Harriet Kluger, MD, is Professor of Medicine and Associate Director of the Hematology/Oncology Fellowship Program at Yale University. She received her medical degree from Tel Aviv University and completed the Internal Medicine residency at the University of New Mexico and Highland General Hospital. Following that, Dr. Kluger joined Yale to further advance her medical training as a Hematology/Oncology fellow and works at the Yale Cancer Center.
As a medical oncologist, Dr. Kluger sees patients with melanoma and renal cell carcinoma and co-spearheads multiple major clinical trials studying the efficacy of novel targeted therapies and immunotherapies in cancer patients. One of the phase I clinical trials that Dr. Kluger participated in using concurrent immune checkpoint inhibitors to treat advanced melanoma patients generated very promising results. In addition, Dr. Kluger is the Principal Investigator of an active research laboratory that studies therapeutic responses of renal cell carcinoma and brain metastases of melanoma.
In this interview, Dr. Kluger discusses the current progress of the study using combination immunotherapy to treat advanced melanoma patients and explains the thought process behind this study. She also talks about the main challenges in conducting cancer clinical trials from a clinician’s point of view. Lastly, Dr. Kluger shares how she first became involved with the field of cancer immunology and her experience in working as a physician scientist.
Could you tell us about the phase I trial of nivolumab and ipilimumab combination therapy in patients with advanced melanoma? What is the current stage of that study?
Ipilimumab was the first FDA [Food and Drug Administration]-approved immune checkpoint inhibitor that inhibits CTLA-4 [Cytotoxic T-lymphocyte-associated Protein 4]. Nivolumab is an inhibitor of PD1 [Programmed Cell Death 1] and was approved by the FDA in 2014. When the nivolumab phase I study started, it was clear that we were seeing dramatic responses. Since we already knew that ipilimumab had worked in around 10 percent of patients, the obvious thing to do was to try to combine the two inhibitors. With the concurrent therapy, we had a high response rate. It was in the order of 40 percent once you got above a certain threshold of the nivolumab dosing, which was about 0.3 milligram per kilogram. The 40 percent response rate was something almost unheard of in phase I studies. Importantly, these patients were treated a few years ago, and their response has often been very durable.
What was also interesting was the degree of toxicity that we were seeing. It was higher than what one would expect for either drug alone. The toxicities were different from what oncologists were used to — these were autoimmune toxicities as opposed to toxicities caused by insufficient specificity of a targeted therapy or chemotherapy directly affecting a given organ. As a result, the management was also different and mainly involved immune suppression; interruption of treatment was not sufficient. There are all sorts of nuances to that, such as how long and how much [of an immune suppressant] to give to patients and when and why to restart treatment. Overall, this study is an evolving art.
Why do you choose to study the effect of nivolumab and ipilimumab combination therapy in melanoma patients? Why does the study focus on the advanced disease stage specifically?
Ipilimumab was primarily developed to treat melanoma. It was given to patients with other diseases as well, such as lung, prostate, ovarian, and renal cancer patients. However, the most activity was seen in melanoma patients. Historical data suggested that melanoma and renal cell carcinoma are more immunogenic than other diseases, based on evidence such as spontaneous regression and autoimmunity, which were rarely seen in other cancer types. However, today we know that there are other cancer types that are also immunogenic, possibly even more so than melanoma.
When we have a new drug or a drug combination, we typically try them first in patients with advanced disease, i.e., unresectable disease, for two reasons: firstly, the end point is shorter. It is easier to see if the tumor is getting smaller or not as opposed to giving the treatment to someone who does not have a measurable disease. In the latter patient group, we have to watch patients for years to see if the disease comes back, so the trial would be much more expensive and requires a larger sample size (hundreds of patients). Conversely, if the study is in patients with measurable disease, the initial sample size for determining drug activity could be 30 to 40, depending on the expected response rate. Second, patients with advanced disease have the least to lose because in theory they are not cured by surgery and/or radiation. If you take a patient whose disease is gone completely after surgery, depending on the depth, nodal status, and other nuances, they still have a chance that they will never have disease recurrence. Therefore, you don’t want deaths in patients who might have been cured from surgery alone. For these reasons, early stage clinical trials are often done on patients with advanced disease.
