Dr Hannah King, postdoctoral research fellow, Doherty Institute
What is immune checkpoint blockade?
Immune checkpoints are proteins on the surface of immune cells that dampen the immune response. They do this by telling the cells not to respond when they encounter a stimulus, or trigger. As a result, cells with lots of immune checkpoints on their surface don’t work very well, and are known as ‘exhausted’ cells.
Immune checkpoint blockade is the process of using drugs to block these immune checkpoints. By blocking immune checkpoints, the cells are reinvigorated and can respond with a strong immune response.
How is immune checkpoint blockade currently used?
Immune checkpoint proteins get expressed on the surface of cells when there is an ongoing, or chronic, immune stimulus. This is largely in response to chronic infectious diseases like HIV, but also Hepatitis B, tuberculosis and recurrent malaria infections, as well as in response to cancer.
Immune checkpoint blockade is used in the treatment of several types of cancer. By giving drugs that bind to immune checkpoints and block their function, immune cells are better able to kill cancer cells, helping eradicate the disease and improve patient survival. The most common immune checkpoint that is targeted is called PD-1, although other drugs also target the immune checkpoints CTLA-4, PD-L1 and LAG-3. Drugs for each of these targets are licensed for use in cancer, and drugs against new targets, such as Tim-3 and TIGIT, are being developed.
Because of this success in cancer treatment, attention has turned to using immune checkpoint blockade as a treatment for chronic infectious diseases which also cause exhaustion of immune cells. In clinical trials of immune checkpoint blockade in people with Hepatitis B infection, targeting PD-1 reduced the levels of viral proteins, a marker of persistent infection, in some participants.
Can immune checkpoint blockade contribute to HIV cure?
Immune checkpoint blockade is being studied for its potential role in an HIV cure. We know that the immune checkpoint PD-1 reduces the immune response to HIV. PD-1 is also involved in keeping HIV in a latent state, where the virus is resting and is not recognised by the immune system. There is encouraging evidence that treatment targeting PD-1 can have a beneficial effect in HIV infection. This includes evidence in cell culture (cells grown in a lab), in animal studies and, most importantly, in clinical trials of people living with HIV. Most clinical trials of PD-1 checkpoint blockade in HIV have focused on people with HIV who also have cancer. Recently, a clinical trial in the USA investigated targeting PD-1 in people with HIV without cancer. This trial showed PD-1 checkpoint blockade led to viral control and a delay in virus rebound in some participants when HIV treatment was stopped.
In Melbourne, we are undertaking a clinical trial testing anti-PD-1 antibodies in people with HIV who do not have cancer. The NIVO-LD study is using very low doses of antibodies to avoid side effects. This trial is ongoing and will give us important information about the benefits of this treatment. The main purpose is to see if the treatment can make the virus visible to the immune system and boost immune responses against HIV.
Dr King’s review of immune checkpoint blockade in infectious diseases was recently published in the Journal of Immunological Reviews.
