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Improving Responsiveness With Immunotherapy in mCRC

Insights From: John L. Marshall, MD, MedStar Georgetown University Hospital; Tanios S. Bekaii-Saab, MD, Mayo Clinic
Published: Friday, Apr 05, 2019



Transcript: 

John L. Marshall, MD:
The gold rush of immunotherapy in all cancers has, of course, also hit colon cancer. And apart from our MSI [microsatellite instability] group, you know we’ve been pretty frustrated. Lots of people doing different things and trying to identify either a biomarker that would enrich, or some logical combination, and there are lots of studies. You have some. We, everybody’s got studies where we’re trying to look at drug A plus B in settings, and it’s been pretty frustrating. You know Dr [Johanna] Bendell [MD]’s study combining cobimetinib and atezolizumab. Everybody was all hot and bothered because of 4 patients in a phase II study and that study in the end, I don’t know how much it cost to do that study. We did it fast, we got the data in fast, and sadly it didn’t work. Do you see a window where we’re going to carve out another section of colorectal cancer that might respond to immune therapy?

Tanios S. Bekaii-Saab, MD: Well, you know there is this CMS [consensus molecular subtypes] classification that’s putting 1 bucket, I think CMS4, into the immune-rich bucket; it may perhaps have a little bit more likelihood to respond to immune therapy. I think when we talk about immune therapy we’re still talking about PD-1 [programmed cell death protein 1] inhibitors. So we’re targeting one axis of the immune component that’s important.

The other thing is with the fact that the study, the ATEZO [atexolizumab] plus COBI [cobimetinib] study, which is theoretically a MEK inhibitor, inflaming the tumor bringing these lymphocytes, although, again, not at a really high rate. But is this the only element that’s important for the PD-1 inhibitor to work well? How about all the other things that seem to be playing against those T cells? So until we understand clearly what components we need to overrun to allow a PD-1, or PD-1 plus, to work in this disease, I think remains to be seen. I’m still optimistic that a good proportion of patients with colon cancer will end up at some point eligible for some form of immune therapy. But today, unfortunately, it’s only 4% and it’s only the MSI-high.

John L. Marshall, MD: And these drugs won’t work unless the T cell is already there, right?

Tanios S. Bekaii-Saab, MD: Yes.

John L. Marshall, MD: They won’t generate an immune response.

Tanios S. Bekaii-Saab, MD: No.

John L. Marshall, MD: So a lot of our work is looking at combining vaccines with immune therapy to see if we can stimulate it. I’m also increasingly fascinated around this microbiome piece and its role it plays in immune response. So the melanoma data saying that your microbiome affects your responsiveness, which we’ve got to figure what’s going on there. And we know that microbiome may be playing a role in colon cancer at metastasis. We know that bacterial DNA can be found in liver METS [metastasis], for example. So I hope there’s something there that says maybe we can alter that relationship in a way to wake up the immune system so that if it does put up a barrier of PD-1, then we can have a therapy.

Tanios S. Bekaii-Saab, MD: Yes, microbiome is pretty complex. I think the microbiome is, there’s the gut component and then there’s the tumor component, and some of the bacteria can be beneficial, can be nonbeneficial. Some of them can alter how effectively your chemotherapy works. And then you get this whole immune medium modulation and how you can either modulate the microbiome or modulate the immune system based on the microbiome finding, at least in theory.

It’s a long way to go I think for that. There are aspects of the microbiome that traditionally have not been classified as microbiomes such as, I’ve recently read a little bit about HPV [human papillomavirus] vaccines, not to prevent HPV, but these are vaccines essentially that carry the protein, but in a way that essentially simulate, when you think about these head and neck cancers and the HPV plus head and neck cancers, how sensitive they are to an HPV is part of the microbiome. It’s a virus. They’re sensitive to chemotherapy and radiation. If you can find a way, if we understand these agents, the viruses, bacterias that are sitting in the tumors and helping sensitize, or becoming resistant. So you take advantage of those and you learn, and essentially for other cancers, you introduce similar antigens into the system, perhaps you can enhance activity. So there are a lot of aspects from the microbiome that are more complex.

John L. Marshall, MD: So the microbiome is not just a bunch of crap.

