File photo of Fred Hutch
Today’s Food and Drug Administration license for Bristol Myers Squibb liso-cel for the treatment of non-Hodgkin’s lymphoma is a milestone in the development of T-cell therapies as potential treatments for cancer.
Dr Stanley Riddell, an immunologist at the Fred Hutchinson Cancer Research Center, conducted an early T cell T-cell study that contributed to the development of this “live drug,” which was genetically engineered to protect the patient’s own immune cells. to target malignant blood cells.
That technology was first licensed to Hutch spinoff Juno Therapeutics, which is now Bristol Myers Squibb company. Fred Hutch ‘s statement on the FDA decision is available here.
Before that decision, we sat down to talk to Riddell, who recently moved his lab to Steam Plant, Hutch’s latest research facility, where he looks for ways to develop immunotherapies. Below are excerpts from that interview, edited for brevity and clarity, on the next generation of T-cell therapies.
Q: Now that this technology has produced an FDA-approved drug, what’s next for CAR-T therapy research?
A: I think the ongoing tests in multiple myeloma are very promising, and I think that is the next disease for which CAR T cells will be affected and which are likely to be approved in 2021. Once approved. , the field needs to determine how best to deliver the treatment to the benefit of the greatest patients. We have a large donation at the 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 treatments for blood cancers, there are still patients who do not respond, or who respond first and then relapse. We are working to understand what these incomplete responses are. I think the current data indicate in a couple of guidelines where we can improve this treatment.
The first is the quality of the cells. When we manufacture these cells, we need to remove them from the patient, innovate them with the chimney antigen receptor and return them to the patient. Not all T cells are the same, and our work in the laboratory is to identify the subsets of T cells that are most effective in immunotherapy. A lot of previous chemotherapy damages the immune systems and may affect the ability to develop a highly effective result.
The second problem in blood cancers is that the cancer can sometimes escape because it loses a sense of the antigen we target with engineered 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 the patient may have billions of cancer cells, it is possible that some of them may have gone around to miss the target, which is called we escape antigen. We are working on a number of strategies to overcome this problem. We have designed receptors that simultaneously target two or even three molecules and have improved sensitivity of cancer cells expressing very low levels of antigen.
The third area is the microenvironment of the tumor. In some blood cancers such as lymphoma, these T cells must enter the massive tumors and function in that environment. And that can be hostile, both because the tumor eats essential nutrients and is not available for the T cells or because the tumors have recruited suppressive cells that inhibit cell function- T.
The fourth area in blood cancers is: How do we take these treatments earlier in the course of treatment? Currently we have been treating patients after all conventional and referral treatments have failed. It would be better if we used T-cell therapies much earlier in the course of treatments, and clinical trials to confirm this are ongoing.
Finally, the big challenge is how do we extend T-cell therapy to common solid tumors such as breast cancer, ovarian cancer, lung cancer, and pancreatic cancer? We have worked in our laboratory to identify targets and how you can design T cells that are better suited to deal with these types of tumors. Much work is underway by many researchers at Fred Hutch to identify T-cell receptors for antigens induced by solid tumors, and several of these are moving into clinical trials. We have not yet seen such amazing benefits as we have seen the blood cancers, but I think there is every reason to hope that we can engineer these cells in ways that would make them very functional. I am hopeful that within the next five years, and hopefully sooner, we will see great progress in that area.
Read more about Hutch CAR T-cell research
T-cell therapy emerged from research on bone marrow transplantation. Hutch scientists wrote a major paper more than 40 years ago.
Riddell drew worldwide attention to advances in CAR T-cell research at a scientific meeting in 2016.
Researchers are studying the side effects of CAR T-cell therapy and how they can be mitigated.
The first signs that CAR T-cell therapy may be extended to multiple myeloma.
Improved T-cell therapies may result from findings about the tumor’s microenvironment.
How T-cell weights and temperature gains are measured to increase the number of patients who could benefit from it.
Q: Does Fred Hutch have special tools and skill sets to get us there?
A: It all starts with science, and I think we are in a good position at Fred Hutch with exceptional scientists. The second is the infrastructure, and the Hutch has made a strong commitment to immunotherapy, which really came out of our bone marrow transplant program. We developed specialized manufacturing facilities to engineer T cells for safe administration to patients. We have made clinical commitment, through the creation of the Bezos Family Immunotherapy Clinic, which was specifically designed to test cell-based therapies in cancer patients. Dr. David Maloney, the medical director, has built an amazing team of physicians, nurses and data managers that allow us to perform these solemn tests and learn from them.
I want to emphasize that Fred Hutch has some of the best scientists in the world. I’m not just talking about the immunology group. We have amazing basic scientists, tumor cell biologists, and computational biologists. The creation of the Integrated Immunotherapy Research Center brings together scientists from all of these fields to develop advanced immunotherapies.
Q: Right now, you’re sitting in a new lab at the Steam Plant. What will that new locale do for your endeavors?
Well, I strongly believe that teams need to be built to deal with very difficult scientific problems. It wasn’t always like that in science. When I first started out, you could have your own little lab and work largely on their own. But now that technologies are so complex and diverse, it is very difficult for one laboratory to master all of these and stay at the very beginning 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 Plant has been designed in many ways to bring together groups of scientists working in transplantation, tumor immunology, cell-based medicine, gene therapy and computational biology in open laboratories. . And all of these topics are very important. I think this environment is visual.
People often talk about ideas and collaborations that start at the coffee center, over a beer or in a social environment. If you go to work and close your office door, you exclude yourself from information and interaction with your colleagues that will help your research. The Steam Plant is designed to encourage interactions between faculty, postgraduate scientists and students across disciplines. I believe this is the key to new discoveries.
Note: Scientists at Fred Hutch have been involved in the development of the findings, and Fred Hutch and some of the scientists may benefit financially from this work in the future.