively affect health.
Researchers were able to devise a stem cell therapy that modifies T cell function. It silences CCR5 gene expression, so no CCR5 receptor portal exists on T cells. The concept is being tested in an ongoing clinical trial at UCLA.
In next generation gene therapies, the CCR5-silencing therapy will be combined with a new gene using engineered chimeric antigen receptors (CARs). These can kill HIV-infected cells, thereby “defending” T cells from HIV infection while simultaneously “attacking” those cells already infected.
The idea of using CARs to fight HIV comes from the cancer world and is one example of the rationale for I3T (immunity, inflammation, infection and transplantation), where advances made in one disease area have an equally important impact in another.
UCLA collaborators are also set to investigate another approach for a cure. Called “shock and kill,” it aims to eliminate the virus completely from infected people so that they don’t have to take HIV-suppressing drugs for the rest of their lives.
There are billions of cells producing HIV in the body of an infected person not using HIV therapy. With antiretroviral therapy, the number of virus-infected T cells drops to about a million, most of which harbor latent or silent HIV.
UCLA investigators are studying the use of chemicals they know will push the virus to reactivate and come out of hiding, followed by the use of CARS, antibodies, or toxins that can then go in and kill the T cells now producing viral particles. The precise hiding places in the body for silent HIV are unknown.
This work is the first test of T cell engineering for an infectious disease.
In order to find these T cells wherever in the body they exist, researchers plan to wrap antibodies in “nano” polymer shells. This will let the antibodies slip into places they don’t normally go, such as the brain, the genital tract and deep inside tissues. These nano-vehicles will also alert other immune cells known as macrophages to swallow the T cells producing HIV, and thus start a broad immune response against the emerging virus.
If these approaches work for HIV then researchers will be able to apply the same technology to other viral and infectious agents. What’s more, what’s learned from HIV can be applied back again to other diseases like cancer, genetic disorders and others.
All of these fields are going to feed off of each other, and that will be the new normal in the next generation of research at UCLA.