Unlocking the immune system against cancerous cells

There are a number of locks, similar to control points, to prevent the immune system from attacking the body’s normal cells.

These locks are created in the first few months of life, and the lymphocyte cells capable of recognizing and destroying the body’s own cells are eliminated. Then, if certain auto-reactive lymphocytes escape this suppression, other mechanisms are able to deactivate them; this is the concept of immunological tolerance.

In order to develop freely, the tumor cells learn to unlock some of these control points. The activation of the immune system alone is not sufficient to trigger a reaction against the tumor cells; physicians and researchers are now fully aware that these control points must be identified and released.

This is, in some respects, the missing link in immunotherapy against cancer, which has just been developed, Loirat explains. Inhibition of the immune system appears to be stronger than all of the methods developed so far to activate it. Unlocking the immune system will no doubt be a component of immunotherapies.


Promising targets for unlocking immunity

These molecules, capable of directing the immune response toward either an effective response or immunological suppression, are known as immune checkpoints. They are expressed at the surface of the lymphocytes, of the dendritic cells or certain tumor cells.

The protein CTLA-4, present at the surface of the T lymphocytes, acts as a switch that keeps them inactive. Also expressed at the surface of the T lymphocytes, the PD-1 (programmed cell death) molecule binds to another molecule present on the surface of certain tumor cells, PD-L1. This interaction renders the tumor cell invisible to the immune system by deactivating (or disarming) the T lymphocyte. It proves once again all the subtleties developed by tumor cells to escape the immune system. All of these molecules have rapidly appeared as two interesting therapeutic targets for unlocking the immune system against tumor cells. Antibodies that block their activity have been developed.


Impressive results

The first molecule developed to block the immune locks – the immune checkpoints – is an anti-CTLA4 antibody known as ipilimumab. This molecule has signaled a turning point in the management of metastatic melanoma, a pathology for which very few therapies have shown any survival benefits. The overall survival of patients treated with the anti-CTLA-4 ipilimumab increased by almost four months, compared with patients who did not receive it. 

The second generation of this class of therapeutic molecule targets the PD-1 and PD-L1 molecules.

In early clinical trials, one of the antibodies targeting PD-1, pembrolizumab, produced a lasting immune response in 38% of patients treated for very aggressive tumors: metastatic cutaneous melanomas. Another antibody directed against PD-1, nivolumab, also demonstrated its effectiveness in controlling certain skin melanomas, kidney cancers and lung cancers. Furthermore, the side effects with antibodies targeting PD-1 seem to be less severe than those observed with antibodies against CTLA-4. Indeed, when the blocks against immunity are lifted, auto-reactive responses against the body’s normal cells may appear as thyroid malfunctions or inflammation of the pulmonary tissue or the digestive tract.

These represent remarkable breakthroughs for patients with metastatic forms of melanoma or lung cancer, since oncologists currently have few options. The anti-PD-1/PDL-1 molecules also prove effective against ENT, bladder, kidney and ovarian cancers. Some 20-40% of patients treated show a significant decrease in the size of their cancer lesions and 10-15% of patients enjoy lasting responses.

These molecules are currently being assessed on a wide variety of other cancers, in particular at Institut Curie. Research continues to identify response markers to these immunotherapy strategies, in particular by the translational immunotherapy team of Eliane Piaggio and Delphine Loirat (https://science.curie.fr/recherche/biologie-interactive-des-tumeurs-immunologie-environnement/immunite-et-cancer/equipe-piaggio-loirat/). A program that began in 2016 at Institut Curie aims to study the role of the microbiota during patients’ response to immunotherapy.

Other options to unlock the immune system are also being studied. Loirat and Piaggio are focusing on the biology and therapeutic applications of the sub-populations of the T lymphocytes and dendritic cells present in the lymph nodes, which are the areas where the immune system cells meet, since it is most likely in the lymph node that the cancer cells inhibit the immune response against cancer. 

Of course, not everything has been resolved. “It is necessary to improve the treatments, for example by combining them with other tumor treatments such as targeted therapies and/or vaccine approaches and to understand why some patients respond and others do not.” These results offer a glimpse of a revolution in oncology, and, in the near future, physicians should be able to rely on this new therapeutic class in their arsenal to combat aggressive cancers.

“In all immune responses, we now know that there are one or more brakes and accelerators,” explains Vassili Soumelis. “Each patient reacts differently. The challenge will be to determine which brake or accelerator to activate for each patient, and this offers the prospect of customized treatments.”