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Expanding the Role of CAR T in non-Hodgkin Lymphoma

Insights From: Nilanjan Ghosh, MD, PhD, Levin Cancer Institute; Leo Gordon, MD, Northwestern Memorial Hospital; Matthew Lunning, DO, University of Nebraska Medical Center
Published: Monday, Dec 17, 2018



Transcript: 

Nilanjan Ghosh, MD, PhD: One of the future directions for CAR T-cell therapy in relapsed/refractory B-cell lymphoma is to see if it can be moved up from second-line, and after failure of second-line to an earlier line. It has good activity in most patients, so this is a natural evolution. The question is, can it be compared to transplantation? There are 3 clinical trials that have been planned for this possibility. There’s ZUMA-1, in which axicabtagene ciloleucel [axi-cel] is being compared to salvage therapy followed by transplantation. There’s a trial called BELINDA in which CTL019 [Kymriah] is being compared to salvage therapy followed by transplantation. All these trials are going to see whether patients who are failing first-line therapy, have relapse, and thereafter can receive CAR T-cell products compared to other salvage therapies.

Leo Gordon, MD: The timing of CAR T therapy is an evolution. Currently, it’s for patients with refractory disease, but perhaps consolidation for patients with responding lymphoma who are high risk for relapse would be a good fit. Should it be used as consolidation for patients in complete remission? This begs the question: Do you need antigen in order for this to work? In other words, do you need some tumor present in order for CAR T-cell therapy to work? Will it work with minimal residual disease with no obvious antigens that are there for the CARs to attach to? We do not know the answer.

At the moment all the patients treated have had visible disease on PET [positron emission tomography] scans and physical exams. Whether it works in patients with no obvious disease, we don’t know. Saying it might be used as a consolidation treatment would probably be premature.

As we try and advance the use of these, ultimately the CAR T therapies themselves are going to be better; there are going to be better costimulatory molecules. There’ll be more educated cells that might be targeting a variety of different targets on tumor cells. Additionally, we’re exploring the so-called Platform study, which is being done with Celgene-Juno with the same JCAR017 molecule cell product. We’re looking at the use of adding certain agents to CARs, such as PD-L1 [programmed death-ligand 1] checkpoint inhibitors.

We’re looking at immunomodulatory imide drugs [IMiDs], a variety of other drugs that we think might enhance the efficacy of these CARs, perhaps by reducing the number of T-regulatory cells, which might get in the way of the CARs working. In the future, there are going to be better CARS and costimulatory molecules, and there will be perhaps the use of combinations of treatment—maybe radiation, which will help release antigens and make the CARs more effective radiations to certain sites of disease.

Matthew Lunning, DO: Clinical trials are ongoing in follicular lymphoma, mantle cell lymphoma, and chronic lymphomatic leukemia [CLL] looking at CAR T cells in these spaces. If you take each one of those diseases—it’s a spectrum—it’s just like large B-cell lymphoma. Patients with follicular lymphoma receive an anthracycline-containing bendamustine [Bendeka] regimen, which in the refractory setting is a front-line therapy that becomes more intensive in the second-line setting as the lymphoma progresses. This is an acceptable patient for CAR T-cell therapy, I think, on a clinical trial.

One could argue that a patient who relapses within 2 years from front-line anthracycline-based chemotherapy is a big deal. Fifty percent of those people are not alive in 5 years, and their likely cause of death is lymphoma. That’s a population in follicular lymphoma that I would want to study with CAR T cells. Mantle-cell lymphoma is another population I would like to study. It can definitely behave like the most aggressive lymphomas in the relapsed/refractory setting.

You have to be able to discern which one of these it is behaving like. The same thing goes for CLL. In mantle cell lymphoma, again, if you’ve gotten front-line chemotherapy and consolidated with an autotransplant, and you relapsed quickly after an autotransplant, that might be an area where CAR T-cell treatment would be a reasonable strategy. Some may argue that that patient should at least get a trial of ibrutinib [Imbruvica] tyrosine kinase inhibitor prior to going to CAR T cell.

