Chris Klebanoff, oncologist: ‘We have to take a much more precise view towards how we treat each cancer patient’

The doctor and researcher at Memorial Sloan Kettering Hospital in New York believes that cancer vaccines, which are still under investigation, will begin to be used in the early stages of the disease, to try to prevent relapse

Chris Klebanoff
Chris Klebanoff, oncologist at Memorial Sloan Kettering Hospital and the Parker Institute for Cancer Immunotherapy, photographed in the garden of the Ateneu Barcelonès.Albert Garcia
Jessica Mouzo

Cancer immunotherapy has been revolutionizing oncology medicine for more than a decade. This strategy, which consists of helping the immune system fight malignant cells, has managed to challenge — and reverse — some of the most dire prognoses in melanoma, lung cancer and a handful of hematological tumors. And although it is not an infallible magic bullet — it does not work in all patients nor for all tumors —, there is still room to further exploit its possibilities, says Chris Klebanoff, 45, an oncologist and researcher at Memorial Sloan Kettering Hospital in New York and the Parker Institute for Cancer Immunotherapy. The doctor, an expert in cellular therapy, visited Barcelona to participate in the first VHIO-BBVA Foundation International Symposium on Cellular Therapies in Oncology.

Question. Has immunotherapy reached its peak?

Answer. I think we are still in the middle of the second part of a three-act play. The first act of the play was the discovery that the immune system could be used as a form of cancer treatment. The second act is to develop new therapies that are more effective in more cancer types. The two major forms of immunotherapy are either the immune checkpoint blockade, which are antibodies that function as if they were taking the break off the immune system; and the other big innovation is reprogramming by genetically engineering the patient’s own immune cells to recognize and eliminate cancer cells, something called CAR-T therapy. The challenge is that the vast majority of cancers that affect adults are solid cancers and perhaps only 20% of all those solid cancers will respond to current immunotherapies. And while that’s wonderful progress, it means that about 80% of adult solid cancers are not responding to currently approved immunotherapies. So I think that shows both the promise, but also where there’s great opportunity to further expand immunotherapies.

Q. What happens to this 80%? Why doesn’t immunotherapy work for some patients?

A. The most likely explanation in those 80% of patients is that they just, for whatever reason, are unable to develop an early immune response against the cancer. And that becomes a clue about what we can do to make responses happen in that 80%. One approach, which is the focus of my laboratory, is to genetically reprogram immune cells to recognize antigens or potential targets that are uniquely expressed by solid cancer cells, but are not expressed by normal cells. So the idea here is that if a patient can’t generate a natural T-cell response, in the lab we can use genetic engineering to synthetically create an immune response, expand these cells outside the body, and then re-infuse them back as a form of cancer treatment to a cancer patient.

Q. Increasingly personalized medicine.

A. Correct. Therapies that are precisely tailored to the patient and, more importantly, precisely tailored to the unique genetic mutations or genetic changes that caused a patient’s cancer to grow in the first place.

Q. CAR-T therapy has shown good results in some types of hematological cancer, but not in solid tumors. Why?

A. One of the major limitations is the fact that in many blood cancers, especially those that begin from either antibody-producing B cells or the precursors of antibody B cells, we can target antigens that are expressed by these cells, but these targets are also expressed by normal B cells. [These antigens] are very uniformly expressed, so they represent ideal targets. And human beings, to my surprise and to the surprise of many of my colleagues, even though the CAR-T cells also eliminate normal, healthy B cells, patients do surprisingly well without normal B cells and the tumor cells regress. Using the same approach for solid cancers has been limited by the fact that we really haven’t found targets that cancer cells express and that, if shared by a normal healthy tissue, the patient can tolerate injury to healthy tissue. So a major limitation for the field is finding immunological targets that are uniquely expressed by cancer cells and are not expressed by normal, healthy tissues.

Q. Regarding these innovative immunotherapies, the U.S. Food and Drug Administration (FDA) has just announced that it will investigate whether CAR-T therapy can cause blood tumors. Are you concerned about this research?

A. I read the FDA announcement, but there is much we in the field still don’t know: we don’t know much about specific cases, we don’t know if secondary cancers express the gene that was used to reprogram CAR-T cells... This is key information to helping us establish what may or may not have caused these cancers. Unfortunately, in general, many kinds of cancer treatments, including chemotherapy and radiation therapy, can be effective in treating the tumor, but they can also cause cancer, in a low frequency of patients, in their own right. What does appear to be the case is that although this may happen, the frequency with which it occurs appears to be extremely rare. Personally, I have never seen this and I have probably treated several hundred patients with CAR-T therapy. I have spoken via email with colleagues who have also treated many hundreds of patients and they have all been surprised by this finding. This isn’t to say that it is not a possibility: in the laboratory we have always been concerned that this was a theoretical risk, but whether it is happening in humans, it is unfortunate, but it is probably very, very rare.

