Cancer immunotherapy has been revolutionizing oncological medicine for more than a decade. This strategy, which involves helping the immune system fight malignant cells, has managed to challenge – and reverse – some of the worst prognoses in melanoma, lung cancer and a handful of hematological tumors. And while it's not an infallible miracle cure — it doesn't work for all patients and not all tumors — there's still room to further explore its possibilities, says Chris Klebanoff, 45, an oncologist and researcher at Memorial Sloan Kettering Hospital in New York York and the Parker Institute for Cancer Immunotherapy. The doctor, an expert in cell therapy, visited Barcelona to attend the VHIO-BBVA Foundation's first international symposium on cell therapies in oncology.
Ask. Has immunotherapy reached its peak?
Answer. I think we're 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 to treat cancer. The second step is to develop new therapies that are more effective in more types of cancer. The two main forms of immunotherapy are either immune checkpoint blockade, which involves antibodies that act as if they interrupt the immune system; and the other big innovation is reprogramming by genetically modifying 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 affecting adults are solid cancers, and only 20% of all of these solid cancers may respond to current immunotherapies. And while this is a wonderful advance, it means that about 80% of adult solid cancers do not respond to currently approved immunotherapies. I think this shows both the promise and the opportunity to further expand immunotherapies.
Q What happens to this 80%? Why doesn't immunotherapy work for some patients?
TO. The most likely explanation for these 80% of patients is that, for whatever reason, they are simply unable to mount an early immune response against the cancer. And that's an indication of what we can do to provide answers in that 80%. One approach that is the focus of my laboratory is to genetically reprogram immune cells to recognize antigens or potential targets that are expressed only by solid cancer cells but not by normal cells. So the idea here is that if a patient can't generate a natural T-cell response, we can create an immune response synthetically in the lab using genetic engineering, grow those cells outside the body, and then infuse them back into a form of cancer treatment for one cancer patients.
Q Increasingly personalized medicine.
TO. Correct. Therapies that are tailored to the patient and, more importantly, 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 cancers, but not in solid tumors. Why?
TO. One of the biggest limitations is the fact that in many blood cancers, particularly those that arise from either antibody-producing B cells or the precursors of antibody B cells, we can target antigens expressed by these cells, but these targets are also expressed by normal B cells. [These antigens] are expressed very uniformly and therefore represent ideal targets. And to my surprise and to the surprise of many of my colleagues, the CAR-T cells also eliminate normal, healthy B cells, patients do surprisingly well without normal B cells and the tumor cells are regressing. The use of the same approach in solid cancers was limited by the fact that we really did not find targets that express cancer cells and that the patient can tolerate injury to healthy tissue when shared by normal healthy tissue. So a major limitation for this field is finding immunological targets that are only expressed by cancer cells and are not expressed by normal, healthy tissues.
Q With these innovative immunotherapies in mind, the US 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?
TO. I read the FDA announcement, but there's still a lot we don't know in this field: we don't know much about specific cases, we don't know whether secondary cancers express the gene that was used to reprogram CAR-T cells… This is important information that will help us figure out what may or may not have caused these cancers. Unfortunately, in general, many types of cancer treatments, including chemotherapy and radiation therapy, can be effective in treating the tumor, but they can also cause cancer themselves in a small number of patients. What actually seems to be the case is that while this can happen, the frequency with which it occurs appears to be extremely rare. Personally, I have never seen this and have probably treated several hundred patients with CAR-T therapy. I spoke via email to colleagues who have also treated many hundreds of patients, and everyone was surprised by this finding. That's not to say there isn't a possibility: in the lab we were always worried that this was a theoretical risk, but whether it happens in humans is unfortunate, but it's probably very, very rare.
Q In any case, these new therapies have risks and side effects. Are these safe strategies?
TO. I think that any cancer treatment carries the risk of side effects. The immune system is an extremely powerful tool of the body, strong enough that some tumors that have spread throughout the body will completely shrink and regress, causing the patient to enter 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 have many very significant side effects. In general, after treatment with chemotherapy, hormone therapy, radiation therapy, and immunotherapy, patients find that the severity of side effects with immunotherapy is far less and better than the type of side effects that can occur with other forms of cancer treatment.
Chris Klebanoff, oncologist at Memorial Sloan Kettering in New York, photographed at the Ateneu Barcelonès, where he attended 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 preventative?
TO. Perhaps nothing has contributed more to improving human health over the past two centuries than the development of reliable and safe vaccines against common infectious diseases. Therefore, it is very tempting and almost romantic to also ask whether we can use vaccines as a strategy for cancer prevention or treatment. There are two vaccines approved today that are fantastic cancer prevention vaccines: those that prevent human papillomavirus infection, do an excellent job of preventing cervical cancer, a significant proportion of head and neck cancers, and cancers that can affect the genitals, done anus. Likewise, there is a routinely administered vaccine that prevents infection with the hepatitis B virus, previously a leading cause of liver cancer, if someone were infected with it. We can also use such preventive vaccines against infectious diseases to prevent certain forms of cancer. The idea of using a vaccine as a therapy is a slightly different way of thinking, but not new. In fact, over the last 30 years there have been many, many clinical trials testing therapeutic cancer vaccines with very, very different strategies and goals.
Q But?
TO. However, these results were negative in the vast majority of cases. Not always, but they had either a very modest or negative effect. The question of whether the RNA vaccines that have proven so effective and useful in preventing and minimizing Covid could also be used to prevent or treat cancer has reignited excitement, but I don't think that actually has led to a clear demonstration of its benefits. 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 experience very few or very manageable side effects. It is unclear whether these new RNA vaccines actually help cancer patients. Therefore, there are now randomized trials to definitively test whether these new RNA cancer vaccines can help cancer patients. Hopefully we will find out the answer in the next two to four years.
Q Can vaccines become a reality in the near future and shift the paradigm like the first immunotherapies did a decade ago?
TO. I think there is so much excitement, largely based on the success of the RNA vaccines against 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 more and more clinical trials looking at this question. Therefore, I think that in a relatively few years we will know with absolute certainty whether this new approach will work. Now it will initially only apply to a subset of cancers, probably cancers where a surgeon has removed all observable disease. That's why we use the vaccine at an earlier stage of the disease and try to prevent the cancer from coming back or coming back. This is the most likely place where cancer vaccines could have an effect. So if they have an effect there, I think they will be tested in other more difficult situations, such as situations where there has been a relapse and cancers in different parts of the body. But as I said, I think we'll find out the answer to that relatively soon.
Q We have more weapons than ever before to fight cancer. But cancer continues to win many battles. What will it take to end this disease?
TO. I think we now have a growing body of evidence that clearly shows that in many types of cancer, at least in some patients, we can use the immune system to put the patient into remission that lasts for many years, decades, or even several The rest of their lives can last for years. This is important to know. I think the ultimate solution is that we need to think much more precisely about how we treat each cancer patient. It is clear that if you study a group of patients with breast cancer, for example, they look very similar under the microscope, and if you do genetic sequencing to study the unique genetic changes that cause this cancer, there are many These types of cancer are very different from each other. We are moving away from treating cancer as a single entity and moving from treating the tissue in which it originated, which looks the same under the microscope, to a much more precise view based on the unique genetic changes that that occur when a person has cancer. . and we're really trying to leverage what we have in our repertoire and more carefully apply the right drug at the right time to the genetic changes of a particular cancer patient.
Sign up for our weekly newsletter to receive more English-language news from EL PAÍS USA Edition