‘Releasing the Dogs’ in the Body’s War on Cancer

Plus Other Strategies in Cancer Immunotherapy

John L. Marshall, MD; Louis M. Weiner, MD; Christopher R. Heery, MD


February 18, 2016

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John L. Marshall, MD: Hello, everybody out there on Medscape. John Marshall, coming to you live from Georgetown University at the Sixth Annual Ruesch Symposium, where we really try to take apart key issues in our world of gastrointestinal (GI) cancer from a multidisciplinary perspective and move the bar in our ultimate goal to cure these common fatal diseases.

One of our hot topics this year is immunotherapy. Everybody's talking about it. I am blessed to be surrounded by some of the smartest people on the planet in regard to immunotherapy, and they are nice enough to come and join us today.

Across from me is a good friend, colleague, and collaborator, Dr Chris Heery, who runs the clinical trials office over at one of my favorite places in the world, the Laboratory of Tumor Immunology and Biology at the National Institutes of Health, Building 10—the biggest brick building in the world. Chris gave a brilliant talk last night to our community partners about immunotherapy, and we're going to hear from him in just a second. Chris, thanks for joining us.

In fact, the smartest guy I know—I have to say that because he's my boss, but he is in fact one of the wisest guys and most brilliant immunotherapists on our planet—is Dr Lou Weiner. He's director of the Georgetown Lombardi Comprehensive Cancer Center and a major contributor to the world of immunotherapy, carrying the flag, if you will, for many, many years until we now have got some traction. Lou, I know you had to be in four places at this moment, so thanks for taking some time.

Louis M. Weiner, MD: Well, thanks for that kind introduction. And boy, my shoulders really are hurting from all of that flag-carrying.

The Immune System: The Body's War on Cancer

Dr Marshall: Lou, give us some perspective. Where are we in cancer medicine and immunotherapy, particularly as it relates to GI cancer?

Dr Weiner: This is a really exciting time for cancer immunotherapy, as you know, John. I think it's really telling to know that the single most active class of agents we have to treat cancers are the programmed cell death 1 (PD-1) checkpoint inhibitor antibodies. These antibodies are showing meaningful antitumor efficacy with long-term treatment outcome benefits in more than 20 different cancers. That's really exciting. It teaches us that this is probably not an exception, but rather a harbinger of what's to come as we unravel the mysteries of the immune response in cancer.

The real war is between the person with the cancer and the cancer itself. It's the immune system that is the army.

The problem, of course, is that these antibodies haven't shown the same level of high-quality responses in the various GI cancers. How is that and why is it? One of my favorite lines has been that we've been at war against cancer throughout all of human history. We declared a war on cancer  formally in 1971, with President Nixon's signing of the National Cancer Act.[1] In fact, the war is fought one person at a time, and there are only two fundamental combatants. The oncologists are actually not part of that war; we are observers on the side, and we lob things in periodically. The real war is between the person with the cancer and the cancer itself. It's the immune system that is the army that the body uses to try to attack a cancer.

Dr Marshall: Do you think some people get cancers and their immune systems clean them up before they ever become clinically relevant?

Dr Weiner: That's a subject that's been debated for quite a number of years. My fundamental answer is yes. I think people do get cancers. I think immune systems do take care of them, but I think that there's a punch and counterpunch thing going on. Periodically, cancers develop a sufficient degree of weaponry to allow them to escape, and that weaponry can be a variety of different things.

We, of course, know about the immune checkpoints, and we know that they are kind of the last line of defense that a cancer uses when the barbarians, or the T cells, are at the gate. Those are what they use to defend themselves against attack, and they do so by disabling the functionality of those T cells, right? But there are lots of other weapons that are used. It's my instinct—and I think we'll hear from Chris about this—that some of the other weapons that these cancers are using, especially GI cancers, are manipulating the local environment to either not allow the T cells to get into the cancer to do their job, or to somehow disrupt the T cells' functionality, even before they get to attack the cancer.

