Bernard Fox, phd: The Promise of Immunotherapy in Curing Cancer

Bernard Fox, phd, will speak at the Oncology Association of Naturopathic Physicians (OncANP) annual conference in Phoenix, Arizona, February 26–28, 2016. He is chief of the Laboratory of Molecular and Tumor Immunology at the Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Center, UbiVac, and an associate professor of molecular microbiology and immunology in the School of Medicine at Oregon Health and Science University.

Dr Fox was part of the team that performed the first-in-human studies of genetically modified cells (National Cancer Institute) and was an investigator on the first clinical trial to genetically modify tumors in patients (University of Michigan), the first gene therapy trial for HIV/AIDS (University of Michigan) and the first trial of gene-modified tumor vaccines in Oregon.

Dr Fox helped develop the tumor immunology training programs between the Earle A. Chiles Research Institute and both Xi’an Jiaotong University in Xi’an, China, and the Ludwig-Maximilians-University in Munich, Germany. A principal goal of these programs is to train scientists and physicians to translate preclinical studies into clinical trials. His research efforts are divided between preclinical animal models and the development, performance, and monitoring of immunotherapy trials for patients with cancer. His research efforts have been supported by the National Cancer Institute/National Institutes of Health, the Department of Defense, biotechnology and pharmaceutical companies, and philanthropic sources.

Integrative Medicine: A Clinician’s Journal (IMCJ): At the Oncology Association of Naturopathic Physicians, or OncANP, conference in February, you will be speaking about cancer immunotherapy. How do immunotherapy treatments work against cancer cells?

Dr Fox: We should start with the following concept: We think that everybody develops cancer over their lifetime, and probably many times. Those who do not have evidence of cancer have an immune system that has managed to eliminate it. It is only when the cancer figures out ways to evade the immune system—developing stealth mechanisms that can allow it to escape detection or by exploiting defects that reduce the capabilities of patients’ immune systems—that we see cancer growing out.

The idea of cancer immunotherapy is to either educate or boost the immune system so that it can eliminate cancer. Recently there have been FDA approvals for a series of agents that can boost the immune response and are increasing survival for patients with cancer.

IMCJ: Are specific escape routes targeted, or is the therapy more of a general strengthening or reinforcement of the immune system?

Dr Fox: The drugs that have been approved recently have focused on taking the brakes off of the immune system. They are called checkpoint inhibitors. The first is normally used by the body to turn off its own immune cells. It is called CTLA-4, or cytotoxic T-lymphocyte-associated protein 4, and it is a molecule found on the surface of activated T cells. When immune cells express CTLA-4 instead of being “boosted” by other immune signals, termed costimulatory signals, the T cells are shut off, effectively putting the brakes on the T cells. So by giving an antibody that binds to CTLA-4—that inhibitor that negatively regulates T cells—the T cells no longer have that braking system and they can fight the cancer continuously. That antibody is anti-CTLA-4. The drug name for it is ipilimumab, or Yervoy, and it is one of the drugs that has been approved.

Another molecule that gets upregulated when T cells are activated to respond to cancer is called PD-1, or programmed death 1. So PD-1, you can imagine, is not a good thing to have on your surface. It is programming you for death or turning you down or shutting you off—maybe transiently or maybe permanently. So when you have a blocking antibody against PD-1, you can take out that negative signal, effectively taking the brakes of off the immune T cells. The reason that this is so important is that many types of tumor cells can express the ligand for PD-1, which is programmed death ligand 1, or PD-L1. Tumor cells can upregulate this ligand, so that when the activated killer cells come in to kill the tumor with PD-1 on their surface, the tumor’s PD-L1 combines with the PD-1 to trigger those T cells and shut them off. By taking that inhibitory signal away—by administering an antibody against PD-1 that blocks the death signal, you can maintain the activated T cells and they can continue their killing mechanisms.

Another facet is that tumor cells have also figured out ways, if they do not express PD-L1, to induce other immune cells to express PD-L1, essentially making a barrier of immune cells that protects the cancer. It is pretty fascinating.

These are recent findings that are providing insights into why patients either respond or progress on immunotherapy. Additionally, new technology which gives us ways to evaluate multiple markers on cells, is providing incredible insight into what is going on in the patient’s tumor, leading to ways to tailor therapy in the future so that patients can have more effective therapy.

