Ralf Kleef, MD, has a private practice in Vienna, Austria. He led a commission to examine fever therapy of cancer for the Office of Alternative Medicine in the National Institutes of Health from 1996 to 1998, and he serves as a training manager for the Naturopathic Physician Module in Germany. He is a sworn, court-certified expert for hyperthermia and complementary medicine in Austria.
Integrative Medicine: A Clinician’s Journal (IMCJ): How did you get into immunotherapy research and practice?
Dr Kleef: My first experience with the power of heat was a Native American Indian sweat lodge when I was 19. I was deeply impressed by the shamanistic ritual of the Native Americans. I participated in several sweat lodges during a United Nations conference in Geneva and I was deeply moved by the experience.
Then, more than 10 years later, I encountered hyperthermia in one of the first German clinics that applied hyperthermia as a heat treatment for cancer. That immediately fascinated me. At that clinic, I was also introduced to fever therapy for cancer, active fever therapy with pyrogens, using Coley’s toxins. The treatment itself with Coley’s toxins wasn’t that dramatically effective, but it caught my sincere attention.
After I was trained as a clinical oncologist in Germany, I decided to apply for a postdoc fellowship in immunology at Sloan Kettering Cancer Center in NYC. During that time in the middle of the 90s, I introduced myself to Helen Coley Nauts, who was the daughter of William B. Coley, MD, himself. Coley is credited as the father of cancer immunotherapy. We clicked immediately and became best friends.
I finished my postdoc and I became a fellow of The Cancer Research Institute, or CRI. My mentor was Lloyd Old, MD, the world-famous immunologist and the director of Ludwig Institute as well as director of the CRI. Lloyd was a big inspiration to me.
Then, I suddenly got an invitation from the very young Office of Alternative Medicine at the NIH, which is now called OCCAM. Back then, it was OAM, Office of Alternative Medicine. Now it’s called Office of Cancer Complementary and Alternative Medicine. Wayne Jonas, MD, was the acting director at that time—this was 20 years ago, and he invited me: “Ralf, why don’t you come aboard and write the scientific history of Coley’s toxin.” I did so. I spent a year in Washington, DC, quite unexpectedly joining this rather young group at the NIH Office of Alternative Medicine.
With that background, I then decided to go back to Europe and to set up my clinic in Vienna. I have done hyperthermia treatment, metronomic therapy using low-dose chemotherapy, and dendritic-cell therapy. We did all that for so many years and we had good results, but about 4 years ago, we found something which seems to be much more promising than anything I’ve done before. I would like to explain what we do, there. That is why I also consented to go to San Diego for the conference.
IMCJ: Is immune-oncology well understood at this point?
Dr Kleef: Yes, there are currently more than 1400 clinical trials on immuno-oncology. It’s a huge, multibillion-dollar market. The market’s probably already bigger than the chemotherapy market. Since checkpoint inhibitors have been awarded the Nobel Prize to 2 men just 2 weeks ago— James Allison for the CTLA-4 discovery and a Japanese scientist for PD-1—it will be an even a bigger business. What they discovered is, basically, how to motivate the immune response towards cancer cells. But there is, of course, a lot of warranted caution and skepticism involved in the whole field.
IMCJ: Is there a particular mechanism that immunotherapy leverages or are there several different pathways involved?
Dr Kleef: Checkpoint inhibitors are substances which inhibit the checkpoints. It’s an inhibitor of the inhibitor, or a braking of the brake. Checkpoints are expressed on the surface of tumor cells, dendritic cells, macrophages, and cytotoxic T cells. They inhibit the specific T-lymphocyte response in the immune system. Those checkpoints can be quite highly upregulated, disturbing or inhibiting the communication between all these players, the dendritic cells, the macrophages, the T cells, and the cancer cells. If you inhibit those inhibitors you can, actually, brake the brake and induce a powerful T-cell response. That work has now revolutionized cancer treatment. The approach has taken the field to a completely different level. In America, the Society of Immunotherapy of Cancer, or SITC, is huge. The corresponding group in Europe is called ITOC, or Immunotherapy of Cancer.
The criticism to the checkpoint inhibitors is that only about 20% of patients really benefit from it. The side effects can be severe. The official death rate is about 1%. Probably, the unofficial death rate, due to the side effects of immunotherapy, is about 2%. Acute side effects include diarrhea, skin rashes, and mild pneumonitis. More serious side effects are hepatitis and pancreatitis. Then there are the late endocrinopathies where, after weeks or even months, you could have a severe disturbance of your thyroid hormone level, either hyperthyroiditis or hypothyroiditis. You could even develop diabetes mellitus type 1. The most serious death rate was due to colonic perforation because such strong diarrhea can break the colon and cause sepsis.