Cancer vs Normal Cells: Recognizing the Enemy

Dr Marshall: Chris did a great job last night of reminding us that we have to be immunologists now. As oncologists, we maybe skipped that class in medical school, and now we've got to remember what was taught. Give us an overview of what's going on down there on the front lines of cancer immunotherapy.

Christopher R. Heery, MD: We should start from the beginning. Where is the process that initiates that contact between the T cell, which is going to do the killing, and the tumor cell? We know that in many cancers that don't respond to checkpoint inhibitors, they have very low numbers of infiltrating lymphocytes within the tumor.

If you take a step back, the reasonable assumption is that those are patients in whom the immune system has not been able to generate a specific response against the tumor. That's step one.

Dr Marshall: Is it because of the "self" thing?

Dr Heery: That's probably a big part of it, yes. Some of the proteins that are most prevalent on the tumor cell are also prevalent on normal human tissue.

Dr Marshall: Whatever the mutations, they aren't enough to trigger an immune response?

The greater number of targets that are foreign, the greater likelihood that one of our T cells will be able to recognize it then expand and attack.

Dr Heery: What we're seeing now in a variety of different cancers is that the mutation burden is well correlated with the likelihood of immune response. As a protein gets changed through mutation and the expression of a mutated protein, that protein becomes a foreign antigen, a foreign target for the immune system to recognize. The greater number of targets that are foreign, the greater likelihood that one of our T cells will be able to recognize it and then expand and attack.

I think the question that we all have to ask is: Does that mean we should try to induce more and more and more mutations? That's pretty dangerous. I think the better way to attack the problem would be to try to break that self-tolerance that you mentioned.

Another mechanism that others have discussed, including Dr Robert Schreiber's group[2] at Washington University, in St Louis, is to identify neoantigens within a tumor and target those by detecting those neoantigens and creating vaccines specifically against those neoantigens. I think those are all mechanisms that we could use.

Dr Marshall: Do you think numbers of antigens or specific antigens [are needed to elicit an immune response]?

Dr Heery: I don't know the answer to that.

Dr Marshall: Come on, come on, we want to know.

Dr Heery: I don't know the answer to that, but I think those are the two hypotheses that are out there: Are antigens specific [for triggering effective immune responses] or is it just a mounting number of antigens and it becomes a lottery [of which antigens trigger T cells]? Personally I don't know the answer, but I do think it's a lottery.

Dr Weiner: So do I.

Dr Marshall: Meaning that there are some specific antigens that if you just have enough, you hit the lottery, or what?

Dr Heery: It's a little more complicated. A peptide has to be able to bind to the major histocompatibility complex, and it also has to bind to a T-cell receptor. Depending on a person's human leukocyte antigen type, there are going to be different peptides that bind to the T-cell receptors that they have. There are algorithms that help us guess which of those peptides for a particular person are good antigens, but those algorithms are not fantastic. We have to test those preclinically. The people who are doing this, trying to identify neoantigens, use those algorithms to get a pool [of possible antigens] and then they test them in vitro to demonstrate that they actually generate T-cell responses in that patient's T-cell repertoire, and that they can kill the tumor.

'Release the Dogs' or Vaccinate?

Dr Marshall: Are there going to be common antigens across colon cancer and pancreatic cancer? Or are you and I going to have different ones?

At least a third of human epithelial malignancies look like they're going to be effectively targeted with just one class of immune checkpoint inhibition strategies.

Dr Weiner: Some, but not all. I agree with Chris's notion that this is a lottery. I think that it's a bit of a stochastic chance as to whether an antigen is going to be tasty to the body's immune system.

I also think we shouldn't be confused by all of this complexity, because at least a third of human epithelial malignancies look like they're going to be effectively targeted with just one class of immune checkpoint inhibition strategies, which means that at least a third of the time, there are antigens that the body's immune system is seeing and that are being held back by immune checkpoints. If you release the dogs [the T cells], they're ready to go.

