Cancer Immunotherapy: Block brakes on tumor cells

Apollinaria Bogolyubova, "Biomolecule" 

Tumor immunotherapy is in a sense a paradoxical field in modern biomedicine. For several decades it has been one of the most fashionable and intensively developing sections of experimental oncology, while in everyday medical practice immunotherapeutic approaches have been in the deep rearguard all this time. However, the striking results of clinical trials of blocking the "brakes" of the immune response marked the beginning of a new era in cancer treatment, in which immunotherapy is certainly one of the main roles.

The interaction of tumor and immune cells has been the subject of close attention of immunologists for more than a decade [1]. This is not surprising: the idea of using your own mechanism of specific, directed killing of defective cells for the treatment of oncological diseases, which has evolved for millions of years, is too tempting. In theory, the task is simple: you just need to let the immune cells "feel" the molecular structure of the tumor, and then help them penetrate into the thick of cancer cells. However, in reality, the high genetic variability of tumor cells gives them the opportunity to deftly avoid immune surveillance, as well as neutralize activated immune cells already ready for battle, transmitting them a variety of inhibitory signals.

Only very recently, immunologists have found a way out of this situation. Using therapeutic drugs based on antibodies, they learned to block inhibitory signals by which the tumor is protected from immune cells, thereby reactivating the protective function of the latter and directing them to fight the tumor [2].

The consequences of ignoring this simple rule could be observed in most wars of modern times, when the unsettled and unaccustomed to the "citizen" military returned to civilian life en masse without proper rehabilitation, after which they went crazy, were submitted to crime or to radical military-political formations. Similarly, in the absence of control over the course of the immune response, activated cells of the immune system can damage the surrounding organs and tissues, disrupt their functionality and even lead to the death of the patient.

Fortunately, our body is much smarter than most of the world's politicians and has developed a considerable number of highly effective mechanisms for adapting immune cells to "peaceful life" after the completion of the immune reaction.

Thus, the CTLA-4 receptor molecule, located on the surface of activated T cells, is a kind of brake ("checkpoint", English checkpoint) for T-lymphocytes. The "inhibitory" signal via CTLA-4 is triggered by the same molecular partners (ligands) – B7 proteins, which recently triggered the opposite process through the CD28 receptor – activation of the T-lymphocyte to perform protective functions (Fig. 1). The binding strength of the CTLA-4 molecule to B7 is much higher than in CD28, and at some point inhibitory signals begin to dominate the activating ones. The division of T cells and their functioning gradually stop, the immune response fades, and the inflamed tissue gradually returns to peaceful life. Another, no less important, "brake" is the PD-1 molecule, which occurs on the surface of many immune cells (T- and B-lymphocytes, cells of innate immunity) and apparently has an even greater spectrum of action than CTLA-4. Interacting with its PD-L1 and PD-L2 ligands, it also effectively inhibits the immune response [2].

One thing is obvious: at the stage when a tumor can be detected using modern diagnostic methods, and even more so at the stage of the appearance of clinical symptoms, the immune system cannot cope with the control of tumor growth. The "molecular environment"* created by a smart and cunning tumor makes it impossible for the immune system to effectively destroy abnormal cells [3]. In particular, one of the strategies for avoiding cancer from the immune response is the use of the above-described "inhibitory" mechanisms. So, the cells of many malignant tumors are able to produce PD-L1 and PD-L2 molecules, deceiving immune cells and forcing them to "calm down" instead of selflessly fighting traitors.

The whole history of the treatment of malignant tumors indicates that they are extremely difficult to deceive. The extremely high genetic variability of tumor cells leads to the fact that they can adapt to almost any therapeutic effect by activating bypass molecular survival mechanisms.

At the same time, normal cells of the immune system are much more honest and straightforward. And what if we act not on tumor cells, but on cells of the immune system – "open their eyes" to traitors, blocking the inhibitory mechanisms of the immune response?

Since the 90s of the XX century, many research teams, coordinated by immunologist James Ellison, have investigated whether antibodies specific to the CTLA-4 receptor are really able to block it and thereby enhance the antitumor immune response (Fig. 1). Many years of work have finally been crowned with success: the effect of such antibodies has been demonstrated in laboratory animals, and later on patients, and in 2010, the drug ipilimumab (monoclonal antibodies against the CTLA-4 molecule) began its triumphal march.

The results of recent clinical trials are striking: the overall survival rate of patients treated with ipilimumab alone increased by almost six months compared to standard chemotherapy protocols. It should be noted here that the patients who participated in these studies suffered from advanced forms of cancer with multiple metastases, and their tumors did not respond to any conventional therapy regimens. For this group of patients, even such a "modest" prolongation of life is truly a miracle. Therefore, it is not surprising that it was thanks to ipilimumab that the field of tumor immunotherapy was named breakthrough of the year by Science magazine in 2013.

Despite the amazing success of the blockade of this particular molecule, a significant part of patients did not respond to such treatment at all, so the next stage in the development of this strategy was the blocking of other "control points".

Immediately after the use of ipilimumab was authorized, clinical trials of antibody blockers of the PD–1 molecule began. Due to the excellent results of previous trials, they followed an accelerated program, and already in 2014, new drugs nivolumab and pembrolizumab (both are monoclonal antibodies against PD-1) were approved for the treatment of melanoma, and then a number of other tumors.

In 2014, the results of the first studies of the effectiveness of drugs blocking the molecular partner PD-1 – PD-L1 became known. As expected, the medicine works very well (Fig. 2), so the next stages of its testing and entry into the pharmaceutical market are not far off [6].

It should be especially noted that PD-1 and PDL-1 blockers give a chance to cure even those patients who did not respond to the shutdown of CTLA-4, and the combination of PD-1 and CTLA-4 blocking increases the frequency of long-term remissions by almost 3 times (!) compared to blocking only one of the braking paths.

Methods of genome-wide sequencing, imaging of tumor and immune cells already allow us to narrow down the range of patients for whom this type of immunotherapy will be most effective. However, the development of a detailed personalized approach to the choice of treatment is still ahead.

Despite the many advantages of this strategy, it inevitably carries serious difficulties in the form of side effects. The fact is that the influence on the regulation of immunological processes inevitably leads to their destabilization. Blocking of inhibitory mechanisms is fraught with increased aggressiveness of immune cells in relation not only to the tumor, but also to normal cells of the body, which is fraught with autoimmune damage to healthy tissues. Even with the use of a single drug, the frequency of autoimmune lesions of the mucous membranes, intestines and / or liver is more than 50%. Therefore, it is extremely necessary to find ways to reduce the undesirable effects of these blockers. So, scientists are trying to use in clinical practice a combination of these drugs with drugs commonly used to treat autoimmune diseases. Such drugs interact with molecules involved in the development of inflammation, block their action and thereby reduce the risk of an autoimmune process, without affecting the effectiveness of the main drug.

Perhaps the most important result of the CTLA-4 and PD-1/PD-L1 blocking trials was that in a significant number of patients receiving this treatment, metastatic tumors disappeared completely and did not reappear during the entire follow-up period. These data do not just indicate the high effectiveness of this type of therapy. In oncology, the term "cure" is not accepted, because the tumor can return at any time months, years or even decades after the seemingly complete destruction of its entire cell mass. The results obtained bring us very close to the recently absolutely fantastic idea of a complete cure for the most neglected metastatic tumors.

06.11.2015