The answer, if you look at the efficacy that’s been displayed across the 3 constructs, is that if it’s going to work, if it’s agnostic to double-hit or triple-hit refractory in 6 months, or after autotransplant, you can still see responses with durability in that patient population. Even in indolent lymphomas where you’re talking about that tough population, there may be the opportunity for efficacy, but you have to be mindful of the potential toxicity. It’s always a risk-benefit discussion with the patient and family regarding CAR T-cell therapy

Transcript Edited for Clarity 
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Transcript: 

Nilanjan Ghosh, MD, PhD: One of the future directions for CAR T-cell therapy in relapsed/refractory B-cell lymphoma is to see if it can be moved up from second-line, and after failure of second-line to an earlier line. It has good activity in most patients, so this is a natural evolution. The question is, can it be compared to transplantation? There are 3 clinical trials that have been planned for this possibility. There’s ZUMA-1, in which axicabtagene ciloleucel [axi-cel] is being compared to salvage therapy followed by transplantation. There’s a trial called BELINDA in which CTL019 [Kymriah] is being compared to salvage therapy followed by transplantation. All these trials are going to see whether patients who are failing first-line therapy, have relapse, and thereafter can receive CAR T-cell products compared to other salvage therapies.

Leo Gordon, MD: The timing of CAR T therapy is an evolution. Currently, it’s for patients with refractory disease, but perhaps consolidation for patients with responding lymphoma who are high risk for relapse would be a good fit. Should it be used as consolidation for patients in complete remission? This begs the question: Do you need antigen in order for this to work? In other words, do you need some tumor present in order for CAR T-cell therapy to work? Will it work with minimal residual disease with no obvious antigens that are there for the CARs to attach to? We do not know the answer.

At the moment all the patients treated have had visible disease on PET [positron emission tomography] scans and physical exams. Whether it works in patients with no obvious disease, we don’t know. Saying it might be used as a consolidation treatment would probably be premature.

As we try and advance the use of these, ultimately the CAR T therapies themselves are going to be better; there are going to be better costimulatory molecules. There’ll be more educated cells that might be targeting a variety of different targets on tumor cells. Additionally, we’re exploring the so-called Platform study, which is being done with Celgene-Juno with the same JCAR017 molecule cell product. We’re looking at the use of adding certain agents to CARs, such as PD-L1 [programmed death-ligand 1] checkpoint inhibitors.

We’re looking at immunomodulatory imide drugs [IMiDs], a variety of other drugs that we think might enhance the efficacy of these CARs, perhaps by reducing the number of T-regulatory cells, which might get in the way of the CARs working. In the future, there are going to be better CARS and costimulatory molecules, and there will be perhaps the use of combinations of treatment—maybe radiation, which will help release antigens and make the CARs more effective radiations to certain sites of disease.

Matthew Lunning, DO: Clinical trials are ongoing in follicular lymphoma, mantle cell lymphoma, and chronic lymphomatic leukemia [CLL] looking at CAR T cells in these spaces. If you take each one of those diseases—it’s a spectrum—it’s just like large B-cell lymphoma. Patients with follicular lymphoma receive an anthracycline-containing bendamustine [Bendeka] regimen, which in the refractory setting is a front-line therapy that becomes more intensive in the second-line setting as the lymphoma progresses. This is an acceptable patient for CAR T-cell therapy, I think, on a clinical trial.

One could argue that a patient who relapses within 2 years from front-line anthracycline-based chemotherapy is a big deal. Fifty percent of those people are not alive in 5 years, and their likely cause of death is lymphoma. That’s a population in follicular lymphoma that I would want to study with CAR T cells. Mantle-cell lymphoma is another population I would like to study. It can definitely behave like the most aggressive lymphomas in the relapsed/refractory setting.

You have to be able to discern which one of these it is behaving like. The same thing goes for CLL. In mantle cell lymphoma, again, if you’ve gotten front-line chemotherapy and consolidated with an autotransplant, and you relapsed quickly after an autotransplant, that might be an area where CAR T-cell treatment would be a reasonable strategy. Some may argue that that patient should at least get a trial of ibrutinib [Imbruvica] tyrosine kinase inhibitor prior to going to CAR T cell.

The answer, if you look at the efficacy that’s been displayed across the 3 constructs, is that if it’s going to work, if it’s agnostic to double-hit or triple-hit refractory in 6 months, or after autotransplant, you can still see responses with durability in that patient population. Even in indolent lymphomas where you’re talking about that tough population, there may be the opportunity for efficacy, but you have to be mindful of the potential toxicity. It’s always a risk-benefit discussion with the patient and family regarding CAR T-cell therapy

Transcript Edited for Clarity 
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