Expert Addresses Toxicity Management for Approved CAR T-Cell Therapies

Frederick L. Locke, MD

Frederick L. Locke, MD

Since the FDA approved 2 chimeric antigen receptor (CAR) T cells for the treatment of non-Hodgkin lymphoma and acute lymphoblastic leukemia (ALL), patients now have more options than before. However, challenges remain in how to manage the toxicities associated with CAR T-cell therapy.

Tisagenlecleucel (Kymriah) is indicated for patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse, as well as for patients with relapsed/refractory large B-cell lymphoma after 2 or more lines of systemic therapy. Axicabtagene ciloleucel (Yescarta) is also approved for patients with relapsed/refractory large B-cell lymphoma following ≥2 prior lines of treatment.

In a presentation during the 2019 Transplantation and Cellular Therapy (TCT) Meetings, given by Frederick L. Locke, MD, it was discussed that physicians now face the challenge of managing the associated toxicities with these therapies. Based on data from pivotal trials, the 2 major types of adverse events (AEs) are cytokine release syndrome (CRS) and neurologic toxicity.

“We’re treating patients in the real world outside of the pivotal trials,” said Locke in an interview withOncLive. “We’re giving CAR T-cell therapy as a standard of care, and in fact, the toxicity rates are similar to the clinical trials that we ran. This is really a manageable toxicity that we are seeing.”

Beyond the 2 FDA-approved CAR T-cell products, research is ongoing for a number of different CAR T-cell therapies.

In an interview withTargeted Oncologyduring the 2019 TCT meeting, Locke, medical director and research director of the Immune Cell Therapy Program and the co-program leader of the Immunology Program, vice chair of the Blood and Marrow Transplant and Cellular Immunotherapy program at Moffitt Cancer Center, discussed the optimal management of CAR T-cell therapy-related AEs.

TARGETED ONCOLOGY:Could you give some background to the history of CAR T-cell therapy?

Locke:CAR T-cell therapy is an exciting cellular therapy. It’s really added a new treatment to our armamentarium against lymphomas and leukemia. CD19-directed CAR T-cell therapy is when a patient’s T cells are removed from their body, engineered with a gene that redirects them all against a singular target—in this case, CD19—and are infused back into the patient. They know where to go—and they go after the lymphoma or the leukemia.

We now have 2 FDA-approved CD19-directed CAR T-cell therapies; one is for both pediatric, adolescent, and young adult patients with ALL, called tisagenlecleucel, and that is also approved for the treatment of [patients with] relapsed/refractory large B-cell lymphoma. We also have axicabtagene ciloleucel, which is also FDA approved for the treatment of relapsed/refractory large B-cell lymphoma.

TARGETED ONCOLOGY:What are the biggest challenges we need to overcome with CAR T cells?

Locke:CAR T-cell therapy can lead to amazing responses that are durable in a subset of patients. We have patients who aren’t responding to any chemotherapy who can go into a complete remission, and up to 40% of patients with refractory lymphoma who aren’t responding to chemotherapy remain in remission after a CAR T-cell therapy for 2 years and counting.

That’s pretty remarkable, but unfortunately, the therapy can cause some serious toxicities. The 2 major categories of toxicity following a CAR T-cell therapy are CRS and neurologic toxicities. One of the main things we need to do as a community is to figure out all the mechanisms that lead to those toxicities and how to prevent them from becoming severe.

We can manage high fevers, but when the CRS leads to low blood pressure or hypoxia, we’ve really gone too far. We have to halt the CRS before it gets to that.

TARGETED ONCOLOGY:What were the key points you made in your presentation for community oncologists?

Locke:The session that I spoke at [covered] the pivotal clinical trials, what the results from these trials were for patients with ALL or DLBCL who were treated with CAR T cells, and what were the toxicity rates. What were the rates of severe CRS and severe neurotoxicity on the different trials, and how did they differ? In fact, one of the reasons that we can’t directly compare those toxicities from trial to trial and from CAR T-cell therapy to CAR T-cell therapy is because of the differences in the construct of the design and of the studies.