Dr Marshall: Are we ready to measure that yet? With lung cancer they've begun to embrace measuring programmed death-ligand 1 (PD-L1).[3,4] Is that a decent biomarker?

Dr Weiner: I think it's a decent biomarker. It tells part of the story, but not all of it. Having PD-L1 expression seems to increase the likelihood that a PD-1 or a PD-L1 targeted therapy will be effective, but it doesn't guarantee it. Having a low level of expression doesn't mean that it's not going to work entirely.

I think there's a lot more that we need to learn, but what I think we can say is that for a lot of cancers there are going to be antigens, and it may be sufficient in some of those cancers to simply "release the dogs," if we understand what the brakes are on the process [holding them back]. In other cases it may be necessary to boost the immune system's functionality through vaccinations. In some cases, it may be that—and I think it's going to be relatively few—there are going to be not a lot of antigens, and a different kind of cancer causation process will be at work. Under those circumstances, the CAR T-cell strategies, the adoptive cellular therapy strategies, might be useful, because then you can basically create an artificial antigen by plopping an antibody fragment onto a T cell, expanding it, and saying, "Go find that cancer."

I think that we're going to end up with a lot of different strategies that can really be useful, but the challenge, of course, is to figure out: In which patient should we use which kind of strategy? That's the work for us over the next decade.

MSI-High Tumors: Forays in GI Cancer Immunotherapy

Dr Marshall: So, today, which patients with GI cancer should we be thinking of as candidates for immunotherapy right from the beginning?

Dr Heery: Unfortunately, if we're talking standard of care, nobody.

Dr Marshall: You wouldn't argue that microsatellite instability (MSI) is walking in the door [as a marker]? Even though we're not approved yet?

Dr Heery: Absolutely you should put patients in the trial so we can get it finished and get the approval.

Dr Marshall: Right. And all of us have studies open for that so we can be done.

Dr Weiner: Absolutely.

Dr Heery: No doubt about it for MSI-high tumors.

Dr Marshall: And that's true for gastric, colon, even bile duct?

Dr Heery: All of them. For gastric cancer, even for patients who have not had MSI testing, it's still a consideration; there are plenty of clinical trials.

When tumor burden is lower, we have a greater likelihood of generating an immune response.

Dr Marshall: But for every patient with metastatic gastric cancer, should we be trying to find a clinical trial right from the beginning?

Dr Heery: As with lung cancer, I would start with standard therapy and start looking for those trials as you begin your standard therapy. And when you hit your maximal benefit and things look like they're starting to turn the corner, I'd try to get them onto that study.

Dr Marshall: Right at the nadir of response.

Dr Weiner: At the inflection point.

Dr Heery: The reasons for that are multifactorial, but essentially there's a lot of evidence that when tumor burden is lower, we have a greater likelihood of generating an immune response with checkpoint inhibitors as well as with other immune therapies.

Dr Marshall: How hard should a community oncologist try who doesn't have this study open or lives 200 miles from whatever study? Is the benefit worth it for a patient to fly out there, or only if it's convenient? What would you say if someone calls you about this?

Dr Heery: That is a really tough question.

Dr Marshall: Is it worth a roll of money? Is it worth selling a car?

Dr Weiner: I think it depends on the patient.

Dr Heery: I always talk to the patient about all of those factors.

Dr Weiner: I would say that for patients who have the desire and the ability to travel for an important clinical trial, they should consider it, because there is a fundamental difference between effective chemotherapy for metastatic disease and effective immunotherapy. A smaller proportion of people in general will respond to immunotherapy because we don't yet understand whom to treat and when to treat them. But when they respond, it can be durable. You can have a transformative effect on somebody's life with effective immunotherapy that you may not be able to have with many effective combination chemotherapy regimens for metastatic GI cancers. If it were my patient, and if they were interested and I could find a clinical trial testing a novel checkpoint antibody strategy or some other immunotherapy strategy for metastatic gastric cancer or almost any of the other cancers, I'd sure be looking for it.