Does the tumor immune activity vary significantly over the course of tumor development? In other words, do you think these drugs or the combination therapy could work on early stages of melanoma?
They could work. It probably depends on the property of the melanocyte itself, the types and numbers of mutations and neo-antigens that it has, and the tumor microenvironment. There are studies ongoing using these drugs, not in combination yet, but individually on early stage melanoma.
Have you observed resistance with nivolumab and ipilimumab or the combination of two drugs in patients?
We have definitely seen resistance with ipilimumab alone. In patients treated with nivolumab alone, at the 2-year point, half of the responders had developed tumor regrowth. With the combination therapy, we have seen some regression and regrowth of tumor, but it might occur less often or later than with nivolumab alone. However, the randomized trial has just been completed and the dates are not yet mature to determine whether the duration of response is longer in patients on the combination therapy than either drug alone. On the other hand, we also do not know if retreatment with these drugs at the time of regrowth will make a difference. For our initial trial, patients were treated for a limited duration of time and then stopped, so the regrowth we have seen in some may not be a result of resistance. It may be reversed by further immune stimulation.
With your experience in clinical trials, what do you think are the main challenges when conducting these studies?
There are massive challenges when conducting clinical trials these days. Financial challenges are considerable. In the state of Connecticut, we are relatively fortunate because insurances that do business in the state are required to cover participation in procedures that are considered the standard of care for patients participating in trials. Patients still have to pay the co-pays. Sometimes we also have trouble getting certain things reimbursed. The second problem is regulation. Over the years, the requirements for safety have been increased. It may be for good reasons, but it is putting a huge burden on the system. The standard budget for putting a patient on a trial is much higher nowadays than it was 10 years ago.
In addition, I think that the academic community has to be careful with becoming a victim of one’s own success. As the drugs get better and therapies get better, more and more patients will be treated with the standard of care, and we will learn less and less as a result. For example, in breast cancer, there are multiple drugs that have activity in metastatic breast cancer but we are still not clear if we are improving the survival by much. Most patients in the United States are being treated with standard approved drugs, one drug after another, which might be convenient but does not help move the field forward and might not be the best thing for the patient. It is possible that we should be trying things that are more creative upfront to avoid losing our window for trying novel therapies, which might be superior to the older, approved drugs. For melanoma and other diseases, we might be going down the same path as therapies get better. I am pretty convinced that we are already seeing an improvement in median survival in patients with metastatic melanoma. We have some institutional data showing that it is better than historical data, and I believe that with time, not a lot of time, we will see that the median survival for metastatic melanoma increases from 6 months, which was reported back in 2003, to something in the order of a couple of years. It is going to become harder and harder to bring those to 2 years to 5 years and to 10 years because of the challenges that I just mentioned. This is something that might be good for individual patients, but we need to be very careful to make sure we continue to do better.
A lot of your clinical and bench work emphasizes immunotherapy. What inspired you to focus on this particular aspect of cancer biology?
To be honest, I started my career by studying targeted therapies in melanoma. When we first started to see responses to ipilimumab, and even to interleukin 2, although it was a small percentage of patients (less than 10 percent), some of these patients were disease-free even a decade later. This type of success cannot be argued with. Of course, the PD-1 inhibitors just took the whole field to a different level, which is very exciting and interesting. I think we are just scratching the tip of the iceberg in terms of what we can do with immune manipulation in cancer therapy. There are going to be many other checkpoints that we can manipulate. Some would have to be stimulated, and some would have to be inhibited. We need to better determine the roles of other immune cells such as macrophages and dendritic cells in immune evasion by cancer cells. There is still a lot of discovery to do and a lot to learn.