Q. In any case, these new therapies have risks and side effects. Are they safe strategies?

A. I think that every cancer treatment has risks of side effects. The immune system is an extremely powerful tool of the body, powerful enough for some tumors that have spread throughout the body to completely shrink and regress, causing the patient to go into complete remission. But we also know — for example, from Covid, which, among other things, causes a very strong immune response — that a very strong immune reaction can also cause many very significant side effects. In general, after patients have been treated with chemotherapy, hormonal therapy, radiation therapy and immunotherapy, patients find that the severity of side effects with immunotherapy are much less and more preferable than the kinds of side effects they might experience with other forms of cancer treatments.

Chris Klebanoff, oncologist at Memorial Sloan Kettering in New York, photographed at the Ateneu Barcelonès, where he participated in a conference organized by the Vall d'Hebron Institute of Oncology.
Chris Klebanoff, oncologist at Memorial Sloan Kettering in New York, photographed at the Ateneu Barcelonès, where he participated in a conference organized by the Vall d'Hebron Institute of Oncology.Albert Garcia

Q. At what point is research into cancer vaccines, both therapeutic and preventive?

A. Nothing has probably done more to improve the health of human beings over the last two centuries than the development of reliable and safe vaccines for common infectious diseases. So, it’s very appealing and almost romantic to also ask if we can use vaccines as a cancer prevention or treatment strategy. There are two vaccines that are approved today that are fantastic cancer prevention vaccines: those that prevent human papillomavirus infection have done an extraordinary job of preventing cervical cancer, a significant proportion of head and neck cancers, as well as cancer that can affect the genitals and anus. Similarly, there is a vaccine that is routinely administered that prevents infection with the hepatitis B virus, which used to be a major cause of liver cancer if someone became infected with it. So, we can use these types of preventive vaccines for infectious diseases to also prevent certain forms of cancer. The idea of trying to use a vaccine as a therapy is a slightly different mindset, but it is not new one. In fact, over the last 30 years, there have been many, many clinical studies testing therapeutic cancer vaccines using very, very different strategies and objectives.

Q. But?

A. But these results were, in the vast majority of cases, negative. Not always, but they either had a very modest or negative effect. What has rejuvenated excitement, but I don’t think it has truly translated into clearly demonstrating its benefits, is whether the RNA vaccines, which have been so effective and useful in preventing and minimizing Covid, might also be used for cancer prevention or treatment. There are some very small clinical trials that show that this approach is feasible, meaning that the vaccine can be given to cancer patients and that patients generally have very few or very manageable side effects. What is unclear is whether these new RNA vaccines are definitively helping cancer patients. So there are now randomized trials to definitively test whether these new RNA cancer vaccines can benefit cancer patients. So hopefully, we’ll know the answer in the next two to four years.

Q. Can vaccines become a reality in the near future and change the paradigm as the first immunotherapies did a decade ago?

A. I think there is so much excitement, based largely on the success of the RNA vaccines for Covid. This, combined with the fact that immunotherapy has generated so much interest and cancer vaccines are a form of immunotherapy, means that there are an increasing number of clinical trials to address this question. So I think we will begin to know with absolute certainty whether this new approach will work in relatively few years. Now, initially it will be only for a subset of cancers, probably cancers where a surgeon has removed all of the observable disease. So, we are using the vaccine in an earlier disease setting, trying to prevent the recurrence or relapse of the cancer. That’s the most likely place where cancer vaccines might show an effect. So, if they show an effect there, I think they will be tested in other more difficult situations, such as in situations where there has been a relapse and cancers in various parts of the body. But like I said, I think we’ll know the answer to this relatively shortly.

Q. We have a lot of weapons to fight against cancer, like never before. But cancer continues to win many battles. What is needed to end this disease?

A. I think we now have a growing body of evidence that clearly shows that for many kinds of cancers, at least in some patients, we can use the immune system to place the patient into a remission that can last many years, decades, or for the remainder of their lives. That’s important to know. I think the ultimate solution is we have to take a much more precise view towards how we treat each cancer patient. It is clear that when you take a group of patients with a breast cancer, for example, that look very similar under the microscope, if you do genetic sequencing to look at the unique genetic changes that cause that cancer, many of those cancers are very different from one other. We are moving away from treating cancer as a single entity, moving from treating the tissue in which it started, which looks the same under a microscope, to taking a much more precise view that’s guided by the unique genetic changes that happen in a person’s cancer, and really trying to take what we have in our armamentarium and more thoughtfully apply the right medicine at the right time for a particular cancer patient’s genetic changes.

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