The Immunotherapy Arms Race

Dr Marshall: Okay, everybody's got one of these now. Two are approved, right? And others are coming along. We have a portfolio of trials. NCI does too. Are we just shotgunning this?

Dr Heery: It is an arms race between the companies that have these agents. I said last night that I'm happy to see that as that race continues, there is a drive for better science. The companies that are behind this are reaching out to academics and saying, "What is it that we can do not just to catch up with the companies that already have approvals, but to bypass them, move earlier in the disease or see a greater benefit?" The companies that have approvals and the companies that don't are much more interested in hearing about how we think we can bolster the immune response to get better activity with checkpoint inhibitors now. Two years ago, it was very difficult to have those conversations.

Dr Marshall: Tell us quickly about some of the strategies that you're working on. How are we going to try to expand the number of patients that might benefit from immunotherapy?

Dr Heery: In GI cancers, in particular, the underlying immune response for the majority of patients with advanced metastatic disease is actually quite weak, as we measure it by infiltrating lymphocytes. One of the ideas is to combine vaccination against self-antigens that are overexpressed on tumors with checkpoint inhibition. We've done that previously in prostate cancer patients. We saw no additional toxicity when we were able to vaccinate against a target in prostate cancer in combination with a checkpoint inhibitor.[5] We are hopeful that it won't lead to additional toxicity above what is expected from a checkpoint inhibitor, and that it may increase the number of responses in patients with non-MSI-high tumors from close to 0% to maybe up to 20% or 25%. Those sound like small increases, but for the 1 in 4 patients in whom that works, that's a huge difference.

We can also use these therapies in combination with standard therapies to generate response against an antigen that maybe we didn't know to pick out.

From there we'll have building blocks that we can add on. Dr Weiner mentioned that one of the other major issues is in dealing with the microenvironment. There's an immunosuppressive microenvironment in many GI cancers. That would be the next layer, and then we'll have other layers that we'll continue to build on. Vaccination, yes, but we can also use these therapies in combination with standard therapies to debulk the tumor and generate response against an antigen that maybe we didn't know to pick out. The chemotherapy kills the tumor, the dendritic cells gobble it up and present it to the T cells, and the T cells start to learn: "Well, this is something that's out there. We'll go looking for it." We think that those combinations have strong rationale, on the basis of preclinical evidence, and they're approaches that we're ready to get going on.

Dr Marshall: But we're not seeing it knocked out of the park yet. We've been doing some of those trials, combining immunotherapy with chemotherapy[6,7] or with radiation.[8] It's not like tumors are melting, so we've still got lessons to learn.

Dr Heery: We have a lot of things to learn.

Microenvironment, the Tumor's Minefield

Dr Marshall: Teach us about this microenvironment.

Dr Weiner: If you think about PD-L1 and other checkpoints as being sort of like the cannons in the castle, defending against the invaders, you have to think of the environment around the castle (or the tumor cell) as being the minefield. As a T cell is trying to navigate its way in or is thinking about navigating its way in, it either gets blown up or disabled or deflected by any one of a number of different signals. A lot of these come from the tumor. The tumor is defending itself against the immune system. That's how the tumor got to survive.

The tumor is elaborating a whole array of immunosuppressive factors, like cytokines and chemokines, that are actively pushing T cells away or are disabling them or altering their functionality so that they're actually promoting tumor growth as opposed to attacking the tumor. It's a great subversion tactic.

I'll give you a couple of examples that we think are interesting. Scientific work being done here at Georgetown by our colleague, Stephen Byers,[9] suggests that cadherin-11, a molecule that is expressed in the tumor stroma, has an important role in regulating immune responsiveness. We and others have done work over the years showing that transforming growth factor receptor beta is an important negative regulator of the tumor microenvironment.[10,11] Various chemokines and cytokines have been shown to negatively regulate that tumor microenvironment, all in the service of the tumor's quest to be protected from immune attack, and to be able to invade and metastasize and do all the things that kill our patients. That's the bad news.

