“Tumors have mechanisms that protect them from the immune system”

Immunologist Ignacio Melero Bermejo is one of the leading experts in experimental cancer immunotherapy. The co-director of the Immunology and Immunotherapy Service of the Navarra University Clinic and a CIMA researcher believes that “we are at the origin of the beginning” of the applications of immunotherapy for cancer treatment. Can it be said that immunotherapy has met the expectations raised when it was introduced? I would say that, as he said [Winston] Churchill, that this was not the end, not even the beginning of the end. It is probably the origin of the beginning. We started to see that we could probably exploit the patient’s immune system to treat cancer. And this was the prelude to being able to further enhance this activity and achieve greater efficiency. Surprisingly, it was found that the inhibition of the immune system, which is mediated by two proteins, PDL1 and PD1, which interact with each other, is very important in a percentage of patients. The view we have now is that there are agents that act on other targets and that probably better suppress the immune system. In addition, there are other immunotherapy strategies in the clinical development phase and we think that they can be combined with each other synergistically. A lot of research is being done to genetically introduce new molecules into CAR-Ts that make them activate better. That being said, we won’t be able to cure a high percentage of patients until some of these synergistic combinations are very potent. Likewise, we are also going to be able to cure more patients as we apply immunotherapy treatments earlier in patients with earlier stages of cancer; for example, by using it around surgery before the surgeon removes a tumor that is initially non-metastatic, the use of immunotherapy prevents or prevents recurrence of both local and distant disease. This is assuming a huge revolution. For example, we have seen that in a series of 51 patients with advanced hepatocarcinoma treated with a combination of immunotherapy that we began to use as a pioneer 6 or 7 years ago, 29% of patients were alive 60 months after starting the treatment. This would obviously be unheard of at a time when I was a resident or medical student; however, we still have 71% of patients who die from the disease. And this situation is repeated in many diseases such as melanoma, non-small cell lung cancer, etc. This is the next barrier we have to break. But I am very optimistic for several reasons: Cancer immunotherapy has attracted a lot of talent to the field. There is so much translational preclinical and early clinical research going on right now that we think surely some of those ideas, and almost all of them are very good ones, will lead to a much stronger therapeutic effect than what we see now. And the a la carte treatment with CAR-T cells? Cellular therapy with T-CART cells is also achieving unprecedented results in certain types of leukemias, lymphomas and multiple myeloma. And all of this is clearly a revolution in progress. How far can we go? Only the future can tell and it is very difficult to predict, but as I say, I am optimistic and I consider that in a situation of the end of the success of cancer treatment we are at the end of the beginning. How can we explain that immunotherapy is effective in some tumors and has not given results in others? We think there are some reasons. The first, and most important, is that tumors are a nest of immunosuppressive mechanisms that are very powerful. For example, the expression of PDL 1. But not only that. But there are many additional mechanisms, and when those mechanisms are in place and potent, intervention simply by blocking PD1 or PDL1 does not have a therapeutic effect. Therefore, tumors have redundant mechanisms that protect them from the immune system and we probably could not block all of them. In addition, there are tumors that have a lot of antigenic poverty. In other words, for a tumor to be, it must have mutations, sequences of its proteins that are not in the body and are only in the tumor, which are called neoantigens. But there are some that have very few neoantigens and are therefore hardly visible to the recognition mechanisms of the immune system. And, in addition, there are probably reasons that we still do not understand and that we do not know, and that is precisely what makes this field exciting. And it is that we probably still do not know more than we do, and the only way to face it is through incisive research from experimental models through early clinical research on patient samples to clinical trials. CAR-T cell therapies work in hematological cancers, but not in solid ones. Is there any reason for it? There are quite a few reasons. One is the accessibility of immune system cells that may have the ability to recognize and kill tumors. Trafficking of immune system cells to solid tumors is clearly worse. In addition, leukemias and lymphomas have a series of signals that make it especially easy to activate these cells with the capacity to kill, and that artificially recognize all the cells of the body. Then there is another problem and that is that it is very difficult to find antigenic targets in the tumor, proteins expressed or present in the membrane of tumor cells in tumors and that are not in vital organs or systems, in such a way that they allow paying the price of destroying normal tissue in exchange for a powerful response in the tumor. Finally, in this sense, what is being done is a lot of research to genetically introduce new molecules into CAR-Ts that make them activate better so that some of these obstacles can be circumvented. In this sense, there is a lot of research aimed at finding ways to get around these obstacles. Some of these strategies, for example, go through the administration of CAR-T cells repeatedly. However, today the results in solid tumors are still poor. One of the demands to optimize these treatments are the biomarkers to know where to apply the therapy correctly. Is this one of the biggest brakes on immunotherapy? We not only need markers to know who is going to respond and benefit from the treatment, but also to tell us who is not going to respond. And it is very important, for at least three reasons. First, to be able to guide clinical trials in which to experiment with new treatments. The second reason is to avoid adverse effects. But there is a third socioeconomic reason, and that is that treatments are a very expensive alternative today and fall on the public coffers. All this increases the need to find biomarkers. We have some, but at the moment they are not satisfactory. At the last American Congress of Oncology (ASCO) data was presented on a colon cancer treatment that achieved an amazing result This is an exceptional article. There is a subgroup, which is about a quarter of colon cancer patients, in whom the DNA repair machinery of tumor cells is impaired, in such a way that they accumulate mutations at a dizzying rate because they are not able to to repair DNA alterations and therefore accumulate many potential antigens. It’s a subgroup of colon cancer that we call colon cancer with microsatellite instability. It is early to know if this will be the best treatment available for patients with this type of colon cancer. The way to find out is to do randomized trials. Related News standard No First study showing that immunotherapy improves survival in the worst breast cancer Esther Armora Adding this treatment to first-line chemotherapy improves the overall survival of patients with advanced triple-negative breast cancer by 27% The vaccine for cancer never ends up coming. What is the current situation? Quoting Churchill again, it is that vaccines in immunotherapy have gone from failure to failure but we hope that they will reach the final victory. Today we already know that the most important antigens in the antitumor immune response are the neoantigens that are individual to each tumor, but are not shared among many patients, with which individualized vaccines must be made. The company that has probably saved us, which has been Biotech with its RNA vaccines, they are making RNA vaccines from neoantigens that pose a biotechnological challenge. In combination with checkpoint inhibitors, they seem to have a very powerful effect.