Reach of CAR T-Cell Therapy Poised to Extend in Oncology

Armin Ghobadi, MD

With improvements to manufacturing processes, efficacy mechanisms, and locating better targets, physicians will be able to extend the reach of chimeric antigen receptor (CAR) T-cell therapy to more malignancies, said Armin Ghobadi, MD.

“CAR T-cell therapy is a really effective treatment, but we need to make it better in terms of efficacy and side effects,” said Ghobadi, assistant professor of medicine, Division of Medical Oncology, Washington University School of Medicine, Siteman Cancer Center. “Additionally, we know that it's really effective for hematologic malignancies, but we need to broaden the spectrum of disease that we go after.”

Currently, there are 2 FDA-approved CAR products on the market—–tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta). Both products are approved for the treatment of adult patients with relapsed/refractory large B-cell lymphoma after 2 prior lines of systemic therapy. Tisagenlecleucel also holds an indication in patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

Lisocabtagene maraleucel (liso-cel; JCAR017), predicts Ghobadi, is likely to be the next CAR T-cell product to join the market.

OncLive: What did you cover in your presentation on CAR T-cell therapy?

In an interview with OncLive^® during the 2018 State of the Science Summit™ on Hematologic Malignancies, Ghobadi discussed the evolution and expansion of CAR T-cell therapy in oncology and how to maximize its application across liquid and solid tumors.Ghobadi: We spoke about the logistics of CAR T-cell therapy, how it works, and why it is revolutionary for patients with hematologic malignancies. We spoke about immune evasion and how the CAR T cell goes around cancer immune evasion. In terms of logistics, how we collect the white cells from a patient to local freezers and then send it to a good manufacturing process manufacturing facility.

Once they are sent to a treatment center, patients usually get lymphodepleting chemotherapy for 3 days, which is typically fludarabine and cyclophosphamide. After a couple days of rest, we infuse them in a way that is similar to blood transfusions. Then, we monitor them for side effects, mainly cytokine release syndrome (CRS) and neurotoxicity. We usually look at the response 1 to 3 months later.

This is a new platform of treatment that is going to revolutionize the way we treat cancer. It has already changed the way we treat patients with hematologic malignancies. As we know, it has been approved in high-grade B-cell lymphoma; there are 2 products that have been approved for that indication. Patients with relapsed/refractory high-grade B-cell lymphoma and pediatric and ALL in patients up to age 25 can get CAR T-cell therapy.

There are adverse events (AEs); CRS and neurotoxicity are the main AEs. The reason that those treatments are given in specific centers is because you need to have experience with managing those AEs. They are almost always reversible. You can treat them with a steroid using interleukin-6 or a receptor-blocking agent like tocilizumab (Actemra). With the combination of those agents, you can manage almost all of them.

Going from blood cancers to solid tumors is one of the more difficult things to tackle. We do have a clinical trial right now with CAR T cells in ovarian cancer. The science of it is evolving. In the next 5 to 10 years, we're going to have more preclinical data and hopefully early-phase clinical trials with effective CAR T-cell therapy for other cancers, such as solid tumors.

When we make CAR T cells, we have to wait. It usually takes about 3 weeks to produce the cells. A patient who needs CAR T-cell therapy has to wait around 4 to 6 weeks to receive it. What about coming up with a CAR T cell that we can give to the patient right away? That is the off-the-shelf or allogeneic CAR T cells. Using a T cell from a donor can cause graft-versus-host disease (GVHD), but there are modifications that we can make to eliminate the risk of GVHD. That includes getting rid of the T-cell receptor (TCR).

Then, you can use a normal donor, take the T cells out, make a CAR T cell, get rid of the TCR, and make an off-the-shelf CAR T cell. There are preclinical data on that approach, and a lot of people are working on that. Off-the-shelf CAR T cells are in early clinical trials. Usually 10% to 15% of patients cannot get CAR T cells because their disease progressed during that waiting time. Off-the-shelf CAR T cells [will overcome those hurdles].