I also summarized the new ASBMT Consensus Grading criteria for both CRS and [immune effector cell therapy—associated] neurotoxicity syndrome, which is also called ICANS. This is a new grading criteria we expect investigators and physicians will use to treat these patients and give us a uniform playing field. Previous grading scales were different in how you graded CRS and neurologic toxicity. We now have an even playing field that we can all use.

It is very difficult to compare the toxicities of different CAR T cells, particularly when the patient populations are different—such as in ALL or DLBCL—or in comparing data from trials that use different CAR T-cell constructs. [This is the case] even in similar patient populations, because the designs of the trials are very different.

In addition, it’s very important that we, as a community, embrace the ASBMT Consensus Grading criteria for neurologic toxicities, because it can help us drive how to manage therapies. There are published algorithms on how to manage CRS and neurologic toxicity after CAR T-cell therapy, including both the National Comprehensive Cancer Network guidelines and the CARTOX Working Group guidelines. I encourage people to look those up if they’re in need of help.

TARGETED ONCOLOGY:Moving forward, where do you see CAR T-cell therapies fitting in the treatment landscape?

Locke:We are now using CAR T-cell therapy for patients with relapsed/refractory disease after multiple lines of therapy. Again, in patients with ALL and DLBCL, we’re starting to test out the theory of CAR T-cell therapy earlier in the disease course. Certainly, there are a number of CAR T-cell therapies randomized against a chemotherapy followed by autologous stem cell transplant.

For CD19-directed CAR T cells, it’s going to move up earlier in the disease course. As far as what other CAR T cells become available in other diseases, the next one we expect is for multiple myeloma with a BCMA-directed CAR T-cell product. After that, there is a lot of work to be done to figure out the technologies and problems that exist.

The other major exciting area is testing an off-the-shelf allogenic CAR T-cell therapy. Currently, we are using patients’ own CAR T cells, which may be dysfunctional because of prior therapy. Now, if we can just take off-the-shelf, a healthy donor’s T cells that have become CAR T cells, that could actually change the treatment paradigm and get rid of that waiting period that we have between collection and actually being able to give the therapy to the patients.

TARGETED ONCOLOGY:What advice would you give to a community oncologists?

Locke:Right now, most community oncologists are not using the CAR T-cell therapy. They may be aware of it or have heard of it, but they probably haven’t referred a patient for it yet. The most important thing in the community is to understand that CAR T-cell therapy can work, even for patients who might be older or might be too sick. More importantly, you should send the patient early. Don’t wait until they have failed 3 or 4 lines of therapy. Send the patient for referral early. This therapy can and does work.

There will be more use of this therapy as time goes on. Certainly, our doors are open at Moffitt Cancer Center, and I know there are other large centers around the country [giving this treatment]. Really, the key is to know that this exists for patients with ALL and DLBCL. Refer those patients early; don’t wait until their disease has progressed despite multiple lines of therapy.

TARGETED ONCOLOGY:What CAR T-cell research are you currently involved in?

Locke:We have ongoing clinical trials for CAR T-cell therapy; I mentioned the ZUMA-7 trial. In addition, we’re testing a number of biomarkers that may predict for toxicities, who might relapse, or who might be more likely to respond or not. There is a lot going on in the CAR T-cell space.

In addition, we are studying patient-reported outcomes at our center. We are trying to figure out what the patient who has gone through this CAR T-cell therapy feels. The early results that we presented at the 2018 ASH Annual Meeting showed that patients do very well with CAR T-cell therapy and they have an acute discomfort; however, within 30 days or 90 days, they’re feeling well and even better than their baseline. The therapy is tolerable and there are many other ongoing research projects.

Reference:

Locke FL. Prevention and management of toxicities of FDA-approved CAR T-cell products. Presented at: 2019 Transplantation and Cellular Therapy Meetings; February 20-24, 2019; Houston, TX.