This is a potentially dangerous strategy. If one provokes the immune system to recognize the cancer cells as targets for destruction, there is a risk of autoimmune side effects with dire consequences for normal tissues of the body, since the cancer cells and the normal cells are close cousins and share most of their molecular features. Nevertheless, several recent successes seem to hold great promise for the future.
One of the many molecules involved in keeping the activity of the normal immune system within safe bounds is a protein called CTLA4 (cytotoxic T-lymphocyte-associated protein 4), which functions as an inhibitory receptor on the surface of T cells. If the function of CTLA4 is blocked, the T cells become more reactive and may mount an attack on cells that they would otherwise leave in peace. In particular, the T cells may attack tumor cells that are recognizably abnormal but whose presence was previously tolerated. With this in mind, cancer immunologists developed a monoclonal antibody, called ipilimumab, that binds to CTLA4 and blocks its action. Injected repeatedly into patients with metastatic melanoma, this antibody increases their median lifespan by several months and, in one large trial, enabled as many as a quarter of them to survive for five years
Figure 20–45 Therapies designed to remove the immunosuppressive microenvironment in tumors. (A) The cells in tumors will produce many mutant proteins. As described in Chapter 24, peptides from these proteins will be displayed on MhC complexes on the tumor-cell surface and would normally activate a T cell response that destroys the tumor (see Figure 24–42). however, as schematically illustrated, during the course of tumor progression, the cancer cells have evolved immunosuppressive mechanisms that protect them from such killing. (B) The cells in tumors often protect themselves from immune attack by expressing proteins on their surface that bind to and thereby activate the inhibitory receptors on T cells. As indicated, this makes the tumor susceptible to specific antibody therapies. In this diagram, two such inhibitory receptors are shown, PD1 and a hypothetical protein X. Different tumors are thought to protect themselves by activating different members of a large set of T cell inhibitory receptors, some of which are not yet well characterized.
or more—far beyond expectations for comparable patients without this treatment. Even more promising are recent clinical trials using a combination of two antibodies, one against CTLA4 and the other against PD1, a second cell-surface receptor on T cells that normally restrains their activity.
In clinical trials using such techniques, a substantial fraction of the patients can respond in a dramatic way, with their cancer being driven into remission for years, while the treatment fails to help others with the same type of cancer. One possible explanation is that, while most tumors express proteins that protect them from T-cell attack, these proteins are different for different tumors. Thus, while some tumors will respond dramatically when treated with an antibody that blocks a particular immunosuppressive agent, many others will not. If true, one can foresee an era of personalized immunotherapy, in which each patient’s tumor is molecularly analyzed to determine its particular mechanisms of immunosuppression. The patient would then be treated with a specific cocktail of antibodies designed to remove these blocks (see Figure 20–45).
Cancers Evolve Resistance to Therapies
High hopes have to be tempered with sobering realities. We have seen that genetic instability can provide an Achilles heel that cancer therapies can exploit, but at the same time it can make eradicating the disease more difficult by allowing the cancer cells to evolve resistance to therapeutic drugs, often at an alarming rate. This applies even to the drugs that target genetic instability itself. Thus, PARP inhibitors give valuable remission of illness, but in the long term the disease generally comes back. For example, Brca-deficient cancers can sometimes develop resistance to PARP inhibitors by undergoing a second mutation in an affected Brca gene that restores its function. By then, the cancer is already out of control and it may be too late to affect the course of the disease with additional treatments.