Expert Highlights CAR T-Cell Breakthroughs

David Maloney, MD, PhD

The oncology community saw the first FDA approval of a chimeric antigen receptor (CAR) T-cell therapy in August 2017, when tisagenlecleucel (Kymriah) was approved for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refectory or in second or later relapse.

The FDA recently approved a second CAR T-cell therapy, the CD19-directed axicabtagene ciloleucel (Yescarta) as a treatment for adults with relapsed or refractory non-Hodgkin lymphoma.

OncLive: Can you discuss the success that has been seen with CAR T-cell therapy in ALL?

In an interview with OncLive that was conducted between the time of these 2 approvals, David G. Maloney, MD, PhD, a member of the Clinical Research Division, Fred Hutchinson Cancer Research Center, discussed the progress made with CAR T cells, as well as the challenges that still exist in the use of this therapy.Maloney: We are doing most of our research in CAR T cells, and that is what I am the most interested in. The process for a CAR gene-modified T cell is that we take out a patient’s normal resting T cells and separate them in the laboratory into different populations and transduce them with a lentivirus expressing a CAR. That CAR gene now makes an antibody transgene on the cell surface that can then bind the T cell to whatever the target is.

Therefore, the success has been with CD19, but there has also been some success with CD20 and CD22 reported in the past. We have treated many patients at Fred Hutchinson Cancer Research Center and there are several companies. Novartis…has…received FDA approval for tisagenlecleucel, so that is tremendously exciting for the field.

T cells are generally separated from the patient’s blood, sent to a center for production, they return in 3 to 4 weeks, then are given back to the patient upon completing chemotherapy—which is done to make space for the CAR T cells and provide an environment for the T cells to proliferate. They then are a living therapy—they replicate, multiply, and attack the tumor. They are remarkably potent; complete remission rates are in the 90% range in refractory ALL, which is just tremendously exciting. However, they are also pretty toxic.

Cytokine release syndrome (CRS) is kind of a new thing that we must watch for. That can be treated with IL-6 receptor blockade with agents, such as tocilizumab and siltuximab, and often with steroids.

The second major toxicity is a neurotoxicity that can occur after the development of CRS 3 to 4 days later. It is very strange; I have patients develop an expressive aphasia with word-finding problems, which can progress to a coma or, rarely, a cerebral edema and patients can die. There is a low risk of dying from CAR T cells, but it is probably in the 1% to 3% range. These agents are the most potent things we have ever seen, and that is why the field is so excited about it.

However, there is a huge number of challenges. The FDA approved tisagenlecleucel for pediatric young adult ALL through 25 years old, which is difficult to understand. Therefore, technically, a 26-year-old would not be able to get this? We have got to fix that.

Let’s continue on that statement. Could the successes that we have seen with CAR T-cell therapies in ALL be translated to other malignancies?

Obviously, we are doing studies in adults, as well. Toxicities are probably a little greater, but [it is] probably manageable. It is personalized medicine; the manufacturer now has to be in line with the patient to be able to make a product from that patient's cells. You clearly need an experienced team to be able to deal with CRS, and you need an intensive care unit (ICU) team to be able to take care of these patients when they get sick. Overall, [it is] a very exciting time, and now we are trying to translate it to other cancers—breast cancer, lung cancer, and other hematologic malignancies.It will be translated, but each [disease is different]. Antibody-drug conjugates are being used in other diseases already, and bispecific antibodies are not clear—they are active in lymphoma but we are unsure about solid cancers. In solid malignancies, CAR T cells have not been very effective to date; however, the studies are very, very limited at this point. The environment is very inhospitable for CAR T cells in a tumor mass; we are not even sure if they can get in there.

Is there a long road ahead for CAR T-cell therapy?

What important points should community oncologists know about the progress being made in ALL with immunotherapy and CAR T-cell therapy?

It is very likely that we are going to have to combine them with other agents. Trials are already ongoing with combinations of checkpoint inhibitor to make CAR T cells work even better. There is a lot of excitement, but we need more time to see if we can translate this into those areas. If you look at this [progress], it really has been amazingly quick...If you look back, those trials only started a couple of years ago. Therefore, they have taken a custom product to an FDA approval in only a few years; that is tremendously exciting and very rapid. The main take-home message is to refer patients for these treatments at the appropriate time, and not to wait for patients to fail every therapy known to mankind. Really, these treatments that use your immune system work better when you generally have less disease, and have disease that is less immunogenic or beat up from prior chemotherapy. Results are only going to get better as we move studies earlier in the disease course. Of course, they must start in relapsed/refractory patients, but they are going to rapidly move forward.

The next trials in lymphoma are going to be comparing [CAR T-cell therapy] against auto transplant. The next trials in leukemia involve trying to not give all the chemotherapy with induction in high-risk patients. It is important for people to think about these new treatments before last-ditch efforts and refer them to centers that can [conduct] them.

Are there any other significant challenges you would like to see tackled?

However, it is going to be awhile before CAR T cells are going to be in the community oncologist centers. It would be the worst thing in the field to try to immediately bring these out to centers that don’t have the most experience. There is a learning curve, and you need to learn how to manage these patients. For now, think of it like a transplant—refer those patients to transplant centers where most of these studies will be done, at least for CARs. [Immunotherapy trials] are being done in a lot of community centers, you just need an expert leukemia division, a good ICU, and good clinical care.The field in personalized medicine has a lot of challenges. First of all, we have to identify the patients, and the companies will have to step up and reliably make a product in a reasonable time frame. If they can't reliably deliver a product in 2 to 3 weeks, then that is going to be a problem. We will eventually have multiple approved CARs for the same indication, and then we will see differentiation based on how well they work and what their toxicity profile is.

The other point is to say, “All CAR T cells are the same” is totally wrong. Each one of these products has a different costimulatory domain; they are in different cells and they are put in different ways. They may have similar toxicity profiles, but they are different. We need long-term follow-up for toxicity and for outcomes to be able to differentiate these products over time, and then they will win in the marketplace based on performance.