Research Remains Focused on Bringing CAR T-Cell Therapy to Solid Tumors

Mark Leick, MD

The development of CAR T-cell therapies has created new later-line treatment options for patients with various hematologic malignancies, and ongoing research aims to bring these types of therapies to patients with solid tumors, according to Mark Leick, MD.

“We’ve already seen the benefit of [CAR T-cell therapy] in [patients with] B-cell malignancies, but we're starting to [explore CAR T-cell therapy] in lots of solid tumors. We will solve those engineering challenges, and it will come to solid tumors,” Leick said.

In an interview with OncLive^®, Leick discussed how the emergence of CAR T-cell therapies have affected the treatment paradigms in various hematologic malignancies, expanded on how persisting challenges with the use of this type of treatment are being addressed, and detailed research into the use of CAR T-cell therapy in patients with solid tumors. Leick is a physician investigator for the CCR Group C Monthly at the Mass General Research Institute, an assistant professor of medicine at Harvard Medical School, and an assistant in medicine in Medicine-Hematology/Oncology at Massachusetts General Hospital in Boston.

OncLive: Could you expand on the evolution of CAR T-cell therapy in the treatment of patients with hematologic malignancies?

Leick: [The first] CAR T-cell therapy [received] FDA approval in 2017, and it has been transformative in hematologic malignancies. We now have patients who were treated on initial trials who are over 10 years [removed] from their therapy and living their lives, [including] pediatric patients who've been completely cured.

There is not a lot of awareness in the general public and even [among some] community physicians about the importance of [CAR T-cell] therapy and how it's expanding so rapidly. Part of [our ongoing] effort is to help ensure that people know that this therapy exists and is available, and [we should be] referring patients earlier. Sometimes we see patients who have advanced-stage lymphomas, and it can be challenging to treat when people have a lot of other complications. [CAR T-cell therapy] is available, and it's coming to a lot of other cancers.

What helped guide the development and implementation of CAR T-cell therapies in the treatment paradigm for patients with different B-cell malignancies?

CAR T cells are targeted against a tumor-specific antigen, and the most successful of those antigens is CD19, which is a marker that's on B cells and expressed in a lot of different types of lymphomas. Because of that, [CAR T-cell therapy] has had success in all these B-cell cancers. Some of the first approvals were in acute lymphoblastic leukemia [ALL], which is a B-cell malignancy, and also in diffuse large B-cell lymphoma [DLBCL]. Since then, there have been approvals in other B-cell malignancies, such as mantle cell lymphoma or the less aggressive follicular lymphoma.

In the last couple of years, we've gotten 2 FDA approvals in multiple myeloma, which is a plasma cell disorder, [meaning] mature B cells. Essentially, we've been able to target the full spectrum of cancers that are mediated by these B cells. Part of the reason for that is the expression of the target is on normal cells in the body, but it's only on normal B-cells, which you don't need those to live. We can artificially replace the immunoglobulins that B cells normally make. We can just give that to patients, and they do fine.

What are some of the challenges and limitations currently associated with CAR T-cell therapy? Is there any ongoing research to address these unmet needs?

It seems like every major biotech company in the world has a large division working on CAR T-cell therapy, so it's a worldwide effort to address a lot of the [current] challenges. Logistically, [administering CAR T-cell therapy] is challenging. Every single CAR T-cell therapy, except for some that are in clinical trials, is manufactured individually for each patient. It's a huge challenge to collect a patient's T cells, send them for manufacturing, and have them returned. Everyone's T cells behave a little bit differently, so that's one challenge. The costs involved in [manufacturing CAR T-cell therapy] are also quite large. That can be challenging for payments and for individuals to get insurance approval.

Other challenges include trying to get CAR T-cell therapy to work in other diseases. Our center and others are working on solid tumors. For example, we have clinical trials in glioblastoma and other solid tumors. [CAR T-cell therapy] hasn't been as effective as we would like [in solid tumors], but there is hope on the horizon.

Investigators at Stanford have recently been using CAR T-cell therapy for a pediatric brain tumor called diffuse intrinsic pontine glioma. They infuse [the treatment] directly into the brain, and they've seen some miraculous results. [CAR T-cell therapy for patients with solid tumors] is coming, and I think it's going to work in those diseases. However, it is just going to take time, and lots of people are working on it.

The last challenge is trying to [create effective] allogeneic products. Rather than making CAR T-cell therapy individually for every single patient, could we have product that we can just pull out of the freezer and give to anyone? I like to compare it to blood donation. When blood donation was invented, we had to learn all about the typing, find donors, and set all that up. That's a little bit what we're doing now, but with modern genetic technologies to try to prevent cross tolerance, graft-vs-host disease, and other things in order to make [allogeneic CAR T-cell therapies] work for other individuals.

