Fred Hutch file
Not many people would describe the best part of their job as the time they had to pull several near all-nighters in a single week.
But not many people get to work on their passion — uncovering the inner workings of the human body while simultaneously developing a technology that could help thousands of people diagnosed with cancer — as a day job.
Fred Hutchinson Cancer Research Center’s Dr. Rachel Perret is one of those lucky few. A postdoctoral research fellow training under the mentorship of immunotherapy expert Dr. Phil Greenberg, Perret spends her days — and sometimes her nights — working toward an “off-the-shelf” version of T-cell therapy.
The type of T-cell therapy Greenberg’s team is developing involves genetically engineering patients’ own immune cells to carry more potent versions of natural immune molecules, known as T-cell receptors, that recognize proteins made by cancer cells but not healthy cells. Such engineered T cells are then transferred back into cancer patients where they are able to better recognize and destroy patients’ tumors. Perret’s broader approach to the already-lifesaving technique could, one day, provide a matched immunotherapy for close to 90 percent of patients with acute myeloid leukemia. Today, nearly 20,000 cases of AML are diagnosed every year in the U.S. and more than 10,000 people die of the disease. Perret’s work could someday apply to other cancer types as well, including lung, ovarian and pancreatic cancers.
Recently, the native New Zealander took a break from her busy research schedule to describe what, exactly, she studies, as well as how she decided to become a scientist and why late nights in the lab are so inspiring.
Can you give me an overview of what you work on?
We’re using T cells, which are a subset of cells from our own immune system, to target cancer and kill it. This has the advantage of being more effective, longer lasting and less toxic than chemotherapy and radiation. Giving a patient one or a couple of doses of these cells could be enough to cure a patient and give them life-long protection against the cancer coming back. We already have some ongoing clinical trials using a particular type of receptor from a T cell that recognizes a piece of the Wilms tumor antigen 1 (WT1) protein, which is a tumor antigen [marker] that’s highly expressed in leukemias and other types of cancer. We’re getting some promising early results with no bad side effects observed, a higher survival rate than with bone marrow transplant alone, and the engineered T cells still hanging around in the patients years later. However, only patients who have the HLA-A2 gene as well as having the WT1 protein in their tumors are eligible for this trial. [HLA genes are involved in immune recognition and determine each person’s tissue type, which is important in transplantation and also for this type of T-cell therapy.] The idea behind my project is to broaden the scope of this therapy to people with other HLA types and who have tumors with different antigenic markers.
How many people have the HLA-A2 gene?
About 40 percent of Caucasians, but in other ethnic groups it’s much less.
When do you see your own work translating to help people?
I’m developing what we call a toolbox of off-the-shelf therapies. We hope to be able to find a panel of about 20 different [T-cell] receptors specific for two tumor proteins: WT1 and Cyclin A1. The plan is then to keep those on hand in the laboratory, and a patient will come in to the clinic and get screened for what antigens their tumor expresses and what HLA type they have. Then we’ll select the receptor that best matches that patient and, in the space of a few weeks, we’ll be able to engineer their T cells and produce the therapy.
As we’re trying to find and thoroughly test up to 20 different receptors, it’s going to take a while to complete the whole project. But the first receptor will hopefully be ready within about a year to go into the clinic [in an early-stage trial].
Will the panel of 20 T-cell receptors cover most AML patients?
If you look at the total U.S. population, we would be able to match close to 90 percent of potential patients — 87 or 88 percent — and we can continue to build on that in the future.
If this panel makes it to the clinic and that’s it, it cures AML — what would you do next?
When you start a Phase 1 clinical trial, you do it in the safest conditions possible. You want to give a therapeutic benefit to the patients, but above all else not have your therapy be toxic or more dangerous than the cancer. In the first trial, we hope there will be some success, but we don’t expect it will be 100 percent.
So the research doesn’t stop there. You keep taking samples of blood from the patients, analyzing them in the lab, figuring out what’s going right and what’s not going so well with your therapy, and then you continue to do research to enhance and improve it. If everything does go well, and we have great success with the first therapy, and we enhance it and make it better — once we’ve got AML covered then we’ll move onto another cancer. There’s really no end to the potential of this therapy.
How did you get interested in cancer research?
When I was in high school, we did a work experience program where we had the opportunity to shadow a professional for a week. I chose to go to the pediatric cancer ward at a local hospital (possibly because I was addicted to the TV show "ER"). I was just blown away by how brave the kids were while they were fighting this terrible disease that was attacking them from the inside. I first thought that I wanted to be a medical doctor and go into pediatric oncology, but as I started my university degree I became fascinated by the immunology lectures and the inspiring researchers who were teaching them. I got the idea that actually working behind the scenes in the lab, inventing the new therapies, was the place where I’d like to play my role, knowing that those therapies get fed forward into the clinic.
How did you end up at the Hutch?
I did an undergrad degree in microbiology in New Zealand. I mainly focused on immunology because I found that so interesting — how it relates to protecting our body from outside attack. Early on, I became captivated by cancer, which is kind of a special case as it attacks our bodies from the inside, and decided I wanted to work toward curing this disease. My graduate thesis was done in a lab in New Zealand that was working on cancer vaccines and that’s where I truly caught the research bug.
I then moved to Switzerland where I did a first postdoc [fellowship] on the role of different immune cell types in cancer. Some of these cells attack cancer cells while others actually help the cancer to grow. I was able to figure out that you can use certain vaccines to get the right balance between these cells. That was a lot of fun and an intellectual challenge, but I didn’t feel it was bringing me very close to helping patients because it was all basic biology with no immediate link to the clinic. When I was looking for my next job, I was searching for labs that had a translational immunology feel to them and Phil being a leader in this field was what drew me here.
If you think about what you were doing 10 years ago, are you doing anything now that you wouldn’t have imagined then?
Ten years ago I was in the middle of my Ph.D. This is exactly the kind of job I would have picked if I was given my first choice, but at that stage I had no idea where I was going to end up. This is pretty much my dream job, working on an interesting and worthwhile project in a great lab with awesome colleagues and being on the frontline of where research meets the clinic.
If you could have any superpower, what would you choose?
I’m not a very patient person, so the superpower I would like is to be able to fast-forward to the end of the experiment and have the answers already. Actually, I suppose I shouldn’t say that, because research is also about the journey, but when you’re looking for cures for cancer you’d often like to speed things up.
What are your favorite memories of life in the lab?
Some of my favorite times in the lab were in grad school where I’d be doing huge, crucial experiments that involved really long days, finishing late at night and starting again early the next morning after only a couple of hours of sleep — doing that for a whole week and feeling so exhausted I thought I’d collapse, but finally getting a successful outcome at the end. Those were pretty great moments.
You describe that as your favorite memory; it sounds kind of daunting!
It’s a wonderful feeling to know that what you’re working on is important and that you have the chance to find out something that no one knew about before. Getting a good result is obviously the best part, but it’s also about the excitement of discovery. Along with that goes the camaraderie of the people around you. I am lucky to have been, and still am, surrounded by other people doing similar work with the same kind of enthusiasm. Had I been alone in the lab it would have been a lot less fun.
Getting those rare successes that we work so hard for is still my favorite part of science. Now the fact that I’m working directly towards the goal of getting therapies into the clinic where they can help patients makes it all the more motivating.
Illustration by Dr. Rachel Perret
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Research Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.
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