Tanios S. Bekaii-Saab, MD: No.


Transcript Edited for Clarity
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Transcript: 

John L. Marshall, MD:
The gold rush of immunotherapy in all cancers has, of course, also hit colon cancer. And apart from our MSI [microsatellite instability] group, you know we’ve been pretty frustrated. Lots of people doing different things and trying to identify either a biomarker that would enrich, or some logical combination, and there are lots of studies. You have some. We, everybody’s got studies where we’re trying to look at drug A plus B in settings, and it’s been pretty frustrating. You know Dr [Johanna] Bendell [MD]’s study combining cobimetinib and atezolizumab. Everybody was all hot and bothered because of 4 patients in a phase II study and that study in the end, I don’t know how much it cost to do that study. We did it fast, we got the data in fast, and sadly it didn’t work. Do you see a window where we’re going to carve out another section of colorectal cancer that might respond to immune therapy?

Tanios S. Bekaii-Saab, MD: Well, you know there is this CMS [consensus molecular subtypes] classification that’s putting 1 bucket, I think CMS4, into the immune-rich bucket; it may perhaps have a little bit more likelihood to respond to immune therapy. I think when we talk about immune therapy we’re still talking about PD-1 [programmed cell death protein 1] inhibitors. So we’re targeting one axis of the immune component that’s important.

The other thing is with the fact that the study, the ATEZO [atexolizumab] plus COBI [cobimetinib] study, which is theoretically a MEK inhibitor, inflaming the tumor bringing these lymphocytes, although, again, not at a really high rate. But is this the only element that’s important for the PD-1 inhibitor to work well? How about all the other things that seem to be playing against those T cells? So until we understand clearly what components we need to overrun to allow a PD-1, or PD-1 plus, to work in this disease, I think remains to be seen. I’m still optimistic that a good proportion of patients with colon cancer will end up at some point eligible for some form of immune therapy. But today, unfortunately, it’s only 4% and it’s only the MSI-high.

John L. Marshall, MD: And these drugs won’t work unless the T cell is already there, right?

Tanios S. Bekaii-Saab, MD: Yes.

John L. Marshall, MD: They won’t generate an immune response.

Tanios S. Bekaii-Saab, MD: No.

John L. Marshall, MD: So a lot of our work is looking at combining vaccines with immune therapy to see if we can stimulate it. I’m also increasingly fascinated around this microbiome piece and its role it plays in immune response. So the melanoma data saying that your microbiome affects your responsiveness, which we’ve got to figure what’s going on there. And we know that microbiome may be playing a role in colon cancer at metastasis. We know that bacterial DNA can be found in liver METS [metastasis], for example. So I hope there’s something there that says maybe we can alter that relationship in a way to wake up the immune system so that if it does put up a barrier of PD-1, then we can have a therapy.

Tanios S. Bekaii-Saab, MD: Yes, microbiome is pretty complex. I think the microbiome is, there’s the gut component and then there’s the tumor component, and some of the bacteria can be beneficial, can be nonbeneficial. Some of them can alter how effectively your chemotherapy works. And then you get this whole immune medium modulation and how you can either modulate the microbiome or modulate the immune system based on the microbiome finding, at least in theory.

It’s a long way to go I think for that. There are aspects of the microbiome that traditionally have not been classified as microbiomes such as, I’ve recently read a little bit about HPV [human papillomavirus] vaccines, not to prevent HPV, but these are vaccines essentially that carry the protein, but in a way that essentially simulate, when you think about these head and neck cancers and the HPV plus head and neck cancers, how sensitive they are to an HPV is part of the microbiome. It’s a virus. They’re sensitive to chemotherapy and radiation. If you can find a way, if we understand these agents, the viruses, bacterias that are sitting in the tumors and helping sensitize, or becoming resistant. So you take advantage of those and you learn, and essentially for other cancers, you introduce similar antigens into the system, perhaps you can enhance activity. So there are a lot of aspects from the microbiome that are more complex.

John L. Marshall, MD: So the microbiome is not just a bunch of crap.

Tanios S. Bekaii-Saab, MD: No.


Transcript Edited for Clarity
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