More than 100 years ago, New York surgeon Dr. William Coley had the first hint of the immune system trying to attack and control cancer when he noticed that sarcoma tumors regressed in patients who had post-operative skin infections and high fevers. Coley experimented with the idea of treating cancer with heat-killed bacteria, but at the time there was very little understanding about what stimulates an immune response.
Immunotherapies activate the body’s immune system to fight cancer. We sat down with our own Steve Davidsen, Ph.D., vice president of oncology discovery, AbbVie, and Diane Hollenbaugh, Ph.D., senior director, oncology biologics, AbbVie, to look into AbbVie’s work in immunotherapies.
What do we know now, 100 years after William Coley made those initial observations and what are the challenges the immune system faces in fighting cancerous tumors?
Davidsen: There is a constant battle between the immune system and tumors. Tumors use various mechanisms to avoid destruction by immune cells. One of the ways they do that is by engaging checkpoint receptors on immune cells. Checkpoint molecules are key off-switches in immune cells and their activation blocks an immune response to target what is identified as “foreign” in the body. When tumors engage these checkpoints, it makes it difficult for immune cells to identify the tumor as something they need to attack, thereby dampening their activity.
What are the most recent advancements in immunotherapy?
Davidsen: The big breakthrough in recent years came when scientists discovered that disrupting these checkpoint receptors could activate immune cells and result in anti-tumor responses. And because it works by reeducating the immune system to recognize the tumor cells, the response has the potential to last a long time. The drugs created to do this are called checkpoint inhibitors.
And is this going to be AbbVie’s approach?
Hollenbaugh: The antitumor activity of checkpoint inhibitors teaches us that tumors can be controlled by the immune system, but checkpoint blockade is only one approach. We have been looking at various approaches beyond checkpoint inhibitors for several years.
Indeed, the immune system is all about balance, full of off and on switches, so we have many ways to explore how to shift the balance to kill tumors. One of the issues with stimulating the immune system is the possibility that our therapy can cause immune cells to attack not only the tumor but also healthy tissue.
An approach that we are using is focused on trying to trigger the immune cells to be activated only in the tumor itself. One of our drug candidates uses our expertise in bispecific biologics to activate immune cells only where the tumor is.
What are the challenges for this field?
Davidsen: It is critical to predict which patients will benefit the most from our drugs. In immunotherapy, what that means is that we need to understand the immune phenotype of the tumor, what types of cells are there and whether there are a lot or a few, and this will ultimately show us if the patient is appropriate for a certain therapy or not. So trying to understand which patients will respond to immunotherapy is critically important.
Isn't that the case with cancer therapy in general?
Hollenbaugh: Well, not exactly, because here we are not only trying to understand the tumor but also the immune cells in the vicinity of the tumor, or even throughout the body.
For example, we know that some tumors are “hot,” with many immune cells present, whereas others are cold with very few immune cells in them. We need to understand what it means to have certain kinds of immune cells in the tumor, or none at all. One opportunity is to find ways to induce immune cells to infiltrate these “cold” tumors so they can kill the tumors when they get there.
How are we leveraging our expertise in both oncology and immunology?
Davidsen: In many ways the two are complementary to each other.
In oncology, we want to turn up the immune system to attack tumors, while for immunological diseases we want to turn it down because it’s doing damage by attacking normal tissue inappropriately.
We have several examples where the oncology team investigated antagonists or agonists while the immunology team was focused on the opposite effect of the same targets. Also, many of the tools and technologies for studying the immune responses are the same, and we leverage our shared expertise, to turn it up or turn it down.
“Historically we target cancer in three ways: surgery, radiation and chemotherapy. I believe that immuno-oncology treatments are rapidly becoming a fourth pillar in treating cancer, but will not completely replace the other three.”
Do you think immunotherapy is the future when it comes to treating cancer?
Davidsen: Historically we target cancer in three ways: surgery, radiation and chemotherapy. I believe that immunotherapies are rapidly becoming a fourth pillar in treating cancer, but will not completely replace the other three.
Indeed, oncology is a science of combination. Patients are treated with cocktails of drugs targeting different mechanisms to treat their cancer. It may be that the most powerful cocktail will be a combination of immunotherapy in addition to something that kills tumors a different way.
The future of oncology therapy will be the combination of targeting the tumor cells and activating the immune system, and we will need both. For example, we may find that we may need to use an immunotherapy combined with radiation, chemotherapy or newer agents specifically targeting cancer cells.