Cancer is produced when a cell becomes immortal (it will no longer die in the normal way) and grows without control in an undifferentiated manner (it does not develop into the normal cell type e.g. kidney, liver, lung etc.). There are many triggers for this situation, some are genetic and some are environmental. However, one interesting viewpoint is that the cell no longer behaves normally and should be recognized as different by the host immune system and destroyed, as with viral infections. Unfortunately, the host immune system has many controls in place to prevent such action against host (self) cells.
In this blog 1 describe a new method for preventing the growth of cancer that uses the body’s own immune system to attack the tumour. To achieve this, key controlling elements are inactivated by binding artificially-produced antibodies to them – these antibodies are produced separately outside of the patient’s immune system and are a replacement for conventional drugs that might achieve a similar result – by switching off these key control elements the patient’s immune system can destroy the tumour cell.
In a simple world, cancer would not exist as the body’s immune system should recognize the tumour as “foreign” and destroy it. However, this does not occur and, in addition, there is a danger in having such a response as the tumour cell is not really “foreign” in the way an infectious agent such as a virus is, but is in fact “self”. An immune response to “self” cells is known as an autoimmune response and it is very dangerous — autoimmune diseases are usually lethal (for example AIDS). Therefore, the human body has a series of controls in place designed to prevent such an autoimmune response. This situation is complicated further by the fact that some cancers actively interfere with the immune system to prevent any such attack against them.
One protein that acts to slow an immune response is CTLA-4 and the important job it does in controlling the immune system and preventing an autoimmune response is clearly seen in mice that have been genetically engineered to remove the CLTA-4 protein — they die in weeks as their own immune system attacks and destroys the mouse’s organs. One concept for “stopping cancer” is that by blocking CLTA-4, this would lead to a vigorous attack, by the immune system, of the tumour and, indeed, this was found to happen. In addition, there is another control system, PD-1, a protein found on the surface of T-cells (an important component of the immune system), which when bound by an external protein will force the T-cell to destroy itself, which in turn slows the immune response. Unfortunately, certain cancer cells have developed surface proteins that elucidate this response from T-cells, by binding PD-1, and consequently triggering an early destruction of T-cells that might otherwise have been targeted against the tumour. If PD-1 could be blocked, the tumour cells could no longer trigger T-cell destruction and the T-cells would, instead, target destruction of the tumour — this provides an ideal, targeted treatment against the cancer. Therefore, the real question of how to “stop cancer” is how to block the function of CLTA-4 and PD-1 in a very accurate way without stressing the body (by avoiding chemical-based drugs) and thus use the body’s own defence system to stop the cancer.
Normally, when developing drugs for the treatment of various illnesses the idea is to target a drug against an important region of a protein, in such a way that the normal function of the protein cannot be achieved. A relatively new technology has, in recent years, been used to block protein function in this way and this technology involves the use of antibodies. To understand how this technology works it is necessary to understand the structure of an antibody.
The important capability of antibodies, that makes possible this blocking function, is their ability to bind very tightly to their antigen. The exactness of binding by an antibody, to its target protein, is a key part of the natural immune response. The immune system has a very effective feedback-amplification mechanism, which allows a specific antibody, that tightly binds a specific antigen, to be recognized and mass produced, these antibodies will only bind to the antigen that they first recognized and can make the immune system react against cells containing that antigen — where such cells are infected by a virus that produces the antigen the immune system can destroy these infected cells. The human immune system is one of the most advanced protective systems in nature and provides both an early response and a long acting immunity to infection, which is one of the reasons we live as long as we do!
However, such antibodies, known as polyclonal antibodies, bind to various regions (epitopes) on the surface of the antigen, which means that they cannot be used to block the SAME specific site on the protein in the way a drug is designed to do and this means that the antibody cannot be used to block that normal actions of CLTA-4 and PD-1 as required. During the 1990s all of this changed when monoclonal antibodies were first isolated, initially from mice — these bind to a specific, single site (epitope) on a protein and, consequently, blocking of protein/enzyme function using a monoclonal antibody became possible. Humanization of monoclonal antibodies, in which the constant region (Fc) is replaced by that from a human antibody, has allowed selective targeting of proteins exposed on the surface of human cells, or specific enzymes that are active within human cells. This novel approach to attacking cancer does not require drug development, but uses monoclonal antibodies that have been produced in a laboratory and are targeted against CLTA-4 and PD-1.
A number of companies have developed these antibodies and trials of this mechanism for controlling cancer is progressing well; although, there are still problems associated with inflammation and local reactions to the antibodies, but anti-inflammatory drugs help control this situation and the reaction are much less severe and short-lived.
A recent (2007) study of the use of monoclonal antibodies to both of these antigens (CLTA-4 and PD-1) in 53 patients has shown more than 50% responded with tumour shrinkage and now >900 melanoma patients are being treated in a more extensive study and the results already look very promising.
Such novel treatments will ease the need for chemical-drug design and development and could provide a more focussed way to treat cancer without the need to use radiotherapy or chemotherapy. Drugs based on the use of antibodies are already making significant inroads into the treatment of a wide range of diseases (e.g. Ebola Infections) and, as we begin to understand biological systems better, more breakthroughs will be possible in this area. What is exciting about this research is that they are targeted through PD-1 binding to specific tumour cells, they use the patient’s own immune system to combat the cancer without drug treatment and, as we understand the biology of the immune system better, there are likely to be more targets for antibody binding. As we begin to better understand the way the immune system works, more such treatment will become possible allowing a multi-target approach to stop cancer.