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Immunochemotherapy for Lymphoma

Panelists: Ian W. Flinn, MD, Sarah Cannon Center Blood Cancer; Krishna V. Komanduri, MD, Sylvester Comprehensive Cancer Center; Andre Goy, MD, MS, John Theurer Cancer Center; Frederick L. Locke, MD, Moffitt Cancer Center
Published Online: Tuesday, Sep 27, 2016



Transcript:

Andre Goy, MD, MS
: What do you think is the handicap to apply this in solid tumors?

Frederick L. Locke, MD: I think, first of all, there’s not a clear antigen as strong as CD19 in the solid tumors. There’s an issue of trafficking of the T cells into the solid tumor microenvironment. So, I think those two are probably the primary issues. T-cell receptor therapy has been tested in solid tumors. That’s a slightly different setting than CAR-T cells. A CAR-T cell does not require the MHC molecules to match, whereas T-cell receptor autologous cell therapy is basically delivering a construct that expresses a native T-cell receptor on the surface of the cells. But it has to be MHC-matched. And so, in that setting, we’re starting to see, perhaps, some early glimmers of responses. But, I think it’s a little more complex in CAR-T cells. Because when you have a native T-cell receptor, it can recognize antigens expressed and presented by MHC molecules, meaning intracellular antigens can be expressed and recognized. With chimeric antigen receptors, CD19 is on the surface. It recognizes a surface protein. And so, one of the disadvantages to CAR-T cells is they can really only be targeted against things that are expressed on the surface of the tumor.

Krishna V. Komanduri, MD: Let me just add that CD19 is also expressed on B cells, and we’ve learned through the effects of rituximab and others that most of us can live without B cells and do pretty well. So, many of the antigens that are expressed on solid tumor cells will also be expressed on other healthy tissues. And how to activate a really potent immune response that can eliminate every last cancer cell without doing damage to healthy tissues is a much bigger problem for most antigens, other than CD19.

Frederick L. Locke, MD: Exactly.

Ian W. Flinn, MD: So, the first monoclonal antibody for the treatment of cancer was rituximab. It was developed in 1997. That built upon decades of work when the original mouse antibodies were developed, the B1 antibody, and eventually led to the chimeric antibodies. And now we have humanized antibodies. A lot going on in the field. What are your thoughts?

Andre Goy, MD, MS: It’s really interesting. When you put it into perspective, Ron Levy’s lab had done a lot of work, and Köhler and Milstein won the Nobel prize for the fusion of clones and tried to deliver the first monoclonal antibody. A monoclonal antibody, for our audience, is an antibody that we can direct the specificity. That’s very critical because it’s a great tool. So, it was developed in the mid-90s, approved in 1997 in relapsed/refractory indolent lymphoma, follicular lymphoma, and was part of the trial that was eventually conducted at MD Anderson and Memorial Sloan Kettering. And it was very interesting to see patients who had very durable responses. Then, we started to, as we are now with the CAR therapies, try to understand them better. We have understood much more about the antibodies. Although, we don’t exactly understand completely which mechanism is involved in a given situation.

To summarize for our audience, the mechanism of antibodies is to engage them in a system to try to fight against the lymphoma cells here. Because it’s an anti-CD20, rituximab, expressed on the surface of all mature B cells. And then, there’s three main mechanisms. The first mechanism is, essentially, antibody-dependent cellular cytotoxicity. Through binding of FC receptor, it attracts effector cells, NK cells, and T cells that can actually kill efficiently the CD20-positive lymphoma cells. There’s complement-dependent cytotoxicity that is, to some degree, obviously demonstrated. We’re not exactly sure in the clinic how important it is; it might be more important for ofatumumab, another antibody.

And then there’s also evidence in the preclinical setting, and from the clinical data results, of the combination with chemotherapy where there may be an anti-cellular effect, an anti-tumor effect by modulation of the BCL-2 pathway and making the cells more sensitive to chemotherapy. All of this, without overlapping toxicity with chemotherapy, became an obvious tool to try to combine with chemotherapy, and that’s what really changed the field in B cell lymphoma, across-the-board indolent lymphoma, aggressive lymphoma, etc.

