As an undergraduate, Christine Brown fell in love with science and discovery. Like many young scientists, she relished the experience of performing experiments that no one had done before. In 2001 when she met pediatric cancer researcher Mike Jensen, who is now at Seattle Children’s Hospital, she discovered the world of CAR T cell therapy.
“This just sounded amazing to be able to re-engineer immunity and re-target a patient's immune system to cancer,” she said. “I really fell in love with the idea.”
Brown has since founded her own lab at City of Hope where she investigates and develops CAR T cell therapies for malignant brain tumors such as glioblastoma. While there is no cure for glioblastoma yet, Brown and her colleagues have seen the potential of CAR T cell therapy in patients enrolled in their clinical trials.
How does CAR T cell therapy work?
The goal of CAR T cell therapy is to reprogram T cells to recognize and kill cancer or malignant cells. We do this by constructing a synthetic immune receptor that we term “CAR,” or Chimeric Antigen Receptor. CAR therapy typically combines a tumor targeting domain derived from a portion of an antibody. It can recognize a tumor cell just like an antibody does. The CAR T cell gets activated, and then it can kill the cell that the CAR directs it to recognize. The goal is to tilt the balance in favor of the immune system, so we generate hundreds of millions of tumor specific immune cells to help in the fight against cancer.
Why use CAR T cell therapy to treat glioblastoma?
Glioblastoma is one of the most common malignant brain tumors. The standard of care has not dramatically improved patient outcomes in decades. It has maybe extended survival for a few months, but that's it. If a patient gets a diagnosis of a glioblastoma, unfortunately there is no curative therapy. So, this idea that immunotherapy might offer something new to this group of patients in desperate need of more novel therapies really is attractive. If we can make an impact in glioblastoma, then it really sets the stage for making a huge impact in solid tumors generally.
What is it about solid tumors and brain tumors that make them so difficult to treat?
One challenge is access to brain tumors because they reside behind the blood brain barrier. A lot of therapies can't cross the blood brain barrier because it’s an immune privileged space. The second is the sensitivity of the brain. When applying CAR T cells to B cell malignancies, for example, those T cells target normal B cells as well. Those off-target effects can be clinically managed, and that treatment has great therapeutic success. But that's not the same when targeting brain tumors because off-tumor targeting would not be tolerated.
Glioblastomas are also highly heterogeneous, as are most solid tumors, and the tumor microenvironment is highly immunosuppressive. So, these tumors have ways of evading the immune system and other therapies. All of that creates a picture of a very challenging tumor. That sounds very dismal, but there's a lot of optimism about what we can potentially do for this patient population.
Where do you get that sense of optimism?
We showed that for one of our first patients ever treated with CAR T cell therapy, a man named Rich Grady, all of his tumors melted away. It was so amazing to see a patient with recurrent glioblastoma with multiple lesions in his brain and spine; when we administered the CAR therapy, all of these tumors became undetectable. While that hasn't occurred for other patients to the same extent, even though we have patients that seem to do quite well on the therapy, it says that it's possible.
What do you think was so unique about this patient?
We think that the CAR T cells targeted the malignant brain tumors, and at the same time they likely activated his own immune response. So, that's been our paradigm for what we want to do therapeutically. We want to develop the best T cell to target the tumor while also engaging and co-opting the host immune system to coordinate and drive a more effective anti-tumor immunological response.
Did the CAR T cell therapy keep that patient’s tumors away?
After about seven and a half months, he started getting new tumors at different sites in his spine and in his brain. His tumors seemed to come back in a way that was more resistant to the CAR T cell therapy and more resistant to his endogenous immune system. The recurrent tumors seemed to express lower levels of our target for CAR T cell therapy and also had decreased gene expression associated with antigen presentation.
How have you used what you learned from this patient to develop new CAR T cell therapies?
The T cells that we tested in this patient targeted a single antigen. My team has been pursuing targeting a greater number of the tumor cells with CAR therapy, almost to box in the tumor so that it's difficult for the tumor to come back in a way that's invisible to the CAR T cells. We have three CAR T cells that we're testing in the clinic: one targeting IL-13 receptor α2, another targeting HER2, and then more recently, a CAR that we developed using the chlorotoxin peptide.
The other lesson is the importance of engaging the host immune system. Most brain tumors are immunologically cold, meaning that there are very few T cells in the tumor microenvironment. We know that cold tumors don't respond well to immunotherapy. There's a lot of work in many aspects of immunotherapy on how to turn cold tumors hot.
What has it been like to work with glioblastoma patients in your CAR T cell clinical trials?
I've had the wonderful opportunity of meeting several of the individuals that have been treated on our trials. There was a gentleman that did relatively well. His tumor didn't come back for a while. When it did come back, it came back in a new location. The doctors thought that maybe the CAR T cells delivered to the first tumor kept that other tumor at bay and let him have more time with his family. During that time, his wife said that he added to his bucket list. He went skydiving — something that he had always wanted to do. I love that I had the opportunity to meet him, show him around the lab, and show him where his cells were being made. Hopefully, we can improve this therapy to give many other patients more time.
What accomplishment are you most proud of so far?
The team effort in making clinical science happen is my most important accomplishment. I've developed a program that brings together so many different types of expertise: how we make the T cells, how we deliver the T cells, and the basic research. Science is not a solo sport. To have an impact, we have to bring teams together with multidisciplinary expertise.
I think about that experience where Rich Grady had a complete response to the therapy. It would not have happened without the team all coming together. My research team did the experiments showing that the route of delivery could make a difference for someone with multifocal tumors. It was the clinical team who said, “We have a patient where this could make a difference.” Then it was our translational team who said, “Okay, we'll submit it to the FDA,” and it was the patient who was willing to be part of our team. What's amazing to me is all of the components necessary to make something happen in cancer research.
What do you wish people understood better about glioblastoma research?
Glioblastoma is a really challenging disease. There has been remarkable success with CD19 CARs and B cell malignancy, and just because we're not seeing that today in CAR T cell therapy with glioblastoma, doesn't mean we won't see it tomorrow. It's time well spent because I think that it's something we will solve. Even though there's more to do, I have great hope that we're going to accomplish great things not far off in the future. When I went to clinicaltrials.gov just last year looking at CAR T cell clinical trials for solid tumors, there were more trials going on in brain tumors than any other solid tumor setting. I think that shows our optimism, and that we're not shying away from tough problems.
This interview has been edited and condensed for clarity.