Could you explain the patient selection criteria for CAR T-cell therapy for those with hematologic malignancies and any factors that are considered?

The different FDA-approved CAR T-cell therapies have specific requirements [for their respective indications in different malignancies]. As we gain experience and comfort with cancer therapies in the last line, meaning in patients who are relapsed and refractory to every [available] cancer therapy, then we can try [CAR T-cell therapy] in earlier lines.

Some of these CAR T-cell therapies, for example in DLBCL, are being tried very early on as part of first- or second-line therapy. [Determining when CAR T-cell therapy is an option] depends on the specific disease and what therapies patients have gotten before.

In terms of patient selection, there are a few different types of CAR T-cell therapies that all have different behaviors. If someone is older and frailer, we might steer them towards one of the other CAR T-cell therapies [or another option] that is less toxic, but perhaps ever so slightly less effective. We base [treatment selection] a little bit on a patient’s age, comorbidities, and their level of interest in dealing with a more intensive therapy.

Could you expand on specific strategies for managing or monitoring adverse effects (AEs) associated with CAR T-cell therapies?

When the first pediatric patient was treated, who is now more than 10 years out, she had a scary syndrome that we've since called cytokine release syndrome [CRS], where her whole body got very inflamed. At the time, they didn't know what it was, and they had measured blood markers called cytokines, and they found that interleukin 6 [IL-6] was really elevated, for which there was already a drug available; they were able to use that, and the is our first-line management for CRS in the clinic.

There are 2 main types of toxicities that we see with CAR T-cell therapy. One is CRS, where patients get inflamed and have high fevers. The other one is neurologic toxicity. People can be confused, they can be very sleepy, and sometimes in its more severe form, [neurotoxicity] can cause things such as seizures and brain swelling. Over the years, we've gotten quite good at managing all these AEs. There are specific algorithms in place that we follow very closely, and there are more drugs at our disposal to manage these toxicities.

We're also working on a number of clinical trials [evaluating] preventative agents to prevent all the toxicity. One big push for us is trying to do more infusions [of CAR T-cell therapy] outside the hospital. That's better for patients and better overall for hospital capacity issues. We've started treating some patients, at least partially, as outpatient procedures, and then if there are any complications, they can come into the hospital. Those are some of the main toxicity concerns and how we deal with them.

Regarding financial toxicities, what is the hope for creating more accessibility to these treatments in the future?

A lot of modern oncologic therapies are quite expensive, and many of them are not curative. In our patients with lymphoma, we know that CAR T-cell therapy [could be] curative in about half of patients, so it’s a one-and-done [treatment]. Especially in pediatric patients who have ALL, you give them CAR T cells and their cancer is hopefully gone for the rest of their life. That probably makes financial sense compared with a lot of other therapies that are given on an ongoing basis.

In terms of some of the strategies to make CAR T-cell therapy more accessible and cheaper around the world is if we could [develop better] off-the-shelf, allogeneic CAR T-cell therapies, where we have healthy donor cells to give. That would decrease the manufacturing complexity because it wouldn't have to be done for every individual patient.

There are some other strategies in the near term [aimed at making] incremental [improvements]. Some companies are working on shorter manufacturing times, which would make CAR T-cell therapy a little bit more accessible to patients who have aggressive disease [since] they would be able to get it faster, and it will hopefully reduce costs in terms of manufacturing.

How do you see CAR T-cell therapy evolving in the coming years? What applications could these therapies have outside the oncology/hematology space?

One of the more surprising things that people didn't think about is that CAR T cells are already demonstrating a strong impact [for patients with] autoimmune disease. There are early-phase clinical trials where CAR T-cell therapy has shown benefit in [for patients with autoimmune conditions] such as lupus, myasthenia gravis, and other rarer [conditions] like anti-synthetase syndrome.

We've been using some cancer drugs as hand-me-downs in rheumatologic autoimmune diseases. [For example] rituximab [Rituxan], which targets B cells, has been used for many years in all these autoimmune diseases. However, it's becoming increasingly clear that CAR T cells superior and [could] eliminate these autoimmune diseases. Those trials are coming rapidly. The greatest thing is, it seems like [patients] with autoimmune diseases are not having the toxicity that we see with CAR T-cell therapy [in patients with cancer]. Patients might have a small fever, but other than that, it mediates a complete remission for them.

We've only dipped our toes into what CAR T cells can do. We're starting to see that they might be able to benefit [patients with] a lot of different diseases. Even for a disease such as Alzheimer's, you could redirect engineered cells to eat up damaging protein plaques or things like amyloidosis. Engineered cells have a bright future.