Could you talk about the projects that your lab is currently working on?
We have melanoma and renal cell carcinoma projects. For renal cell carcinoma, we are looking at predictive biomarkers for targeted therapies. These projects were started 7 to 8 years ago, but it took a long time to complete clinical trial accrual and to receive tumor samples, so now some of the projects finally are approaching their end. Even though targeted therapies for renal cell carcinoma are less exciting than immunotherapies, they are still widely used. Moreover, not everyone is responsive to immunotherapies. Identifying biomarkers predictive of response to targeted therapies in renal cell carcinoma is still critical, and of course we are now moving toward immunotherapy. We are collecting tumors from patients treated with the immune checkpoint inhibitors and analyzing them along with patient blood samples.
In addition, we have a specific focus in the lab on melanoma brain metastasis, primarily because about 50 percent of our patients develop brain metastases at some point during their illness. It can be very challenging to manage brain metastases. One of the reasons is that historically, these patients were excluded from clinical trials until only 3 years ago. Some of the seminal studies completely excluded patients with brain metastases even after they were treated with radiation or surgery. Then we started seeing studies requiring 3-month stability of brain metastases after radiation. If a cell got into the brain and settled in one place resulting in a tumor, it is likely that there were others that trailed behind but might not have proliferated sufficiently for a tumor to be visible on imaging. Therefore, waiting for 3 months to make sure these patients do not develop new metastases is very difficult. As a result, brain metastasis patients over the years had limited access to novel therapies. Along with other colleagues in the field, we started to push for earlier evaluation of newer therapies on patients with brain metastases using studies that specifically focus on this patient population. We are working very actively on that.
As a practicing clinician and also a Principal Investigator of a research lab, what led you to decide to work in both fields? What do you think are the challenges? How do these two different experiences benefit each other?
I think that they are highly synergistic. Over the years, all of the grants that I have had in the lab started with a clinical question. A patient walked in with a specific question that provoked the thoughts about a series of experiments that we could do. Having the privilege of working both in the lab and the clinic has been most helpful, but it is also difficult since you only have 24 hours in a day. Sometimes it is challenging to manage time and to be at both locations monitoring things and making sure that everything is progressing as it should. I am going to try to do this as long as I can. I love my job and both aspects of it. It’s very satisfying.
To conclude, as a physician scientist, what suggestions would you give to research scientists and clinicians who are interested in studying disease-oriented translational research but have limited access to the opposite end of the field? Do you think communication or understanding each other’s ‘language’ could be a big challenge during collaboration?
Collaborations are key. If research scientists do not engage clinicians, they will not have the same access to appropriately annotated specimens and are less likely to engage in clinically relevant research. On the other hand, clinicians need to be humble. Many of us, myself included, do not have the training of a basic scientist, and we need help from collaborators. I have a lot of them and really depend on them. It appears that the NIH [National Institutes of Health] research apparatus is moving more toward a model of interdisciplinary collaborative research efforts and there are specific funds for this, which are very beneficial. Interdisciplinary collaborations are sometimes challenging but definitely worthwhile.
Meanwhile, communication can be a challenge. Leadership on both ends of the spectrum needs to make sure that individual contributions are recognized and that everyone has a piece that they can “own.” I think we all need that, especially when there is competition for limited resources. In terms of understanding each other’s “language,” working in an environment like this is most helpful. I came to Yale with no bench experience. I remember going to the Yale Cancer Grand Rounds as a first-year fellow and listening to the talks. Sometimes I could understand a lot, but there were lectures given by basic scientists in which I could only understand 20 percent of what was being said. I persevered, and now I can understand the majority of what is being said. I would presume that for basic scientists to really understand the “language” of a clinician, s/he would have to come to clinical meetings such as tumor boards and listen to presentations of the clinical picture, the pathology, and the imaging. This requires investment of time and effort and a lot of mutual respect and cooperation.