In honor of June containing National Cancer Survivors Day, we want to update you on the latest advancements and research in cutting-edge cancer treatments, specifically cancer immunotherapy and CAR T cell therapy.
To do so, we spoke with our Co-Founder and Chief Science Advisor, Chris Roselle, who is a leading researcher in the field.
What is cancer immunotherapy?
At the most basic level, cancer immunotherapy is any cancer therapy that leverages the immune system to fight cancer. Although a surprisingly wide range of therapies fall into this category – for instance, radiation can induce cell death that drives immune activity that contributes to tumor clearance and can technically be considered a form of cancer immunotherapy – most people associate cancer immunotherapy with checkpoint inhibitors and chimeric antigen receptor (CAR) T cell therapies that gained widespread use in the last decade. Both of these therapies are unique because they leverage the ability of T cells, which can be thought of as soldiers of the immune system, to directly kill cancer cells.
The special attention given to these forms of cancer immunotherapy is due to the remarkable ability of T cells to rapidly clear pounds of tumor and in some cases lead to durable, long-term remission in late-stage cancer. There’s still a lot of progress to be made, but doctors and scientists are excited by the potential upside of using T cells and the rest of the immune system to fight cancer.
For the sake of completeness, cancer vaccines, monoclonal antibodies that target cancer cells for immune mediated cell death, and other types of cell therapies also fall into the category of cancer immunotherapy and include staple cancer drugs like Herceptin and rituxumab.
How does it work?
To understand how T cell-based immunotherapies work, it’s important to take a step back and understand how T cells recognize and interact with cancer cells. To stick with the soldier analogy, T cells are constantly surveilling the body looking at each individual cell for any abnormalities that might signal a problem.
The abnormality could be due to a viral infection, which introduces what we call “non-self” proteins that T cells can recognize as foreign, or even cancer-associated mutations, which can similarly trigger a T cell to recognize a mutated cell as being foreign, due to the presence of mutated, “non-self” proteins.
Once a T cell is activated and recognizes its target, it rapidly kills by quite literally shooting proteins at the target cell that kill it. An individual T cell can do this repeatedly and live for decades while continually surveilling for the same target. And this is something that happens in what we would consider a healthy cancer-free person – you may not realize it but T cells are eliminating cells that are or could become cancerous.
Interestingly, the more mutations a cancer cell has, the more foreign it looks, which can make it more visible to the immune system. As a result, cancers like melanoma which have high mutational burden are very responsive to immunotherapy.
So you might be wondering why people still end up getting cancer if T cells can recognize and kill cancer cells. This is a complex area of active research, but one important reason is that cancer cells often evolve different resistance mechanisms to inhibit the anti-tumor function of T cells or even evade detection altogether.
One of these resistance mechanisms involves cancer cells putting inhibitory molecules on their cell surface that can cause a T cell to become inactive and dysfunctional when it finds the cancer cell instead of killing it.
This is where checkpoint inhibitors like pembrolizumab (Keytruda) come into play. These antibodies bind to tumor reactive T cells and prevent this type of inhibitory interaction from taking place and allow T cells to go back to killing tumor cells.
So, we can think of checkpoint inhibitors as a tool to prevent cancer cells from tricking T cells into becoming inactive. For certain types of cancers, checkpoint inhibitor therapy can be extremely effective and lead to dramatic tumor reductions in late-stage disease. But checkpoint inhibitors are only one of the two types of T cell-based immunotherapies. CAR T cell therapy is the other and works differently.
What is CAR T cell therapy?
CAR T cell therapy is another T cell-based immunotherapy that has caused a lot of excitement within the scientific and medical community and is what I work on.
CAR T cell therapy involves taking a patient’s T cells out of their body and then genetically engineering them to make a new receptor that allows them to “see” and kill tumor cells that they previously couldn’t see. So, in the case of CAR T cell therapy, the therapy is literally the patient’s own genetically modified T cells. With this approach, doctors have a way to redirect hundreds of millions to billions of T cells to eliminating a tumor that they previously couldn’t see.
CAR T cell therapy has worked remarkably well in patients with late-stage acute lymphoblastic leukemia (ALL) that are unresponsive to other forms of therapy. There are many dramatic examples of patients being brought back from near death to leading normal lives after CAR T cell therapy, including the well-publicized story of Emily Whitehead. It definitely represents a big step forward in cancer therapy, at least for particular types of cancer.
Currently there are five FDA approved CAR T cell therapies that are all currently used for treatment of different types of blood cancers.
How does it differ from other common treatments such as chemotherapy and radiation?
There are many differences between CAR T cell therapy and more traditional treatments. For one, CAR T cell therapy is very specific since CAR T cells can only kill cells that have the particular marker that they’re genetically engineered to recognize. So, it can be thought of a more of scalpel whereas chemotherapy and radiation are blunt tools that kill cancer cells but also many healthy cells.
Another important difference is that CAR T cells are living drugs and can remain within the patient long-term and continue to look for tumor cells over a very long period of time, which can help prevent relapses.
But with these advantages also come some specific challenges to CAR T cell therapy. CAR T cell therapy is a personalized drug that is very expensive to manufacture since it can’t be produced in bulk like chemotherapy drugs. As a result, scientists are working on other forms of CAR T cell therapy that can be made in larger batches from non-patient sources so that they’re available “off-the-shelf.” However, there are no approved options that fall into that category at the moment.
What types of cancers is it good for treating? What types is it not good for?
As I mentioned earlier, CAR T cell therapies are only approved for use in specific blood cancers. Although this is a great advancement, roughly 90% of cancer deaths are from what we call “solid tumors” - for instance, lung, liver, colon, and breast cancer - which are more challenging to treat with CAR T cell therapy.
There are several reasons that CAR T cells have been less successful to date in treating solid tumors, but an immense amount of resources are going into finding solutions to these challenges. Because CAR T cells are genetically engineered outside of a patient’s body, we’re able to use the full complement of cutting-edge synthetic biology and genetic engineering tools. So, there are still many hurdles when it comes to solid tumors, but there is reason to be optimistic about reaching a point when we can successfully treat late stage metastatic patients and right now, there are hundreds of active clinical trials evaluating CAR T cells in solid tumors.
What is your personal area of research?
I work on trying to understand why CAR T cells stop working when they’re under high stress conditions, such as those that would be encountered while trying to clear a large amount of tumor. CAR T cells, and T cells more generally, are put under an enormous amount of stress when they’re clearing tumor cells because they often have to function in low nutrient, low oxygen, acidic environments all while having to still execute the metabolically demanding functions associated with tumor clearance.
Imagine having complete a really intense physical workout for a prolonged period of time, under incredibly harsh conditions. You’re going to wear out really fast. And in the case of CAR T cells, wearing out means they either die or become dysfunctional to a degree that they can’t kill tumor cells and the therapy fails. And in many cases the T cells that are collected from a patient to make CAR T cells are already quite beat up from prior chemotherapy and effects of the disease.
My research is specifically focused on trying to modulate one of the key stress responsive pathways that dictates how CAR T cells respond when they’re put under intense stress. We have some exciting data that will be published soon and think that we’ve identified an underappreciated approach to making CAR T cells capable of operating better under these harsh conditions.