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The Future Treatment of Follicular Lymphoma

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Peter Martin, MD, MS, Weill Cornell Medicine; Loretta J. Nastoupil, MD, University of Texas MD Anderson Cancer Center; Grzegorz S. Nowakowski, MD, Mayo Clinic; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Published: Monday, Feb 12, 2018



Transcript: 

Ian W. Flinn, MD, PhD: Peter, CAR T cells are now approved for the treatment of refractory diffuse large cell lymphoma with some really impressive activity and also some concerning toxicity. There are certainly trials that are ongoing to accrue patients with follicular lymphoma. Are we going to be treating everyone with any form of lymphoproliferative disorder with CAR T cells?

Peter Martin, MD, MS: Tomorrow, no, but maybe at some point in the future. It’s hard to deny the attractiveness of a strategy that’s potentially curative in a population that doesn’t currently have a cure. Although we’ve talked about people with follicular lymphoma having a life span that’s often consistent with people without lymphoma, the majority of them still die from lymphoma. And so, if we can come up with strategies that manage it better, that’s great. The challenge, as you said, is balancing toxicity of CAR T cells with the efficacy. If you’ve got a curative strategy, but it also puts people in the ICU for a month, it’s a problem, right? So, I think one strategy is to pick the people with the worst prognosis in follicular lymphoma. Those are, right now, probably the patients to go after: the ones who are ultimately double refractory to chemotherapy and rituximab or potentially the early progressors, although that may be a little bit of a push from that perspective. Maybe we’ll find out the right approach. And then, we’re still testing the agents that are moving toward approval pretty early in CAR T-cell development. They’re second-generation CAR T cells, and people are on the fourth and fifth-generation of CAR T cells, so we may learn that we can do better. It’s moving really fast. There’s room for encouragement.

Ian W. Flinn, MD, PhD: It’s amazing how fast it’s moving, and the ability to perhaps have suicide switches where you could turn things off, or a variety of other approaches to decrease the toxicity, makes it really attractive. I thought that the bispecific antibodies might be a short cut. It’s a universal product to treat with that you don’t have to customize to each patient. However, there are some significant side effects, at least in the ones we tested, that are almost the same as some CAR T cells. There is some scary neurotoxicity, so perhaps they’re not all that better.

Peter Martin, MD, MS: That’s an example of something that may be toxic, but on the other hand, it tells you that you’re on the right track.

Ian W. Flinn, MD, PhD: Maybe we can find ways to turn that up and turn that down. Of course, there are all the combinations of all of these things, the combination of a checkpoint inhibitor with CAR T-cell therapy. I remember the first time I heard that, I was thinking, “Whoa, maybe we should get the toxicities figured out.” But that seems to be like a very exciting avenue of research.

Anas Younes, MD: Data will be presented at this meeting actually showing that one mechanism for resistance, a short duration of response, for CAR T cells is upregulation of PD-L1 and also loss of CD19. It makes a lot of sense from a mechanistic point of view, being mindful of the side effects and toxicities, to combine these 2 approaches, in some of these patients at least.

Ian W. Flinn, MD, PhD: Great. Are there things that you’re excited about that we haven’t talked about or different areas of research that are new? Loretta, I’ll start with you. Is there anything that comes to mind?

Loretta J. Nastoupil, MD: It’s not necessarily a new area of research, but in one of the sessions later today, you’re going to hear about a newer version of lenalidomide that might actually be different. That is CC-122, which may have a little bit of a stronger impact on cereblon modulation. It’s more potent than lenalidomide, but the toxicity profile doesn’t look to be that much different. So, that looks to be encouraging in follicular lymphoma.

Ian W. Flinn, MD, PhD: Anas, anything?

Anas Younes, MD: I think we’ve covered most of these things. I think the future will be to continue to look for biomarkers and to select patients for proper therapies, because now we have multiple options. We have to tailor treatment—chemotherapy-free, single-agent, more intensive therapy—based on biomarkers. I think the future of immune therapies is still way in the beginning, and I think there are going to be tremendous advances based on exploring new therapeutic advantages with these old immune therapy platforms.

Ian W. Flinn, MD, PhD: We didn’t talk about vaccines. Do you think those are going to make their way back in?

Anas Younes, MD: Well, define “vaccine.” You can consider immune checkpoint inhibitors as a vaccine now, because you’re going after neoantigen for immune response. I don’t know. The old-fashioned vaccine that we knew it, where you take a tumor out, grind it, and give it back to the patient, I think is probably going to go away.

Peter Martin, MD, MS: Maybe the in vivo vaccine strategy that came out of the Levy Lab is still an exciting concept, where you administer something intratumorally and then give a little bit of radiation and look for an abscopal response. There’s clearly something there, right? It would be great if we see more of that kind of research. I think it would be really nice to see really creative small studies in follicular lymphoma. The other thing that I’ll mention, which is coming out of the Mayo Clinic and Carrie Thompson, is our understanding of the patient experience with follicular lymphoma. So yes, we should do better with therapy, but we should also help these people to live with lymphoma, to better understand anxiety that can often be significant and understand the things that they and their caregivers cope with on a day-to-day basis. I think that we’re likely to see a lot of that kind of research come out over the next few years, and I think that’s going to have a major impact on our ability to care for patients.

Ian W. Flinn, MD, PhD: That does sound like an important area of research. Greg, what are your thoughts?

Grzegorz S. Nowakowski, MD: I agree with everything that was said. I think what Anas mentioned about the biomarkers is really key. We discussed that there is a subgroup of patients who will not do well with chemoimmunotherapy and standard therapies. We have a number of very active options now for those patients, but nevertheless, it’s a limited number of options. And identification of those patients early on is important to move the field forward. Things are looking great now in follicular lymphoma.

