Transcript: Ian Flinn, MD: There are incredibly exciting data that I think is probably going to change outcomes for a lot of patients with mantle cell lymphoma, but not all are candidates for CAR [chimeric antigen receptor] T cells. We still have a few other new therapies that are being developed outside the cellular therapy world. What excites you most, Javier? Do you have anything else that’s exciting you in mantle cell lymphoma? Is there any other specific therapy?

Javier Munoz, MD, FACP: Beyond the presentation from Michael Wang, particularly when it comes to that construct that will be presented during this ASH [American Society of Hematology Annual Meeting & Exposition] in 2019, there are some other cellular therapies that look attractive. Actually, we have collaborated on some of them. The ACTR, which stands for antibody-coupled T-cell receptor, is another cellular therapy that looks attractive. It’s different. The construct is going to have a CD16—a costimulatory domain and an internal domain that is going to stimulate T cells. The CD16 is going to engage the FC [fragment crystallizable] domain of a monoclonal antibody, so the specificity comes from the monoclonal antibody you choose.

We have been part of a trial that uses rituximab, because we’re targeting CD20, to see if there are good responses in patients with multiple subtypes of aggressive B-cell lymphomas, including diffuse large B-cell lymphoma. Actually, that was the most common subtype studied. Mantle cell lymphoma was allowed as well. I’m attracted to that technology, and we will have to see if the data pan out.

Ian Flinn, MD: I’m a little biased because I’m investigating a similar product using a CD28 construct with the same approach. I think it’s an exciting approach because you can combine it with any antibody. You can treat mantle cell lymphoma. You can treat breast cancer. At any rate, it’s an interesting approach. Tycel, is there anything else that you think is exciting in mantle cell lymphoma? What is your take on the bispecific antibodies?

Tycel Jovelle Phillips, MD: There are bispecific antibodies, or BiTEs, as we commonly refer to them. I like to call them a poor man’s CAR T-cell therapy. They are utilizing our immune system to try to get tumor responses. My experience of using some of the agents that we have currently is in the clinical trials. We’ve seen some good responses, even in mantle cell lymphoma patients. Most of these patients are very refractory and very similar to what we see with the patient population of ZUMA-2. With this, cost isn’t as much of an issue compared with CAR T-cell treatment, at least until we can minimize some of the cost on that. Obviously, regarding the toxicity profile, you do see some CRS [cytokine release syndrome], but not to the degree that has been reported in some of the CAR T-cell trials. It’s a very exciting time, as far as utilizing our immune system. It seems like time goes back. We sort of reinvented the IL-2 days, which means better treatment and better tolerability, hopefully.

Ian Flinn, MD: All these approaches are trying to get around the chemotherapy resistance using immunologic therapy, and it’s very exciting. Bijal, what are you most excited about in terms of mantle cell lymphoma, beyond what you’ve already talked about?

Bijal Shah, MD: I was going to say everything. I’m excited that we’re moving biologics forward. I think we intimately understand that part of mantle cell lymphoma is not just cell cycle dysregulation but also impaired DNA-damage response. We know that intuitively, and we know that when patients relapse, their chemotherapy responsiveness is decreased because we’re selecting those particular clones that are going to do worse.

Now we’re putting it into practice, so I’m extraordinarily excited that this is the direction we’re moving in. In terms of specific therapies, building on the immune therapy concepts, I really like the approach of allogeneic CAR T-cell therapy, whether it’s the CAR-NK [CAR—engineered natural killer cells] or the Precision BioSciences CD19-directed CAR T-cell treatment. I like it because, for the first time, we’re starting to think about cellular therapy more as a drug. “I’m going to reach in the fridge. I’m going to give you some of this. If there’s still some disease, I’m going to give you some more, or maybe I’m going to target a different antigen. I’m going to give you some of this.” It’s this product that’s—for lack of a better term—infinitely available, so we can reach into a fridge and deliver. That, to me, is a really cool concept.

There are other things like the CD47s, the CD19s, and other targeted approaches, which not only may be applicable in their own right, but they are actually ones we can build onto all the therapies that we’re talking about. We’re not talking about sequential; we’re talking about new combinatorial biological approaches.

Ian Flinn, MD: Well, this has been great. Before we conclude, I’d like to get final thoughts from each of our panelists. Tycel, let’s start with you.

Tycel Jovelle Phillips, MD: For all of us, this is a very exciting time. There are a multitude of novel ways we’re trying to manage our patients and a plethora of new drugs. Some are a bit repetitive, but that gives us various options that we didn’t have before in mantle cell lymphoma. An NHL [non-Hodgkin lymphoma] orphan has moved quite a long way in the last several years. I’m very excited and very hopeful for my patients at this point, because we have a multitude of treatments now that we can use to start extending survival and improving outcomes in our patient groups. I think the next 5 years for all of us will be hopefully very monumental, and we’ll be looking back on some of the old days and thinking, “Oh, why do we give chemotherapy when we can do things so much better?” I’m very excited about some of these drugs now.

Ian Flinn, MD: I look forward to that day. Javier?

Javier Munoz, MD, FACP: Having multiple therapeutic options is a good problem to have. Comments for my colleagues in community practice: talk to your pathologist, make sure the diagnosis is correct, make sure you have that accurate information when it comes to Ki-67 and TP53. Try to shy away from chemotherapy in the relapsed/refractory setting and at least think about novel therapies. Think about clinical trials. Consider referring the patient to a specialized cancer center. The future is definitely bright when it comes to mantle cell lymphoma.

Ian Flinn, MD: Those are very important considerations. Bijal?

Bijal Shah, MD: I echo all of the above. Some of the resounding things that come up from our discussion—and also things that I think about in the clinic—are who’s going to benefit and who is not as we begin this biological revolution. It’s going to take a lot of data. It’s going to take a lot of clinical trials and comparative clinical trials. We don’t have a large population to do all those trials, and some of this is going to be perhaps through in silico clinical trials, but we’re going to have to start to dissect on a molecular level and on an MRD [minimal residual disease] level how we’re going to get there. Taking that whole part aside, it still comes down to tolerability and cost, and we have to be very cognizant of both of those as we begin to move forward.

Ian Flinn, MD: Perfect. Well, thank you. On behalf of our panel, we hope you found this Peer Exchange^® discussion to be useful and informative.

Transcript Edited for Clarity