Perl Highlights Latest CAR T-Cell Therapy Advances

Alexander E Perl, MD

Alexander E Perl, MD

The addition of the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah) in acute lymphoblastic leukemia (ALL) has transformed the treatment paradigm, explains Alexander Perl, MD.

“Historically, we have had no effective salvage therapies for ALL,” Perl said. “Patients were either cured with frontline therapy or relapsed with no ability to make them better. We could get short-term responses to chemotherapy, but not long-term benefit, except in rare cases.”

Tisagenlecleucel was explored in the pivotal ELIANA trial, which showed that the therapy induced an overall remission rate of 81% in children and young adults with relapsed/refractory B-cell ALL. Following these findings and tisagenlecleucel’s August 2017 FDA approval, researchers continue to investigate the potential of CAR T-cell therapy against other targets and malignancies.

OncLive: CAR T-cell therapy was recently named ASCO’s Cancer Advance of the Year. How has this treatment changed the paradigm for hematologic malignancies, such as ALL?

In an interview with OncLive, Perl, an associate professor of medicine at the University of Pennsylvania, discussed the implementation of CAR T-cell therapy in ALL and other advances with this unique treatment across the spectrum of hematologic malignancies.Perl: The CD19-directed therapies have really changed that process, whether it’s panitumumab (Vectibix)—which is an antibody that targets CD19 and directs T cells to it—or more recently, CAR T-cell therapies. Now, we are seeing both high rates of response and much more durable responses. In particular, with CAR T-cell therapy, not all of these patients need a subsequent transplant because patients who get durable responses and persistence of their CAR T cells can live without additional therapy in sustained remissions.

Can you comment on the long-term follow-up of tisagenlecleucel in the ELIANA trial?

That has really been a game changer for ALL. It’s also been exciting that patients who have had salvage therapy and have not responded to it continue to respond to CAR T-cell therapy. Having a different modality that works by such a different mechanism has really opened the doors to real treatment outcomes that we couldn't have imagined years ago. The most exciting thing about the ELIANA study showed that you can do [the treatment] everywhere. When you have the training to look after these patients, it doesn't have to be from a single-center treating their own patients who get referred in. Generally, studies like that are very exciting but may have very “cherry-picked” data. What was eye opening about the ELIANA study was that you could track how many patients went in from start to finish and see, of the patients referred, how many were collected, and how many were infused, and get a sense of the whole treatment package compared with just how likely this therapy is going to help patients.

What other CAR agents are being explored in ongoing clinical trials?

What hematologic malignancies will we begin to see CAR T-cell therapies enter in next?

The fact that toxicities were very uniform between the single-center data and also the multicenter data has been encouraging. This is highly specialized therapy though, and physicians need a lot of training on it. There is a learning curve to it. These are durable responses and, while it’s true that not everyone has seen long-term benefit, the rates of long-term benefit are reasonably high enough to say that this is significant in terms of the objective benefit. For ALL, there has been interest in patients who lose response to CAR T-cell therapy, and one mechanism of resistance has been loss of expression of the target of the CAR T cells. The other disease that’s been very interesting in terms of development of CAR T-cell therapy has been myeloma, where there has been some development of CD19-targeted therapies, but B-cell maturation antigens (BCMA) have been where a lot of the action seems to be happening. Though BCMA is still in early stages of development, myeloma practitioners are seeing quite a bit of real treatment benefit.We're already trying to look to see if acute myeloid leukemia (AML) can be treated with immunotherapy, and the hardest challenge there is deciding which antigens to go after. There were data presented at the 2017 ASH Annual Meeting by City of Hope researchers looking at CD123-directed CAR T-cell therapies. There have been centers looking at that, including the University of Pennsylvania. CD33 has been looked at and other antigens, as well.

One of the challenges is defining an epitope to design a CAR that is unique to the leukemia and isn't shared with either normal tissues or normal hematopoietic cells, so that you get a therapeutic index of the treatment and avoid off-target toxicity. Though it’s much harder to design an AML CAR, our hope is to be able to because the incidence of AML is much higher than ALL and it currently curates relatively low in that disease.

What other challenges are we seeing with CAR T-cell therapy?

In terms of other hematologic malignancies, they are approved for diffuse large B-cell lymphoma, but that’s only a fraction of all the cases of lymphoma that are seen. Certainly, there's interest in other types of B-cell lymphomas that could benefit from the same approach, given how ubiquitous CD19 is on B-cell malignancies.The big problem is how to make T-cell therapy safe for patients and available everywhere. That has been a real challenge, because cytokine release syndrome—having seen it firsthand—is quite traumatic and can be life-threatening. The neurotoxicity is unpredictable, and we don't currently have an appropriate therapy to fully mitigate its complications—particularly, the products that can be associated with cerebral edema where the neurotoxicity can be really quite dangerous.

We're still trying to figure out our best supportive care practices and trying to figure out ways we can optimize patients to reduce the risk of these toxicities so that it’s less likely the patients will need hospitalization for management of toxicities remote from the administration of the product. We’d also like to see if we can extend this therapy to more patients and see a benefit.

Finally, how can we achieve durable responses? There are patients who get responses and then lose responses. There are patients who never get a response in the first place. Why is it that we're not seeing more uniform and durable responses? That has been a big question in the field, and we're still trying to optimize our approach both in terms of the design of CAR T cells themselves and also the selection of patients for these therapies.

Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Eng J Med. 2018; 378:439-448.