So, in large cell lymphoma, the last real innovation was R-CHOP. This was presented in 2000 by the, at the time, Groupe d’Etude des Lymphomes de l’Adulte (GELA), which is now LYSA (The Lymphoma Study Association) group. Also, the SWOG study at the same time, and ECOG study, showed that R-CHOP and rituximab plus CHOP clearly improved the outcome, initially in patients more than 60 years old. Although now the new 60 is 40, the over-60-years-old group, and demonstrated afterwards by a number of groups around the world, showed that there is a clear benefit in the CR rate, PFS, and overall survival that is maintained over time. This has changed and set the new standard in large-cell lymphoma. And we are still trying to make progress since the R-CHOP regimen emerged almost 20 years ago.

That’s in follicular lymphoma. This has been also very critical in follicular lymphoma because we discussed earlier that, in fact, this is an indolent disease. There was a lot of discussion about whether you should treat with chemotherapy because with chemotherapy, you kill the good guys and the patients will have a shorter and shorter duration of response. And then, with rituximab and chemotherapy, you can induce much, much higher CR rates. Because, by itself, follicular lymphoma is really highly responsive to rituximab; it’s about an 85% response rate. The CR rate is 20%, 25%; it’s not very high. As I mentioned before, a subset of patients that is going to achieve CR and get a small short consolidation can do really well. But, typically, that would not be sufficient, so the next step is how we can build up from there.

The next step after doing R-chemotherapy was to use maintenance therapy, and maintenance rituximab has been studied enormously across the board in all B-cell lymphomas. There’s no evidence in large cell lymphoma that maintenance is beneficial if you have received R-chemotherapy. And in follicular lymphoma, and probably in some situations in mantle cell lymphoma (MCL), there’s no question that it improves the PFS and duration of response, maybe the survival in MCL in some patients who are responders to R-CHOP. I would actually question this. This is really a small number of patients from the original large trials, selected from the double randomization process from the European trial. But this is really something that has been an enormous tool and has changed the field in B-cell malignancies.

Transcript Edited for Clarity

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Transcript:

Andre Goy, MD, MS
: What do you think is the handicap to apply this in solid tumors?

Frederick L. Locke, MD: I think, first of all, there’s not a clear antigen as strong as CD19 in the solid tumors. There’s an issue of trafficking of the T cells into the solid tumor microenvironment. So, I think those two are probably the primary issues. T-cell receptor therapy has been tested in solid tumors. That’s a slightly different setting than CAR-T cells. A CAR-T cell does not require the MHC molecules to match, whereas T-cell receptor autologous cell therapy is basically delivering a construct that expresses a native T-cell receptor on the surface of the cells. But it has to be MHC-matched. And so, in that setting, we’re starting to see, perhaps, some early glimmers of responses. But, I think it’s a little more complex in CAR-T cells. Because when you have a native T-cell receptor, it can recognize antigens expressed and presented by MHC molecules, meaning intracellular antigens can be expressed and recognized. With chimeric antigen receptors, CD19 is on the surface. It recognizes a surface protein. And so, one of the disadvantages to CAR-T cells is they can really only be targeted against things that are expressed on the surface of the tumor.

Krishna V. Komanduri, MD: Let me just add that CD19 is also expressed on B cells, and we’ve learned through the effects of rituximab and others that most of us can live without B cells and do pretty well. So, many of the antigens that are expressed on solid tumor cells will also be expressed on other healthy tissues. And how to activate a really potent immune response that can eliminate every last cancer cell without doing damage to healthy tissues is a much bigger problem for most antigens, other than CD19.

Frederick L. Locke, MD: Exactly.

Ian W. Flinn, MD: So, the first monoclonal antibody for the treatment of cancer was rituximab. It was developed in 1997. That built upon decades of work when the original mouse antibodies were developed, the B1 antibody, and eventually led to the chimeric antibodies. And now we have humanized antibodies. A lot going on in the field. What are your thoughts?