What does the future hold for CAR T-cell therapy?

There are people looking at making CAR T cells using induced pluripotent stem cells, so that you can generate CAR T cells all the time. That will affect making an off-the-shelf CAR T cell. Secondly, it will be significantly less expensive and hopefully become available for patients not just in the United States, but all around the world.One thing is going to be manufacturing CAR T cells faster. That's already happening, even for autologous [stem cells]. Secondly, making off-the-shelf CAR cells that are readily available. The third aspect is increasing their efficacy. For patients with diffuse large B-cell lymphoma or high- grade B cell lymphoma who fail 2 lines of treatment, the chance of response to standard chemotherapy is 25%; the chance of complete response (CR) is 5% to 7%. With axi-cel, for example, in the ZUMA-1 trial, the overall response rate was more than 80% and the CR was around 55%. That's a dramatic improvement, but what about making the 55% CR rate 80% or 90%?

The next thing is the durability of response. We think that 30% to 40% of patients are going to be long-term survivors, but we don't have enough follow-up to say that for sure. It seems that people who are in remission 6 months after getting CAR T-cell therapy stay in remission. That rate is around 30% to 40%. Why not make that 70% to 80% or higher? There is room for improvement.

As I mentioned, it’s a pretty safe treatment. The rate of complication and dying of it is similar to that of autologous stem cell transplant, which is usually 2% to 3%—CAR T cells range from 3% to 5%. The rate of high-grade CRS that requires going to the intensive care unit, or neurotoxicity and brain complications such as seizures and confusion, is relatively high, although almost always reversible. Those are the 2 AEs that we need to look at to see how we can prevent from happening.

Have there been any new developments with liso-cel?

You mentioned financial toxicity. What will it take to drive the cost down?

Lastly, is going to be the way we combine chemotherapy, such as with CHOP, for example…The ideal situation is going to be a combination of those regimens that will be more curative for many patients.Liso-cel is under review. That's most likely going to be the third product that is going to be approved for relapsed/refractory high-grade B-cell lymphoma and large B-cell lymphoma. That's a very effective product with response rates of more than 80% and a CR rate of close to 60%. The 6-month CR ranges from 35% to 40%. All 3 products are very effective, though there are some minor differences.It's going to be a combination of things; one will be the manufacturing process. One of the main drivers of cost is vector production for the transduction of T cells. That cost is probably going to drop dramatically in years to come. When we first did human-genome sequencing, it cost around $3 billion to do a whole-genome sequencing. Right now, you can do it for $1000 to $5000.

Are any other targets under development?

There has been a significant improvement in technology. I am hopeful that that is going to be the case here—–that technology is going to improve vector production, and that vector production is going to get better, ultimately driving down the cost of production. Obviously, competition is always a force in the market. Also, we need to come up with off-the-shelf CAR cells. With off-the-shelf products, we can make CAR T cells for tons of patients with 1 donor. We could be using T cells from 1 donor to make CAR T cells for maybe 10, 15, even 100 patients.One major area that we can improve on is target finding. We went after CD19 because it is a very easy target. The next one that will probably be approved is a BCMA-targeted CAR in multiple myeloma. We don't have a good target in acute myeloid leukemia. It's a really common hematologic cancer and is tough to cure.

With CAR T cells right now, we mainly go after the antigen that is on the surface of the T cell. What about going after antigens that are not expressed on the surface of the tumor cells? It is difficult to make, but people have made it already, and there are groups that are working on doing so. That's one area that's will help—going after not only hematologic malignancies, but also more solid tumors.

The other problem with solid tumors is the negative inhibitory environment that inhibits the function and the penetration of CAR T cells in the tumor microenvironment. There is a lot of research in that area, such as making CAR T cells resistant against the negative environment or even converting a negative inhibitory receptor to a receptor that activates CAR T cells. There are a lot of good, beautiful, and interesting designs that will hopefully make them more effective for solid tumors.