Dr. Yi Lin is a hematologist and chair of the Cellular Therapeutics Cross Disciplinary Group at the Mayo Clinic. She has been studying a new cancer treatment called chimeric antigen receptor (CAR) T-cell therapy, which involves collecting patients’ T-cells and sending them to a central manufacturing center where the cells are genetically modified to direct them against the patient’s cancer. Once modified, the CAR T-cells are sent back to the hospital for intravenous infusion back into the patient.
Lin was the Mayo Clinic site principal investigator for the multi-center study that led to the FDA approval of axicabtagene ciloleucel (Yescarta), a CAR T-cell therapy for certain types of lymphoma. She’s currently co-principal investigator for a clinical trial where researchers are looking at using CAR T-cells in an earlier setting for lymphoma patients and also looking at the effectiveness of CAR T-cell therapy compared to stem cell transplants.
Lin is also the principal investigator in a newly launched clinical trial looking using
CAR T-cell therapy in a frontline setting for lymphoma.
HealthCentral: Can you explain how CAR T-cell therapy works?
Lin: When I explain this treatment to my patients, the comparison I make is that T-cells are very much like the foot soldiers. The immune system is a big part of what can fight cancer. There are types of immune cells that are more like generals—they direct the action—and there are immune cells that function more like soldiers—they do the actual job of killing cancer cells.
T-cells are one of the white blood cells where one of their main functions is that they can kill tumor cells. That’s why T-cells are the focus of a lot of the new developments coming out.
HC: Currently, when are lymphoma patients eligible to receive CAR T-cells?
Lin: The FDA approved CAR T-cell therapy for lymphoma patients who have had at least two prior lines of therapy. So, for instance, a patient who has been diagnosed with B-cell non-Hodgkin’s lymphoma, you would have a first-line treatment, and if you still have residual disease or it comes back, the standard of care is that you would still receive chemotherapy in the second-line setting, and at that point if you reach a partial response or better, which is a 50 percent reduction of your tumor or more, the standard of care would be that you would go on to receive an autologous stem cell transplant [of stem cells that have been harvested from your own body].
Let’s say you receive that second-line chemotherapy, but it didn’t work well, you didn’t see the reduction in your tumor, or your lymphoma continued to progress. That’s a situation where the FDA has approved that patients can be evaluated to receive CAR T-cells.
Or, let’s say, you did OK with your second-line therapy and your lymphoma is at least partially gone. The standard of practice would be to take that patient to autologous stem cell transplant. But if you relapse or have residual disease after that, that would also be a situation where the patient may be eligible for CAR T treatment. (Residual lymphoma consists of cancer cells that have survived the treatment.)
HC: Can you tell me a little about the clinical trials you are heading, and what you are looking in terms of the effectiveness of CAR T-cell therapy for lymphoma patients?
Lin: One clinical trial is looking at, is there a role to giving CAR T treatment earlier and does that potentially give the patients more benefit from that treatment? It’s not proven yet; it’s being studied.
With stem cell transplant, we have decades of experience. We know it’s not going to work as well if the patient hasn’t responded well to chemotherapy. Because with an autologous stem cell transplant, you’re trying to wipe out any residual lymphoma with even stronger chemotherapy. If the lymphoma hasn’t responded to second-line chemotherapy, it’s even less likely to respond to the [higher levels of] chemotherapy needed as part of a stem cell transplant.
So, we’re looking at using CAR T a little earlier, at the time that you’re considering that second-line treatment. As part of the clinical trial, we have a number of randomized controls. So, if the patient has already had first-line chemotherapy, but we don’t know yet how they’re going to respond to second-line chemotherapy, we’re randomizing them at that point. So, a computer decides if the patient will get second-line chemotherapy for stem cell transplant, or CAR T.
We will study the response rate and if the survival is better with CAR T-cell than with stem cell transplant. It’s important to study in a controlled clinical trial setting while trying to control for other potential contributors. So, if you see a difference in outcomes, it’s truly in that controlled setting and not because of another factor.
Another clinical trial that we’re doing is looking at using CAR T even earlier. The standard practice of care for a patient diagnosed with lymphoma is often a combination chemotherapy, typically given in six cycles. In the middle of that first-line treatment, after about two or three cycles of chemotherapy, we typically restage the cancer. This is most commonly done with a PET scan to scan the whole body to see if we’re at least seeing that the cancer isn’t progressing. Hopefully we’re seeing some regression already, but at the minimum we don’t want to see progression. If the treatment is already not working well, we may need to consider changing the treatment.
So, in the second clinical trial, when we do the disease assessment in the middle of treatment, if there’s still residual disease and it hasn’t completely disappeared, we will try to get the patient to CAR T to see if that’s also a good time point to get a response from that therapy.
Obviously, we’re going to do this with a higher-risk lymphoma patient population. With a less-aggressive, lower-risk population, the odds of patients doing well after completing all six cycles is still very good. So, we wouldn’t necessarily take low-risk patients to CAR T cell, because this treatment does have a lot of logistics involved and it’s a more complicated treatment.
HC: What are some of the big challenges you have run into with your research?
Lin: There are several big challenges we’ve faced. One is the logistics of what it takes to get the treatment to patients, that’s a challenge nationally and probably internationally.
First you need to collect the cells from the patient. Before you do this, the patient needs to be off of all treatment for a period of time for those drugs to wash out of their system, so the immune cells are in a better state to go through the manufacturing.
But the patient is someone with active, growing disease in their body, lymphoma, and you’re trying to get them to a period in between drug treatments. You’re trying to get them to collection, which requires working with an apheresis center (where the blood is withdrawn from the patient and their T-cells are collected). And that center is collecting cells not just for CAR T-cell patients, but also collecting cells for people going through stem cell transplant and other treatments.
You also need to work with the company that’s doing the manufacturing; they also need to have a slot that’s available. So, you can see it gets complicated really quickly. We work closely with the transplant practice and apheresis center so we can come up with prioritizations so we can serve both our stem cell transplant patients and our CAR T patients.
HC: How is manufacturing time currently a limiting factor for CAR T-cell therapy? How are researchers working to improve this process?
Lin: Manufacturing CAR T-cells from the patient’s own cells takes time. Depending on the technology being used, the shortest time would be with Yescarta products, but that’s still around three weeks and the average time is around four to five weeks, or longer.
This is a timeframe when patients have active, aggressive lymphoma that hasn’t responded well to prior treatment. When we look at trials, there are a percentage of patients who had their cells collected but couldn’t get their own CAR T-cells infused back because they became too sick. That’s a realistic consideration. How do you manage these patients while CAR T-cells are being made? How do you select the right patients, considering our current technology and the manufacturing time? CAR T may not be the right treatment and they may need to look at other options.
There is research innovation looking at ways to make the CAR T-cells in a shorter timeframe. That’s what’s going to help in terms of potentially getting more patients to the treatment. If we can reduce the manufacturing time, and get the CAR T-cells to the patient in, let’s say, one to two weeks instead of four to five weeks, that could make a difference. That’s a pre-clinical development, so not anything being tested in a clinical trial setting, but researchers are trying to work on that in the laboratory.