By Kristina Houck
Researchers from La Jolla Institute for Allergy and Immunology and their collaborators from other institutes recently discovered a potential new target for cancer immunotherapy.
Led by Dr. Amnon Altman and Dr. Kok-Fai Kong, the study revealed a new way to block the function of CTLA-4, an immune inhibitory checkpoint receptor that could help fight cancer. An antibody that blocks CTLA-4 is already in use for advanced melanoma.
Altman, who serves as director of scientific affairs and head of the division of cellular biology at the Institute, recently sat down with this newspaper to talk about the study, as well as the current and emerging role of immunotherapy in cancer.
What immunotherapies are currently approved to treat cancer?Altman: There are, broadly, three types of cancer therapies, which we can define as “immunotherapy.”
The first one is the use of antibodies that recognizes proteins that are expressed on the surface of cancer cells, but not — or at a much lower level — on the surface of normal cells. Those are potentially targets for these antibodies, which bind to these tumor cells and can kill them. This is an immunotherapy that targets, specifically, the tumor itself.
There are two other forms of therapies that take advantage of the power of the immune system to fight cancer. Those are therapies that do not target the cancer directly, but instead target the immune system and are aimed at enhancing the immune system in order to increase its ability to fight cancer.
The first one is the use of cancer vaccines. There are different types of vaccines that contain proteins or antigens that are specific to the tumor cell. The idea is — just as you immunize children against infectious diseases — that by vaccinating a patient with proteins that are specific to their tumor cells, you wake up the immune system and allow it to better fight the cancer.
The third type of cancer therapy, which currently creates a lot of excitement in the field, is immunotherapy based on engineering certain types of cells of the immune system — T lymphocytes (or T cells) — to recognize a tumor and kill it.
What types of cancers have shown the greatest response to immunotherapy, so far?Altman: It depends on what type of immunotherapy, but for the type of immunotherapy that relies on transferring the patient’s own T lymphocytes — which have been engineered to recognize and kill the cancer cells — the type of cancer where this has been mostly applied is certain forms of leukemia, which are cancers of the blood cells.
For the type of immunotherapy that is based on blocking an inhibitor pathway in order to allow a more effective immune response against the cancer, it has been most successful with melanoma.
Why do you think immunotherapy is a major approach in cancer therapy?Altman: It would be hard to define an immunotherapy strategy that would be most effective or most successive in a global way for all cancer. Different types of cancer differ in the way they interact with the immune system. Depending on the cancer type, you would need to select the appropriate type of immunotherapy.
I think that taking advantage of the immune system to fight cancer, even in the future, will probably need to be used in combination with other therapies like chemotherapy. But perhaps, if we find effective ways to use immunotherapy against cancer, we can lower the amounts and toxic side affects of traditional therapies like chemotherapy and radiation therapy.
What are the key findings of your study?Altman: One way the immune system regulates itself is to put the brake on excessive undesired immune responses. This is important in order to prevent autoimmune diseases, but the price that we pay for that is this same inhibitor mechanism has the potential to inhibit a beneficial immune response against cancer cells. In this case, we would like to block this inhibitory mechanism.
One major such inhibitor mechanism is carried out by a cell called “regulatory cell.” This is a type of T cell that puts the brake on an excessive immune response. Those are the kind of cells that, eventually, we would like to deplete or get rid of in cancer in order to have a more effective immune response. One important mechanism to which these regulatory T cells inhibit a response is through a receptor that they express on the surface. That receptor is called CTLA-4, it’s the CTLA-4 protein.
CTLA-4 is a target for antibodies that are currently being used in the clinic to treat melanoma patients. Antibodies against CTLA-4 actually have shown some very encouraging results in melanoma patients, in terms of prolonging their survival. In this case, we are talking about blocking antibodies that block the inhibitory activity of CTLA-4 from outside the cells. These antibodies do not get inside the cells; they bind to CTLA-4 on the surface of these regulatory T cells and block these regulatory T cells from exerting their inhibitory activity.
Our finding also relates to CTLA-4, but now we are talking about biochemical changes that occur inside the cells when this receptor is stimulated. We identified a novel interaction between immune cell receptor CTLA-4 and an intracellular enzyme Protein Kinase. We found that that enzyme is required for the immune suppressive activity of regulatory T cells. In the absence of this enzyme, regulatory T cells were not able to inhibit anymore.
What is one thing cancer patients should take away from your study?Altman: Potentially, we have a new way of interfering with the activity of a receptor that plays a very important role in blocking an effective immune response against cancer cells.
How did it feel when you, your team and your collaborators discovered this?Altman: Among several discoveries that we’ve made over the past 30 years or so, this certainly ranks among the most exciting ones. … Here is a research project where we potentially see the distance between our very basic research work and potential application, which of course, is still years away, but could lead to very interesting future results.
How do you see immunotherapy as a cancer treatment evolving in the next 5, 10, 15 years?Altman: I think that this is a tremendously exciting field. There will be a lot of interesting and exciting progress made in the next 10-15 years. In 2013, “Science Magazine” described cancer immunotherapy as the ‘most exciting scientific discovery of the year.’
I think that in particular, one form of immunotherapy that raises the most excitement and where most focus will probably be, is the form of immunotherapy that is based on engineering the patient’s own T lymphocytes to become effective cancer killers. … Right now, it’s used mostly for certain forms of leukemia. But as we identify proteins that are specifically expressed in other types of cancer, we will be able to engineer T cells that can become effective killers of many other forms of cancer. This is probably where most of the progress in the coming years will be accomplished.