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File photo of Fred Hutch
Today’s approval by the Food and Drug Administration of Bristol Myers Squibb’s liso-cel for the treatment of non-Hodgkin lymphoma is an important step in the development of T cell therapies as potential cancer cures.
Dr. Stanley Riddell, immunologist at the Fred Hutchinson Cancer Research Center, conducted early research on CAR-T cells that contributed to the development of this “living drug,” made by genetically manipulating the patient’s own immune cells to target the cells. malignant blood.
This technology was first licensed to Juno Therapeutics, a spin-off from Hutch, now a Bristol Myers Squibb company. A statement from Fred Hutch regarding the FDA decision is available here.
Prior to this decision, we spoke to Riddell, who recently moved his lab to the Steam Factory, Hutch’s newest research center, where he continues to look for ways to improve immunotherapies. Below are excerpts from this interview, edited for brevity and clarity, on the next generation of T cell therapy.
Q: Now that this technology has led to an FDA-approved drug, what does it hold in store for CAR T cell therapy research?
A: I think the ongoing trials in multiple myeloma are very promising, and I think this will be the next disease that CAR-T cells are going to have an impact on and are likely to be approved in 2021. Once approved , the field will have to determine how to best position the therapy for the benefit of the greatest number of patients. We have a large grant at Hutch with Drs. Geoffrey Hill and Damian Green, as well as researchers at Emory University, to develop next-generation approaches in multiple myeloma.
Q: What about further down the road?
A: For these new therapies against blood cancers, there are still patients who do not respond, or who react initially and then relapse. We are working to understand what underlies these incomplete responses. I think the current data points to several directions in which we can improve this therapy.
The first is the quality of the cells. When we make these cells, we have to take them from the patient, make them with the chimeric antigen receptor, and give them back to the patient. Not all T cells are created equal, and our work in the lab consists of identifying the T cell subsets that are most effective in immunotherapy. Many previous chemotherapy drugs damage the immune system and can affect the ability to develop a highly effective product.
The second problem with blood cancers is that sometimes the cancer can escape because it loses expression of the antigen that we are targeting with the modified T cells. [Antigens are telltale proteins that are expressed, or displayed, on the surface of tumor cells, and are typically the targets that T cells home in on.]
If you are targeting a single molecule on a tumor, especially when there may be billions of cancer cells in the patient, it is possible that some of them have mutated to lose the target, which we call the leakage. ‘antigen. We are working on a variety of strategies to overcome this problem. We designed receptors that would simultaneously target two or even three molecules and that would have improved sensitivity to cancer cells that express very low levels of antigen.
The third area is the tumor microenvironment. In some blood cancers, such as lymphoma, these T cells must enter large tumors and function in this environment. And this can be hostile, both because essential nutrients are consumed by the tumor and are not available to T cells, or because tumors have recruited suppressor cells that inhibit T cell function.
A fourth area in blood cancers is: How can we get these therapies earlier in the treatment? We are currently treating patients after all conventional therapies and transplants have failed. Ideally, we would use T cell therapies much earlier in treatment, and clinical trials to test them are underway.
Finally, the big challenge is how to extend T cell therapy to common solid tumors such as breast cancer, ovarian cancer, lung cancer, and pancreatic cancer? We worked in our lab to identify targets and how to design the best-suited T cells to treat these types of tumors. There is a lot of work going on by many researchers at Fred Hutch to identify T cell receptors for antigens expressed by solid tumors, and several of them are in clinical trials. We have yet to see such dramatic benefits as blood cancers, but I think there is every reason to hope that we can design these cells to make them highly functional. I am optimistic that in the next five years, and hopefully sooner, we will see major progress in this area.
Learn more about Hutch CAR’s T cell research
T cell therapy arose out of bone marrow transplant research. Hutch scientists wrote a key article over 40 years ago.
Riddell drew the world’s attention to the progress of CAR-T cell research at a scientific meeting in 2016.
Researchers are studying the side effects of CAR-T cell therapy and how to mitigate them.
Early indications that CAR T cell therapy may be extended to multiple myeloma.
Improved T cell therapies may come from findings about the tumor microenvironment.
How to assess the risks and benefits of T cell therapy will be used to increase the number of patients who could benefit from it.
Q: Does Fred Hutch in particular have unique tools and skills to get us there?
A: It all starts with science, and I think we are very well positioned at Fred Hutch with exceptional scientists. The second thing is infrastructure, and Hutch is very committed to immunotherapy, which really evolved from our bone marrow transplant program. We have developed specialized manufacturing facilities to design T cells for safe administration to patients. We have made a clinical commitment, through the creation of the Bezos Family Immunotherapy Clinic, which has been specially designed to test cell therapies in cancer patients. Dr. David Maloney, the medical director, has put together an incredible team of doctors, nurses and data managers who allow us to do these sophisticated trials and learn from them.
I want to point out that Fred Hutch is one of the best scientists in the world. I’m not just talking about the immunology group. We have fantastic basic scientists, tumor cell biologists, and computer biologists. The creation of the Integrated Immunotherapy Research Center brings together scientists from all these disciplines to develop improved immunotherapies.
Q: Right now, you are sitting in a new lab in the Steam Factory. What does this new localization do for your efforts?
Well, I am a firm believer in the need for teams to tackle really difficult scientific problems. This was not always the case in science. When I started you could have your own small lab and work largely in isolation. But now that the technologies are so complex and diverse, it is really difficult for a single lab to master all of this and stay on top of the knowledge that is being created in the field. So it’s really important to bring scientists together.
The environment in which you bring scientists together is also important. The Steam Factory was designed in many ways to bring together groups of scientists working in the fields of transplantation, tumor immunology, cell therapy, gene therapy, and computational biology in open laboratories . And all of these disciplines are critically important. I think this environment is visionary.
People often talk about ideas and collaborations that start at the coffee stand, over a beer or in a social environment. If you go to work and close your office door, you close yourself off to information and interactions with your colleagues who can help you in your research. The Steam Factory is designed to promote interactions between faculty, postdoctoral fellows and students from all disciplines. I believe this will be the key to new discoveries.
Note: Fred Hutch scientists played a role in the development of these discoveries, and Fred Hutch and some of his scientists may benefit financially from this work in the future.
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