In 1998 the biotech company Genentech launched Herceptin for the treatment of certain types of breast cancer. Herceptin was an example of a ‘therapeutic antibody’ and was the first of its type for cancer treatment. Antibodies are proteins in our immune system that can target abnormal cells (or bacteria, toxins, viruses, etc.) in the body, and on arriving at the target can set in motion a whole set of biological events that in principle can remove or degrade to a non-dangerous state the abnormal cells.
Frequently, antibodies that we should produce as a natural response to cancer cells that may develop in an organ or tissue are somehow either inhibited from forming, or where they do form are poorly effective at destroying the cancer. To combat this ineffectiveness, specific antibodies against targets on the cancer cell can be made in the laboratory and then reintroduced into the human body, causing the cancer cell to ‘self-destruct’, or become sensitized to natural immune processes that aid the cancer cell killing.
In commenting on the efficacy of such antibodies in the treatment of cancer, delivered to an international antibody conference in San Diego in December 2012, Professor Dane Wittrup (MIT) reminded the audience how limited the response rate (~10%) of current antibody therapies has been. While there may be different views on the reasons for this, we can be reasonably certain that it is due, in part, to some or all of the following: the development of tumor resistance after repeated therapy, the presence of side effects serious enough to warrant interruption or even cessation of treatment, or limited antibody efficacy in the real tumor environment. Despite the investment of billions of dollars in antibody research it is clear that the human immune system still retains many secrets, the decoding of which has been, and continues to be, a long and complex process.
Current antibody therapies target specific ‘circuits’ in cancer cells that are important for the growth of the cancer, either shutting down or blocking key points in specific cellular circuitry, thereby reducing the cancer cell viability. Unfortunately, a cancer is a population of cells and as the inhibitory antibodies move into attack mode, biological changes within the cancer cells over time can activate alternative survival circuits that allow the cancer to evade the antibody effects, effectively becoming ‘resistant’. (For example, some breast cancers are known to become resistant over time to repeated treatment with Herceptin.) To counteract this effect, therapeutic modalities have been developed where two antibodies targeting different sites (circuits) within the cells, or an antibody coupled with a highly toxic drug or toxin molecule, are being adopted. While more effective than the single antibody approach, there is still a heavy hitting part of the immune system, the so-called Cytotoxic T-lymphocyte, or CTL (‘T’ for thymus-derived) mediated response, that often stands idle while the antibody arm of the immune system goes about its work. Why might that be?
In the late 1980s and early 1990s, research groups working at research laboratories in Marseille and a pharmaceutical company in Princeton described two new proteins associated with cells of the immune system that appeared to regulate their activity, allowing them to discriminate between normal tissues and abnormal tissues such as cancer cells. These new proteins were named ‘immune checkpoint receptors’ and are now known to be instrumental in deciding whether or not CTLs become active. When CTLs receive the correct activation signal, they are primed to engage an abnormal target with a view to destroying it in what is part of the ‘adaptive immune response’. Within the cells of the immune system, these checkpoint receptors are part of a complex activating and damping signaling system involving a receptor and a second molecule (or ‘ligand’) that interacts with the receptor in a sort of pas de deux. When the two find each other, as in normal tissues, a CTL attack is prevented (if this did not happen, an autoimmune response could be initiated). So, if the same ligand signal is somehow offered by a tumor cell masquerading as a normal cell, the ‘call to attack’ signals will be overridden and a CTL assault will not occur. In many tumors, just such biochemical changes are known to occur that fool the immune system into ‘thinking’ that the tumor consists of normal human cells thus avoiding attack by CTLs.
As with many aspects of biological systems, the adaptive immune system is a balancing act between allowing effective immune responses to alien agents, such as bacteria, viruses, toxic molecules, and the like, and at the same time avoiding mounting similar responses to our own tissues, organs, and cells that could lead to ‘autoimmunity’. Immunologists use the term ‘tolerance’ to describe this protection that self-tissues and organs experience as the immune system goes about its work. Lupus erythematosus and multiple sclerosis are two examples of autoimmune responses where the normal regulatory controls have been interrupted and immune antibodies or cells have attacked normal, healthy tissues with often debilitating effects. It is currently thought that checkpoint receptors and their partner ligands play an important role in maintaining this tolerance state in normal healthy persons, preventing unwanted autoimmune responses.
But what if antibodies could be targeted to these checkpoint receptors, blocking the ability of the tumor cell to interact with the receptors on CTLs, and hijacking their deceptive “I am normal” signal? (see Figure 1). This would mean, of course, that in theory, any cell, normal or abnormal, could be a target for CTL killing since both types of cell would have their “I am normal” signal blocked. Dangerous? Possibly, if not controlled. Desirable? If a tumor is so aggressive (e.g. melanoma, pancreatic cancer, etc.) that some autoimmune side effects could be tolerated or clinically managed in order to rid the body of the cancer, perhaps the therapeutic modality would be justified.
Well, we can do better than ‘in theory’. In a recent study of patients with advanced melanoma, one of the most aggressive tumors known and refractory to most therapeutic regimes, two different antibodies against each of the two most characterized immune checkpoint receptors showed spectacular results. In summary, the Phase I/II clinical trial results showed that 40% of patients treated with the combined antibody therapy experienced tumor shrinkage, and 65% of patients experienced shrinkage or stable disease. While these results truly are impressive we cannot yet declare that the war against cancer is approaching resolution, despite the claims of some enthusiasts.
As I noted above, immune checkpoint receptors are important in avoiding immune responses to our own tissues and organs. If their regulatory role is undermined by antibody blockade then autoimmune effects could be anticipated. In fact, in all clinical trials so far conducted with antibodies against these targets, autoimmune responses have been seen, including colitis, dermatitis, hypophysitis, pneumonitis, and hepatitis. These are classes of side effects the clinical community is not accustomed to seeing during antibody therapy, and will require stringent observation during treatment while improved therapeutic regimes are developed that manage these autoimmune effects.
Despite the embryonic nature of this approach, we have truly entered a new age for antibody therapy. As with all checkpoints, two way traffic is ever present, and while in one direction there may be freedom, in the other may lie painful experiences that have to be managed. The key for the future success of this approach will be the development of immune strategies that allow the benefits of immune checkpoint inhibition in cancer treatment to be counterbalanced by clever therapy designs that avoid, or at least minimize, the associated disadvantages.
Header image: Breast cancer cell. Public domain via Wikimedia Commons.