The good news is that all of those functionalities are targetable. They're targetable by drugs, they're targetable by antibodies. It's super-complicated, and trying to understand which ones to inactivate or to attack, and under what circumstances and how safe it's going to be, is difficult, but it's doable. And we're doing it.

Oncologists everywhere can get involved by participating in the clinical trials that are being conducted—by referring people to clinical trials.

I was just reflecting on Chris's notion of this being a kind of arms race, and yours is a shotgun. I agree completely. I think that's exactly what it is. Frankly, I don't think that any of us are smart enough yet to figure out what the exact right way to go is, so the more the merrier. Let's get everybody involved. This is really, in my view, a scenario where oncologists everywhere can get involved by participating in the clinical trials that are being conducted—by referring people to clinical trials when it's appropriate. I think if we work together as a large sort of mega-community, we're going to have signals and those signals will teach us where we've got to go. Then that's really where the science can bring to bear what has to happen. Because we didn't need any kind of fancy science to tell us that the checkpoint antibodies were working. Our patients told us that. And then we started figuring it out. We went backwards. It's backwards translation.

Dr Marshall: Biomarker in the rearview mirror, as I call it.

Dr Weiner: I am happy with backwards translation if it's working and if it's helping my patients.

Immune Therapy as the Fourth Modality of Cancer Therapy

Dr Marshall: Here's the last question, and this is obviously kind of philosophical. I'm old enough to remember when angiogenesis inhibitors came out, the cover of the New York Times. Jim Watson of Watson and Crick [co-discoverers of the structure of DNA] was quoted as saying, "Cancer will be cured in two years."[12] Well, that was a while ago.

Dr Weiner: He didn't say on which planet.

Dr Marshall: There are ads during football games for immunotherapy for lung cancer now. There's all sorts of hype. Do we need other kinds of treatments? Or if we just figure this out, are we done? Or are we still going to need targeted therapy, chemotherapy? What's the impact of immunotherapy going to be once we get a little smarter? What big piece of the pie do you think it'll take? Chris?

Dr Heery: For now I think we need all of it. I'd say everything we have we're going to need. What I think is really interesting right now is that we're starting to understand the interplay between these therapies that we thought were purely cytotoxic therapies and the immune system and the tumor. That biology, as Dr Weiner mentioned—people used to laugh at you when you said it. Now if you look at grant applications, everything is an immune therapy.

Dr Marshall: Everybody wants their drug to be considered immune therapy.

Dr Heery: Exactly. I think particularly lower doses of some of these agents may have a very important role in modulating some of these factors that we see in the microenvironment. It will take some courage on the part of oncologists to buy into using low doses of tyrosine kinase inhibitors that they know aren't the level that reach the serum concentration that cause killing of a tumor, but combining it with an immune therapy might actually allow you to get over this hurdle that you need to get the T cells into the tumor.

Immune therapy is finally going to be the legitimate fourth modality of cancer therapy.

Dr Marshall: Ten years from now, what piece of the pie is immunotherapy? Is it the primary modality for GI cancers?

Dr Weiner: Immune therapy is finally going to be the legitimate fourth modality of cancer therapy. I think it's going to, in some cases, be the predominant (if not the only) thing we do. But for other cancers, we're going to still need to do more.

Exactly where this all ends up I think is hard to foresee in the crystal ball. I will say that for some cancers, immunotherapy may be enough. For Hodgkin's disease, it seems like it may be all you need. For other cancers it won't be enough, but it's going to be a part of almost everything we do.

Dr Marshall: Lou, Chris, I can't thank you enough for taking the time. It was very helpful and I know it's helpful for the folks watching it and learning about this. Again, thanks for all the help and collaboration you've done over the years for GI cancer.

On behalf of the Ruesch Center, Medscape, and Georgetown University, I really want to thank you guys for listening in. I hope it was helpful to you. Refer those patients or get access to these drugs in the right setting. Change their lives. John Marshall for Medscape. See you later.


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