So there is some justified criticism to the therapy. Of course, the scientific community gets better and better at discovering those immune-related adverse effects, or irAE. You need to know a lot about this whole field, with a lot of clinical experience to manage patients properly. The knowledge is growing rapidly all over the world. Some mild side effects, including fever, are actually good. Then we know things are working, but you need to know when that goes too far.
IMCJ: Have markers or characteristics been established for identifying patients who would be better candidates for immunotherapy?
Dr Kleef: Yes, of course. The most important beneficial prognostic factor is a high microsatellite instability, such as in colonic cancer, which means they have a mutation load which qualifies them for immunotherapy. Interestingly, lung cancer patients who are smokers or ex-smokers have a better chance to benefit from immunotherapy because they have mutations on the surface of the epithelium, which makes the epithelial surface more receptive for checkpoint inhibitors.
Of course, then there is the direct quantitative measurement of the expression of the checkpoint. Normally, this is done by a pathologist with immunohistochemistry However, we are collaborating with an excellent laboratory in Germany, which goes far beyond that and is looking at pCR technologies to identify the expression strength over a variety of checkpoints, including PD-1, PD-L1, CTLA-4, IL-2, IL-1, and so on. We believe that provides a much better way to look at the individual patient. I’m going to show all these techniques, of course, during my talk.
IMCJ: Which varieties of cancer are most responsive to immunotherapy?
Dr Kleef: Currently, about 7 cancer types are licensed. The old ones were melanoma and hypernephroma. Now we have Hodgkin’s lymphoma, non-small-cell carcinoma of the lung. We have head and neck cancers, a very promising one. Hodgkin’s lymphoma and/or urothelial cancer. They’re also about to work on breast cancer. Triple-negative seems to be more immunoresponsive than hormone-receptor-positive breast cancer. They even have started looking at glioblastoma. In the next few years there will be a multitude of new indications for immunotherapy. Remember this is huge market. The problem is, if all those cancer patients want to have checkpoint inhibitors—which can cost anywhere between $200 000 and $400 000 per year, per patient—it could actually be a severe challenge to the whole health care system, to the whole way how we pay for oncology treatments.
IMCJ: Is there a different structure or framework that has to be used when performing immunotherapy research as opposed to the standard clinical trial?
Dr Kleef: Yes. You must have a sound molecular-biology analysis of the tumor microenvironment. You should look at the expression of the varied checkpoints to determine whether the patients qualify. You also should look at possible inhibitor mechanisms, such as wrong macrophage polarization, expression of T-regulatory cells, or lymphocytopenia, per se, following chemoradiation therapy. All these play a role.
IMCJ: How receptive are patients to using immunotherapy?
Dr Kleef: That is what I think is so fascinating about this new field. Patients are seriously interested in that now-a-days. If you can tell patients, “This is not just chemo or radiation. This is something where we will stimulate the healing power within, which is called the immune system,” then you have the patient involved in a completely new way. Where they were previously just receivers—passive sheep getting radiation and aggressive chemotherapies—where they weren’t sure whether there would be a benefit at all, now there is a justified hope that something completely different is happening, a healing from within. That is an extremely interesting development, where the patient should also be taken into this whole picture and not left out.
We know that our thoughts, our feelings, our thinking, and our expectations do play an enormous role in healing Just to mention the work of Kelly Turner, PhD, on radical tumor remission: It must not be underestimated, whether the patient believes in this miracle of healing and puts everything—all the power within—that this will be effective or just takes a skeptical perspective and says, “This is trial-and-error and it will not work.”
Checkpoint inhibitors or immunotherapy of cancer allows a patient to be a more proactive partner in this whole play and not just be a patient who receives something which may or may not work.
IMCJ: Are there complementary therapies that go along with immunotherapy that support the immune system and its response?
Dr Kleef: Yes, definitely. We know that the gut-associated immune system is closely linked to the efficacy of immunotherapy. That had been published in September 2017 in Science, the extreme importance the microbiome plays in immune response. Human beings have 10 billion cells and here we host 100 billion bacteria. The motivation of the gut microbiome is actually mandatory, I believe. I’m sure naturopathic physicians can be better in assisting patients with a very sophisticated approach of how to support a good microbiome. Lactobacillus brevis and L longus are both very important.
Also, talking about the side effects, plant medicine can play an enormous role in mitigating the side effects, as well as in helping the cytotoxic T-cell function to be more effective, such as medical mushrooms. Some practitioners out there are very good with that or simple things as vitamin D3. They all play a role in the equation. Ultimately, the naturopathic approach is going to play an enormous role in mitigating side effects and making things more specific.
IMCJ: What more will attendees learn from your presentation?
Dr Kleef: I’m going to talk about our unique approach, in which we believe takes immunotherapy to even another dimension. We’ve shown that in a large group of patients, already—that we can have even better objective and overall response rates. These are dozens of patients—not hundreds, yet—who against all expectation went into lasting, complete remission in stage I V. I’m going to show exactly how we did it. We have something very significant to contribute to that conference.
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