IMCJ: Is this leading in the direction of individualized medicine?

Dr Fox: It is individualized in terms that we can tailor therapy, for example, administer anti-PD-1 to patients with tumors that contain PD-L1+ cells, but it is not individualized in the sense that you have to make a product just for that patient. However, using biopsies to determine which drug, or combination of drugs, a patient should receive, is coming. The FDA has already approved a companion biomarker test for PD-L1 expression. It enriches for patients who are likely to respond to treatment with anti-PD-1. This is just a start, but it is getting there. I saw a paper this weekend, on a disease called diffuse large B-cell lymphoma, from a Japanese group that looked at more than 1000 patients and were able to separate and identify a new cohort of these B-cell lymphomas that express the PD-L1 molecule. It is a very small percentage. I do not remember the numbers offhand. I think it was 10% or 15%.

For those 10% or 15%, since the cancer expresses PD-L1, you would want to try to do a clinical trial treating those patients with an antibody that would eliminate the negative effect of that PD-L1 molecule. You would imagine, that may be why those patients do so badly, is because the cancer figured out ways to turn off the killer cells so it can continue to grow uncontrolled.

IMCJ: What are the advantages for immunotherapy for patients, as opposed to treatments that are more often used in oncology?

Dr Fox: I will give you an example. Hodgkin’s lymphoma is a disease that can be treated effectively in a number of patients through bone-marrow transplant or stem-cell transplant. I think everybody reading this knows that in a stem-cell transplant, you do lethal doses of chemotherapy and, in many cases, radiation. You come back and rescue the patient by giving them a stem-cell transplant. This is a risky procedure but it can cure people of their disease.

The data are still early, but it looks like Hodgkin’s lymphoma patients who have failed bone-marrow transplant are having an 80% response rate to treatment with anti-PD-1. This is amazing.

Here you have a drug, so I do not want to minimize the fact that it has some very serious toxicities that can lead to death. For example, you can have really bad diarrhea, pneumonitis, or hypophysitis, and you can be taking a pill for the rest of your life. But this is different than being taken to the edge of death, through the elimination of your whole immune system and repopulating it with a bone marrow transplant. In this case, immunotherapy is giving an IV every 2 or 3 weeks and many people do not have serious side effects.

That is where we think the field is going. As someone who has been in immunotherapy for more than 25 years, I see this moving to where we will eliminate the use of chemotherapy in many histologies. You will certainly want to use surgery to cut out whatever you can. Radiation will be used for some diseases, but I think we are going to get to the point where we can figure out what goes on and understand how cancer evades the immune system. We will then be able to take those escape mechanisms away and we will be able to eliminate those cancers.

That view is not shared by a lot of people, but there were very few people that thought immunotherapy would be used for 60% of cancers, and that the biggest blockbuster drug of all time in oncology (at least until the next new immunotherapy arrives) would be anti-PD-1. It is clear—it is working across a majority of cancer histologies. Positive results from immunotherapy trials is shaking up the field in such a way that I think it is not unreasonable to think about a world where chemotherapy is rarely used. I think Hodgkin’s lymphoma is going to become the poster child for that concept of being able to eliminate chemotherapy.

IMCJ: How is immunotherapy faring as far as remission and recurrence rates are concerned? Can these downstream observations be measured yet?

Dr Fox: For the new drugs that we are talking about, it is way too early to know how that is going to work out. For immunotherapy in general, I would have you look at interleukin 2, or IL-2, which is a drug, a hormone of the immune system, a cytokine, and a T-cell growth factor. It has no effect directly on cancer cells, because they do not have the IL-2 receptor. The drug works by boosting the immune cells and can lead to complete remissions in a small percentage of patients with melanoma and renal cancer. That can be in the 5% to 10% range. For those who obtain a complete response, complete response is maintained in 70% to 90% of patients at 20 years.

We have data from 1 group that showed 90% at 20 years. Another group showed about 70% at 20 years. There is actually a woman with metastatic melanoma who was treated at the National Cancer Institute in 1984 who had a complete response and who is now out 30 years. This is a patient with melanoma that had failed treatment with many other therapies and was cured by immunotherapy.