Andre Goy, MD, MS: It’s really interesting. When you put it into perspective, Ron Levy’s lab had done a lot of work, and Köhler and Milstein won the Nobel prize for the fusion of clones and tried to deliver the first monoclonal antibody. A monoclonal antibody, for our audience, is an antibody that we can direct the specificity. That’s very critical because it’s a great tool. So, it was developed in the mid-90s, approved in 1997 in relapsed/refractory indolent lymphoma, follicular lymphoma, and was part of the trial that was eventually conducted at MD Anderson and Memorial Sloan Kettering. And it was very interesting to see patients who had very durable responses. Then, we started to, as we are now with the CAR therapies, try to understand them better. We have understood much more about the antibodies. Although, we don’t exactly understand completely which mechanism is involved in a given situation.

To summarize for our audience, the mechanism of antibodies is to engage them in a system to try to fight against the lymphoma cells here. Because it’s an anti-CD20, rituximab, expressed on the surface of all mature B cells. And then, there’s three main mechanisms. The first mechanism is, essentially, antibody-dependent cellular cytotoxicity. Through binding of FC receptor, it attracts effector cells, NK cells, and T cells that can actually kill efficiently the CD20-positive lymphoma cells. There’s complement-dependent cytotoxicity that is, to some degree, obviously demonstrated. We’re not exactly sure in the clinic how important it is; it might be more important for ofatumumab, another antibody.

And then there’s also evidence in the preclinical setting, and from the clinical data results, of the combination with chemotherapy where there may be an anti-cellular effect, an anti-tumor effect by modulation of the BCL-2 pathway and making the cells more sensitive to chemotherapy. All of this, without overlapping toxicity with chemotherapy, became an obvious tool to try to combine with chemotherapy, and that’s what really changed the field in B cell lymphoma, across-the-board indolent lymphoma, aggressive lymphoma, etc.

So, in large cell lymphoma, the last real innovation was R-CHOP. This was presented in 2000 by the, at the time, Groupe d’Etude des Lymphomes de l’Adulte (GELA), which is now LYSA (The Lymphoma Study Association) group. Also, the SWOG study at the same time, and ECOG study, showed that R-CHOP and rituximab plus CHOP clearly improved the outcome, initially in patients more than 60 years old. Although now the new 60 is 40, the over-60-years-old group, and demonstrated afterwards by a number of groups around the world, showed that there is a clear benefit in the CR rate, PFS, and overall survival that is maintained over time. This has changed and set the new standard in large-cell lymphoma. And we are still trying to make progress since the R-CHOP regimen emerged almost 20 years ago.

That’s in follicular lymphoma. This has been also very critical in follicular lymphoma because we discussed earlier that, in fact, this is an indolent disease. There was a lot of discussion about whether you should treat with chemotherapy because with chemotherapy, you kill the good guys and the patients will have a shorter and shorter duration of response. And then, with rituximab and chemotherapy, you can induce much, much higher CR rates. Because, by itself, follicular lymphoma is really highly responsive to rituximab; it’s about an 85% response rate. The CR rate is 20%, 25%; it’s not very high. As I mentioned before, a subset of patients that is going to achieve CR and get a small short consolidation can do really well. But, typically, that would not be sufficient, so the next step is how we can build up from there.

The next step after doing R-chemotherapy was to use maintenance therapy, and maintenance rituximab has been studied enormously across the board in all B-cell lymphomas. There’s no evidence in large cell lymphoma that maintenance is beneficial if you have received R-chemotherapy. And in follicular lymphoma, and probably in some situations in mantle cell lymphoma (MCL), there’s no question that it improves the PFS and duration of response, maybe the survival in MCL in some patients who are responders to R-CHOP. I would actually question this. This is really a small number of patients from the original large trials, selected from the double randomization process from the European trial. But this is really something that has been an enormous tool and has changed the field in B-cell malignancies.

Transcript Edited for Clarity
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