Training T Cells to Attack Cancer
Five Questions with Pawel Muranski, Director of Cellular Immunotherapy at Columbia University Medical Center
The recent FDA approval of CAR-T cell therapy--the first cancer treatment that genetically engineers a patient’s own immune cells--may represent the beginning to a whole new approach to treating cancer using cells from the patient's immune system.
Researchers like Pawel Muranski, MD, director of cellular immunotherapy at CUMC, Herbert Irving Comprehensive Cancer Center, and NewYork-Presbyterian Hospital, are working on multiple ways to use a patient’s T cells to attack cancer and to fight infection.
Dr. Muranski worked with immunotherapy pioneers Nicholas Restifo and Steven Rosenberg at the National Cancer Institute before coming to Columbia University Medical Center in 2017. He is now setting up a laboratory to manufacture immune cells for patients at NYP/CUMC participating in clinical trials.
We recently talked with Dr. Muranski about CAR-T therapy and the future of cell-based cancer treatments.
Q: How does CAR-T therapy work?
A: There are two components that make the therapy work. One is the massive number of cells that can potentially be delivered to attack cancer. The other component is genetic engineering.
CAR-T cells are T cells that are taken from the body of the patient and engineered in the lab so they produce a completely artificial molecule that can recognize certain “flags” called antigens on cancer cells. In the case of the Novartis therapy, the engineered T cells recognize the CD19 antigen on the surface of cancerous B cells.
The engineered T cells are extremely powerful and completely eliminate all cells that express CD19, including normal and cancerous B cells.
Q: The Novartis therapy has been approved to treat a specific type of leukemia, acute lymphoblastic leukemia. Can CAR-T therapy be used to treat other types of cancer?
A: CAR-T cells directed against CD19, like the Novartis therapy, only have the potential to work in cancers that affect B cells (e.g., non-Hodgkin’s lymphoma and chronic lymphocytic leukemia).
But there’s been an explosion of research on all types of CAR-T cells. There is quite a bit of very promising data on CAR-T cells that detect the B-cell maturation antigen (BCMA), which is expressed on the surface of affected B cells in multiple myeloma. Other CAR-T cells are being developed for a range of antigens, for example, CD123, CD33, and CD20, that are expressed on cancer cells in other blood cancers.
Q: All these are cancers that affect blood cells. Can CAR-T work against solid tumors?
A: The general problem with immune therapies of cancer is that there are relatively few safe targets. We need to target a molecule that is only expressed on cancerous cells rather than on every other vital tissue.
Most of the safe targets we have currently are in hematological malignancies, because cells originating from the bone marrow, hematological cells, express many unique molecules that are not found in any other parts of the body. We cannot easily target something that is expressed in the tumor and in the brain, for example, because the normal cells will be killed along with the cancer cell.
It is much more difficult to target solid tumors with CAR-T cells. Solid tumors are not the primary target of the immune system and they may not have very good molecules on their surface that are easily targetable.
So far the experience with targeting solid cancers with CAR-T cells is relatively limited and relatively disappointing.
Q: Are there other ways T cells could be manipulated to better attack solid cancers?
A: Yes, and that’s something I’ve been working on for 10 years. My biggest research interest is to target other cancers with other types of T cells that recognize tumor antigens in a more natural way than CAR-T cells.
T "helper" cells, for example, are relatively unexplored as factors targeting cancer, but emerging data suggest that they can be really very powerful. They may be the missing link in improving the efficacy of other immunotherapies in cancer.
T helper cells allow us to target cancer antigens that are not just on the surface of the cells, but also inside the cells. This is how normal T cells in the body typically recognize infected cells or cancer cells. Antigens inside cells are processed in a certain way so T helper cells can detect them.
That is the advantage of using normal T cells over the CAR-T cells, and I think the majority of cancers can be targeted with T helper cells rather than with CAR-T cells.
Q: Can T cells be used to treat other conditions besides cancer?
A: Yes. People with compromised immune systems, including people who have received an organ transplant, could be helped with T cell therapies.
We all have viruses in our body that are normally kept in check by a healthy immune system. But the immune system is suppressed in transplant patients, and there is a high risk of virus reactivation. This reactivation can become very serious and can lead to very difficult complications.
At the National Institutes of Health, I developed a protocol aimed at preventing viral reactivation. We tested the safety of infusing donor-derived T cells primed to recognize certain common viruses (CMV, EBV, adenovirus, and BK virus) into patients immediately after transplantation. Reactivation of viruses can happen very early, so we wanted to completely suppress this reactivation rather than wait for full-blown severe disease.
We discovered this procedure is relatively safe, with no increase in transplant complications. We are going to move to Phase 2 of this trial at NIH soon, and it is these types of therapies we will be developing at NYP/Columbia when our new cell manufacturing lab is ready.
I arrived in June this year and building my team is my first task. I hope within a year we should have a clinical product for use in a patient.
Dr. Muranski also is an assistant professor of medicine at CUMC and a principal investigator at the Columbia Center for Translational Immunology.