This is a great thing about the immune system, it can provide life-long immunity. Once you have had measles it does not come back. Once you have had mumps, you are protected—unless your immune system is knocked out— and it can provide lifelong immunity. The Society for Immunotherapy of Cancer has a t-shirt that says, “Cure. Yeah, we said it.” We think that if you can obtain complete responses with immunotherapy, it will lead to lifelong cures for patients. That is very different from small molecules for targeted therapy that can have complete remission rates of maybe 9 to 12 months in many diseases before the tumor evades—with the exception of chronic myeloid leukemia, where there can appear to be very long-term durable remission.

However, the studies with these new immunotherapies in patients with solid cancers are not getting all of the patients into a complete response. For patients who have a partial response, we expect that the cancer cells that remain are going to find ways to evade the immune system. Some, including myself, think patients have a partial response because the immune system has not been educated to see enough of the variant cancer cells present in the tumor. To overcome this, we may need to induce broad immunity against 10s or 100s of targets expressed by the cancer. So, the future for our field is going to be in figuring out how to broaden a patient’s anticancer immune response to prevent the tumor cells from escaping—from turning off this gene or that gene that the immune system sees, so that tumor cells can not evade. We expect that the cancer cells will not be able to eliminate all those proteins, or it will cease to be a cancer cell. From my perspective, inducing broad anticancer immunity is one of the major goals for the next decade.

IMCJ: What challenges are you encountering in cancer immunotherapy?

Dr Fox: We are not getting all those patients into complete remission, but some of the patients with partial remissions are having stability for a very long period of time, 4 to 5 years. However, I am concerned, because cancer is a very tough adversary. It can evolve. It continues to evolve. If you have not eliminated all of the tumor cells, they’re going to continue to evolve.

One of my concerns is that we may be breeding tumors that will learn to escape the immune system in some other way. That is why we need to be pushing for the complete response—getting complete response rates that are very high.

For lung cancer, the study, which contributed to the approval of anti-PD-1 in lung cancer, has seen a doubling of response rates over chemotherapy. That is a great start, looking at only 1 agent—and that agent is only targeting 1 escape mechanism (PD-1). But again, while response rates are relatively high, many of these patients are not having a complete response and remain at risk of having their cancer progress.

What we have been talking about are antibodies that are checkpoint inhibitors, However, there are other ways that we can boost the immune system: by giving costimulation or by directing the immune system to see the cancer better by employing cancer vaccines.

We think the reason that checkpoint inhibitors do not work in some patients is because the patient receiving the checkpoint inhibitor does not have their immune system turned on so that it is able to recognize their tumor. While it is not perfect it is working in nonsmall cell lung cancer. It is also working in triple-negative breast cancer and is having an effect on gastric cancer, renal cancer, and bladder cancer. I believe anti-PD-1 is currently active in approximately 12 different histologies.

That is just by itself. As soon as these drugs were approved, partnerships started combining these immunotherapies with other things like chemotherapy or small molecules. That is where a big part of this field is going. There are as many as 200 trials going on in the United States, alone, using immunotherapies—anti-PD-1, in particular—for many different histologies.

IMCJ: Is cancer immunotherapy giving us insight into which cancers are more treatable?

Dr Fox: There is a paper in Nature Reviews Cancer by Wolf Fridman, md, phd,1 that reviewed more than 100 papers. This is now more than 3 years old. It looks at cancers and looks at how many different cancers show evidence that when you look at the patient’s biopsy, if there are immune cells present—certain types of immune cells—then those patients do better, regardless of the therapy. It is the prognostic biomarker for success. While this is well known in colon cancer, it is also true in 18 of the 20 malignancies that Dr Fridman looked at. This tells us 2 things: First, in all these cancers, we think that the immune system is really important. But, it also tells us that in cancer cases, where we catch them early and do not do anything for those patients, for instance stage I or II colon cancer, it turns out that patients with no immune cells present in their resected tumor have a high likelihood that their cancer is going to come back.

Currently most centers do not offer treatment to these patients as the vast majority will do well and the 5-year survival rate is greater than 90%. However, if you could identify the patients who will progress in the next 2 years, you could offer them a clinical trial. One option might be a cancer vaccine that might prevent recurrence.

