Shaughnessy Speaks to the Rapidly Evolving Role of CAR T-cell Therapy in Hematologic Malignancies

Paul J. Shaughnessy, MD, discusses how CAR T-cell therapy is being utilized in hematologic malignancies, challenges faced with this modality, and ongoing research efforts being made to better leverage its use.

Paul J. Shaughnessy, MD

CAR T-cell therapies elicit durable remissions in adult patients with relapsed/refractory non-Hodgkin lymphoma and pediatric patients with acute lymphoblastic leukemia (ALL), according to Paul J. Shaughnessy, MD, who added that several research efforts are underway to reduce associated toxicities and increase accessibility.

“We're still in the early days of CAR T-cell therapy, and treating patients with relapsed/refractory disease can be very difficult,” said Shaughnessy. “We still have a lot to do with this modality. To this end, we want to get these patients referred early so that we can assess [them] and get them on clinical trials when possible. That way, we can continue to advance this therapy and hopefully make it safer and more effective. We also want to develop new, better CAR T-cell therapies in the future.”

In an interview with OncLive during the Institutional Perspectives in Cancer webinar on Leukemia and Lymphoma, Shaughnessy, a hematologist and oncologist, as well as the medical director of the Adult Blood and Marrow Transplant Program at the Methodist Hospital, discussed how CAR T-cell therapy is being utilized in hematologic malignancies, challenges faced with this modality, and ongoing research efforts being made to better leverage its use.

OncLive: What is the role of CAR T-cell therapy in hematologic malignancies?

Shaughnessy: CAR T-cell therapy is a very important new therapy that we have to treat adults with relapsed/refractory non-Hodgkin lymphoma, as well as young adults or pediatric patients with relapsed/refractory ALL. Now, in clinical studies, we're using CAR T-cell therapy to treat multiple myeloma and other forms of lymphoma, as well. We'll see many applications [of this modality] in the future; they are currently under investigation. CAR T-cell therapy for hematologic malignancies is rapidly evolving and [may be used for] solid organ malignancies in the future, as well.

What are the key products that are available, and what are some of the data that support their use?

One product is axicabtagene ciloleucel (axi-cel; Yescarta) and the other is tisagenlecleucel (Kymriah); these are available for adults with relapsed/refractory diffuse large B-cell lymphoma who really have failed all standard approaches and [have no remaining treatment options]. There's a real gap in the availability of treatments for these patients.

CAR T-cell therapy now provides very meaningful responses in these patients, some of which have been very durable, lasting for several months or even years. CAR T-cell therapies are very important in filling this gap in [the treatment of] patients with relapsed/refractory lymphoma. Also, in young patients or pediatric patients with relapsed ALL, again, no standard therapy is available. CAR T-cell therapy is offering durable remissions for a percent of these patients.

What are some of the challenges still faced with this modality?

The biggest challenge we see is that patients who need CAR T-cell therapy can be very sick if they have relapsed/refractory disease, [and their disease] can be rapidly growing. Some of these patients don't have time to have their own lymphocytes collected, genetically engineered, and grown into these CAR T cells. We can lose several patients or be unable to treat them in a timely manner. We are making efforts to overcome that [challenge]. Experimental methods are being used to make CAR T-cell therapy from allogeneic donors where the CAR T-cells will then be available off-the-shelf or in a more timely manner, so that we can treat more patients more quickly.

Also, with these very advanced cancers, we still see many patients relapse, so we are trying to prevent this by making better CAR T-cell therapies. [These efforts] include making the CAR T cells target 2 antigens instead of just 1, augmenting the therapy with other agents that may increase the immune response, or using radiation to treat relapses before or after the CAR T-cell therapy. We're going to see many future advances made to make these therapies more readily available, and hopefully more active and effective in our patients.

What does the safety profile of these therapies look like? What advice do you have for managing patients who go on to develop adverse effects (AEs)?

CAR T-cell therapy does have unique AEs, but they are very well described at this point. We see cytokine release syndrome (CRS); this can be very profound, where patients develop high fevers, hypotension, and need to go to the intensive care unit (ICU). We can use drugs to block the cytokines, such as tocilizumab (Actemra), which blocks interleukin 6 (IL-6), or anakinra (Kineret), which blocks IL-1. We can control some of these cytokine release phenomena by using corticosteroids when we need to, as well.

The neurologic toxicities can be very frightening and profound. Patients can range from acting a little off or maybe have a little tremor, to being encephalopathic, comatose, and having seizures. It can be a very scary time, [although] most of these patients will recover with treatment. We can treat the neurologic toxicity with high-dose corticosteroids to try to get the patients better and control their symptoms until they can recover from the therapy. We're also developing CAR T-cell therapies with “off” switches. Here, we would give another drug that would turn the CAR T-cell therapy off and use this to prevent life-threatening complications from this modality.

As we continue to do research on CAR T-cell therapy, part of those efforts are [dedicated to determining] when it’s best to intervene to prevent these toxicities. Can we do things to prevent or treat toxicities earlier on to prevent them from becoming severe and keep patients out of the ICU? Can CAR T-cell therapy [be received in] the outpatient [setting]? Some advantages exist for patients able to be treated and managed as outpatients throughout their treatment with this modality. If we [take the necessary measures] to safely manage patients in the outpatient clinic, that could be an advancement in the future. Research studies are being done right now to better explore the use of drugs like tocilizumab earlier on, as well as other cytokine blockers and corticosteroids, and how to safely do this. The research will provide answers to many of those questions.

Do you see CAR T-cell therapy being moved earlier in the treatment journey?

I do see CAR T-cell therapy moving up into earlier lines of treatment. That has always been a problem when drugs become approved in the relapsed/refractory setting. These patients are very difficult to treat with any therapy. If we can move an effective therapy up to an earlier line of treatment, it's possible that it may be even more effective. We might be able to rescue more patients before they become refractory. These randomized, controlled studies are already examining CAR T-cell therapy compared with standard of care in adults with non-Hodgkin lymphoma, as well as in those with multiple myeloma. Comparing outcomes with CAR T-cell therapy versus standard-of-care therapies in the first- or second-line setting will help us treat more patients, more effectively, and with fewer AEs—[especially] if we can treat patients earlier on in the course of their disease.

Are any promising agents on the horizon?

Several studies are being done that I am very interested in. The work being done with allogeneic CAR T cells, and the idea of being able to use these therapies off-the-shelf, having them readily available, and potentially just as effective as the current commercially available CAR T cells is exciting; this would be a big step forward. Also, using CAR T cells that are made with natural killer (NK) cells or other types of immune cells may be beneficial in the future, may have fewer AEs, and may be just as effective; this research is in the earlier stages. Additionally, some of the agents we're using to treat or prevent CRS may be helpful in how we control the AEs [associated with] these drugs. I am anxious to see this research move forward; it will be very exciting in the next few years to see a whole new generation of CAR T-cell therapies come to fruition.

Is there anything else that you would like to add?

Referring patients early, calling [cancer centers] to see if we have trials available, and working to get more patients on these trials [is essential]. It can be very difficult to get trials open and to get patients on these trials. We need to keep making those efforts; that's really what's going to advance the field.

Editor’s Note: This interview was conducted before the July 2020 FDA approval of brexucabtagene autoleucel (Tecartus; formerly KTE-X19) for the treatment of adult patients with relapsed/refractory mantle cell lymphoma.

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