Ian W. Flinn, MD, PhD: On behalf of our panel, we thank you for joining us, and we hope you found this OncLive® Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity 

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Transcript: 

Ian W. Flinn, MD, PhD: Peter, CAR T cells are now approved for the treatment of refractory diffuse large cell lymphoma with some really impressive activity and also some concerning toxicity. There are certainly trials that are ongoing to accrue patients with follicular lymphoma. Are we going to be treating everyone with any form of lymphoproliferative disorder with CAR T cells?

Peter Martin, MD, MS: Tomorrow, no, but maybe at some point in the future. It’s hard to deny the attractiveness of a strategy that’s potentially curative in a population that doesn’t currently have a cure. Although we’ve talked about people with follicular lymphoma having a life span that’s often consistent with people without lymphoma, the majority of them still die from lymphoma. And so, if we can come up with strategies that manage it better, that’s great. The challenge, as you said, is balancing toxicity of CAR T cells with the efficacy. If you’ve got a curative strategy, but it also puts people in the ICU for a month, it’s a problem, right? So, I think one strategy is to pick the people with the worst prognosis in follicular lymphoma. Those are, right now, probably the patients to go after: the ones who are ultimately double refractory to chemotherapy and rituximab or potentially the early progressors, although that may be a little bit of a push from that perspective. Maybe we’ll find out the right approach. And then, we’re still testing the agents that are moving toward approval pretty early in CAR T-cell development. They’re second-generation CAR T cells, and people are on the fourth and fifth-generation of CAR T cells, so we may learn that we can do better. It’s moving really fast. There’s room for encouragement.

Ian W. Flinn, MD, PhD: It’s amazing how fast it’s moving, and the ability to perhaps have suicide switches where you could turn things off, or a variety of other approaches to decrease the toxicity, makes it really attractive. I thought that the bispecific antibodies might be a short cut. It’s a universal product to treat with that you don’t have to customize to each patient. However, there are some significant side effects, at least in the ones we tested, that are almost the same as some CAR T cells. There is some scary neurotoxicity, so perhaps they’re not all that better.

Peter Martin, MD, MS: That’s an example of something that may be toxic, but on the other hand, it tells you that you’re on the right track.

Ian W. Flinn, MD, PhD: Maybe we can find ways to turn that up and turn that down. Of course, there are all the combinations of all of these things, the combination of a checkpoint inhibitor with CAR T-cell therapy. I remember the first time I heard that, I was thinking, “Whoa, maybe we should get the toxicities figured out.” But that seems to be like a very exciting avenue of research.

Anas Younes, MD: Data will be presented at this meeting actually showing that one mechanism for resistance, a short duration of response, for CAR T cells is upregulation of PD-L1 and also loss of CD19. It makes a lot of sense from a mechanistic point of view, being mindful of the side effects and toxicities, to combine these 2 approaches, in some of these patients at least.

Ian W. Flinn, MD, PhD: Great. Are there things that you’re excited about that we haven’t talked about or different areas of research that are new? Loretta, I’ll start with you. Is there anything that comes to mind?

Loretta J. Nastoupil, MD: It’s not necessarily a new area of research, but in one of the sessions later today, you’re going to hear about a newer version of lenalidomide that might actually be different. That is CC-122, which may have a little bit of a stronger impact on cereblon modulation. It’s more potent than lenalidomide, but the toxicity profile doesn’t look to be that much different. So, that looks to be encouraging in follicular lymphoma.

Ian W. Flinn, MD, PhD: Anas, anything?

Anas Younes, MD: I think we’ve covered most of these things. I think the future will be to continue to look for biomarkers and to select patients for proper therapies, because now we have multiple options. We have to tailor treatment—chemotherapy-free, single-agent, more intensive therapy—based on biomarkers. I think the future of immune therapies is still way in the beginning, and I think there are going to be tremendous advances based on exploring new therapeutic advantages with these old immune therapy platforms.

Ian W. Flinn, MD, PhD: We didn’t talk about vaccines. Do you think those are going to make their way back in?

Anas Younes, MD: Well, define “vaccine.” You can consider immune checkpoint inhibitors as a vaccine now, because you’re going after neoantigen for immune response. I don’t know. The old-fashioned vaccine that we knew it, where you take a tumor out, grind it, and give it back to the patient, I think is probably going to go away.

Peter Martin, MD, MS: Maybe the in vivo vaccine strategy that came out of the Levy Lab is still an exciting concept, where you administer something intratumorally and then give a little bit of radiation and look for an abscopal response. There’s clearly something there, right? It would be great if we see more of that kind of research. I think it would be really nice to see really creative small studies in follicular lymphoma. The other thing that I’ll mention, which is coming out of the Mayo Clinic and Carrie Thompson, is our understanding of the patient experience with follicular lymphoma. So yes, we should do better with therapy, but we should also help these people to live with lymphoma, to better understand anxiety that can often be significant and understand the things that they and their caregivers cope with on a day-to-day basis. I think that we’re likely to see a lot of that kind of research come out over the next few years, and I think that’s going to have a major impact on our ability to care for patients.

Ian W. Flinn, MD, PhD: That does sound like an important area of research. Greg, what are your thoughts?

Grzegorz S. Nowakowski, MD: I agree with everything that was said. I think what Anas mentioned about the biomarkers is really key. We discussed that there is a subgroup of patients who will not do well with chemoimmunotherapy and standard therapies. We have a number of very active options now for those patients, but nevertheless, it’s a limited number of options. And identification of those patients early on is important to move the field forward. Things are looking great now in follicular lymphoma.

Ian W. Flinn, MD, PhD: On behalf of our panel, we thank you for joining us, and we hope you found this OncLive® Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity 
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