IMCJ: What are the newest directions being explored?

Dr Fox: The latest thing is probably the chimeric antigen receptor T cells. In this case you engineer immune cells with a receptor that can bind cancer cells. When these engineered immune cells bind a cancer cell, this new receptor turns on the killing mechanisms of the immune cell and the cancer can be destroyed This approach is working incredibly well in leukemias, lymphomas, and liquid tumors. They have not yet worked well in solid tumors, though. However, it is likely that they eventually will work well because there are a lot of really smart people putting in a lot of energy, and now they have financial resources to support the required research.

Another strategy to direct immune cells to the cancer without having to genetically engineer a patients immune cells are called biospecific antibodies. These are small molecules that have at least 2 ends to them. One end binds to the immune cells, the other end binds to the cancer. That way they can redirect the T cells without having to engineer them. This is a very exciting area of clinical research. An area that I am also working on is cancer vaccines that can broaden the immune response against more targets expressed by cancer.

IMCJ: Is immunotherapy poised to become a mainstream tool in the oncologist’s toolbox, or is it still at a point where access is restricted to those participating in a clinical trial?

Dr Fox: Now that it has been approved for second-line treatment of the number 1 cancer, which is lung cancer, I think it is going to become a more common tool of the oncologist. In the next 2 to 3 years, you are going to see many more approvals. Probably in the next 6 months, we are going to see approvals. That is going to really broaden the application of these new agents.

A current challenge for the field is to educate physicians and educate patients as to what the side effects are, how to give these drugs safely, and what to watch for. It is very different from the approach oncologists are used to when prescribing chemotherapy. For example, when somebody has diarrhea, you do not give them antibiotics, you give them steroids. We have got to educate people to do those sorts of things, because if you don’t, it can lead to ulcerations or other situations where patients will die.

There is still a long way to go to get the general oncologist to become comfortable with this. Having said that, the American Society for Clinical Oncology’s meeting—the largest meeting in the world of medical oncology—this past year had significant time dedicated to immunotherapy oncology. It was in many of the major sessions and symposia. So, docs who are going to this meeting are learning about immunotherapy pretty rapidly, and that’s going to be the major way to get the information out.

Then there are societies like the Society for the Immunotherapy of Cancer, which puts on a program called Advances in Cancer Immunotherapy day courses to help educate oncologists on to how to administer these drugs and what to look for.

IMCJ: What more will you cover for attendees at the OncANP conference in February?

Dr Fox: I think one of the big holes for the future of cancer immunotherapy is that our response rates, while they are great and they are going up, they are not perfect. There is all this wonderful news about these response rates. But, the response rate is still less than 30%. We can pick patients who have immune systems that are amazing and get it up to 40%, but that still means 60% of patients are not being helped. What are the next steps? What do we need to do so everybody can benefit from this? I don’t think that it is unreasonable to be thinking about increasing response rates to greater than 90%.

I just came from The Society for Immunotherapy of Cancer annual meeting, and one of the big questions came from a think tank called the Cancer Immunotherapy Trials Network. They were talking about what our next steps will be. Almost universally, we think it is going to be vaccines, because many of us do not think chemotherapy and/or radiation alone are going to turn on the immune system in most patients. We need to find ways to educate the immune system to see cancer. From my perspective, that is going to require vaccines.

There are many different strategies. All of them need to be tested, because nobody can figure out what is going to work until you test it. The immune system and the body are very complex. I am tending to bet more on the broader approach of looking at turning on immunity against as many things as possible. This idea that the tumor continues to evolve and escape immune detection, unless you can bombard it with immune cells against all kinds of components, means that you are not going to be successful. The solution is not just turning on the T cells, but turning on the other arms of the immune system, as well. I think you loose a lot if you just try to target T cells, or turning on the B cells so they can make antibodies against these tumors. We are looking at strategies to turn on the natural killer cells and other approaches to go after the cancer, too.

We think that a vaccine strategy that uses other immunotherapeutics in combination to turn on all arms of the immune system is where the future is going to be for patients. That way, we hope we can get to a 100% cure rate, which of course, is what everybody wants. It has been hard to even imagine that—even just a few years ago—but it is coming.