Dr Gale Highlights Transplants, Cell Therapies for CLL

Robert Peter Gale, MD, PhD, DSc (Hon), FACP, FRCP, FRSM, Centre for Hematology Research, Department of Immunology and Inflammation, Imperial College London, United Kingdom, highlights transplants and cell therapies, including hematopoietic cell transplants (HCT) and chimeric antigen receptor (CAR)-T-cells, for patients with chronic lymphocytic leukemia (CLL).

Transcript:

I'm Dr. Robert Peter Gale. I'm a hematologist and oncologist. I'm a Visiting Professor of Hematology at the Imperial College London, School of Medicine in London.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

Dr Gale: The issue that we're discussing is the cell therapy of chronic lymphocytic leukemia (CLL). It's an issue that my colleagues and I tackled perhaps more than 40 years ago, when we first started to do transplants—HCT for CLL.

We had some interesting results. I mean, of course we were transplanting people who had advanced disease at a time when we had relatively few drugs to treat CLL.

It's always a delicate balance between the dangers of a transplant and the potential benefits. We had some successes—some interesting successes—but it's use sort of tapered off over the years.

One was the fear of complications of transplants. A second is that CLL typically occurs in older people we wouldn't ordinarily consider for a transplant. Now, we have a number of very effective drugs. Lots more drugs to treat CLL. So transplants died off, I could say. I hate to use that word.

Now, recently there's been considerable interest in chimeric antigen receptor or CAR T-cells. They're being used in a number of lymphoid cancers, lymphomas and related diseases. CLL is a B-cell cancer. It's closely related to lymphomas. So, the question arises: Can CAR T-cells be used to treat CLL? That's really the topic of our review.

OLN: Please briefly describe your study and its findings.

Dr Gale: In the context of HCTs, what we found is that over these years we've been able to reduce the dangers associated with transplants.

Very importantly, we've been able to reduce the intensity of the drugs and radiation that we use, which makes it safer for older persons.

Finally, it's been possible to extend the number of people that can be a donor. So, instead of having to have a perfectly matched sibling, or to have a genetically identical twin, one can now use almost any relative that is half identical. That has sort of reopened the question of what is the role of HCTs in CLL.

After this decline that I described over the last 40 years, we find an uptick in that.

It's also related to the fact that we are seeing CLL in slightly younger people, so more of them are potential transplant candidates.

Our conclusion is this is not a routine treatment for CLL. This is reserved for people that have failed our current therapies. It's especially important in younger persons who, it's unusual, but a person of 20 or 30 or 40 who might be looking at a lifetime of drug treatment. That's the story with HCTs.

The story with CAR T-cells is also somewhat complex, because the way CAR T-cells work is you need to remove T-lymphocytes from the person and then genetically modify them and give them back. In a person with CLL, it's very hard to get the necessary number of T-lymphocytes to take out.

Many years ago, we reported that in fact, the T-lymphocytes from people with CLL are not normal. They are either primarily or secondarily adversely affected by the disease. The challenge of making CAR T-cells against CLL is much more difficult than it is to treat lymphomas.

While there's been some progress and some long term survivors, we are still very much far behind the use of CAR T-cells in treating people with CLL.

Our conclusion is that there are some novel approaches, perhaps in people that we can identify as having a very poor prognosis. Intervening earlier, before their T-cells are completely beat up, might result in a better outcome. Or targeting antigens that we're not currently targeting might result in a better outcome.

OLN: Were any of the outcomes particularly surprising?

Dr Gale: I think what I've described—the accomplishments and the challenges—they're both readily anticipated.

It's very clear that, while this is an exciting area, that these kinds of interventions that I'm discussing—cell therapies of CLL—are really only applicable to a very small portion of people with CLL who tend to be over 60 or tend to be over 65, half of whom actually don't die from CLL.

They die with CLL, being older and having comorbidities like heart disease and diabetes.

A key part of this, aside from the interventions, is trying to improve our ability to predict which people with CLL are going to do poorly. That will help us direct these extraordinary therapies to the right population at the right time.

OLN: What are the possible real-world applications of these findings in clinical practice?

Dr Gale: Will these cell therapies be used routinely? Clearly that's not going to be the case.

Let's talk about transplants. Transplants are going to be done at transplant centers. They're not going to be done in an office in Beverly Hills. They are going to be restricted to physicians with special expertise, both in leukemia and in transplantation.

The transplant part is a technical part. The challenge, as I said, is identifying the correct recipient at the right time.

Now CAR T-cells—The market for CAR T-cells in this particular cancer is relatively small compared to lymphomas, so that very few pharmaceutical companies are willing to make the investment in developing CAR T-cells for CLL. Doesn't make any commercial sense.

The studies that are being done are fundamentally being done at research centers at universities. Now, physicians, we have several licensed CAR T-cell therapies (4 actually) that are directed against B-cells. It does mean that physicians, in theory, could use these products off label to treat people with CLL.

But I imagine this requires special expertise. The average physician is not going to be doing either transplants or giving CAR T-cells to treat people with CLL, at least in the near future.

OLN: Do you and your co-investigators intend to expand upon this research? If so, what are/will be your next steps?

Dr Gale: Although this is not something that's commonly used, as a doctor, as a hematologist, as a physician, we deal on the level of the patient. We don't deal with how many people; we have one person in front of us. If we have someone who is progressing, failing current therapies, it's our responsibility to look for novel approaches.

I think in the realm of transplants, we pretty much know where we're going. I mentioned the innovations such as less intensive pre-transplant therapy, more effective post transplant therapy, better supportive care.

I don't expect any big surprises in the sphere of transplantation. It's really a matter of application.

In the field of CAR T-cells therapies it's a different story, because we need to figure out ways to get our hands on healthier T-cells, either earlier in the disease, or ways to prevent them from what's called T-cell exhaustion from sort of beating themselves to death.

So that's one challenge. The other challenge is at the level of the target. What should be the target, or the targets, of these CAR T-cells? That's an area of active research.

Then, the final one is really fixing those two. Can we develop more effective CAR T-cells, CAR T-cells that are better killers? One, in the area of transplants it's a practical application of what we already know with no big surprises.

In the area of CAR T-cells, it's going to be a series of phase 1 and phase 2 clinical trials trying to improve on the therapy, and trying to select patients at an earlier stage of their disease.