Over the past decade, there has been renewed interest in developing immunologic therapies in cancer. The U.S. Food and Drug Administration (FDA) has approved several new biologic agents that target a patient’s immune system, some of which have produced profound clinical responses. However, the cellular interactions in the immune system are complex, involving many cell types and various chemical mediators. To shed some light on this emerging field, The ASCO Post recently spoke with Gerald L. Messerschmidt, MD, FACP, Chief Medical Officer of Precision Oncology, Flemington, New Jersey.
Pioneers in the Immune System
The concept of the immune system having the power to identify and kill cancer cells is not new. Please offer our readers a glimpse into pioneers in the immune system and how their work presaged today’s interest in immunotherapy.
The concept of the immune system and its relationship with cancer has existed for more than 150 years. At the end of the 19th century, the German scientist Paul Ehrlich provided a description of cells in the body’s self-defense mechanisms, known today as the immune system.
Therapies that blockade tumor cells’ immune checkpoint mechanisms have proved to be successful in reversing the inhibitory immune reactions engendered by tumors, which have achieved immune escape.— Gerald L. Messerschmidt, MD, FACP
During that same period, William Coley, MD, an American orthopedic surgeon and cancer researcher, observed that some patients with cancer who had infections seemed to have durable remissions in their cancers. He hypothesized that the infection activated some type of immune response, which could recognize and fight cancer cells. We have also seen, although rare, complete spontaneous remissions in cancer patients with advanced disease who had no infections or had not undergone any treatment.
And I think the takeaway from Dr. Coley’s infection-based remissions and the spontaneous remission phenomenon—as well as a lot of other work in between—is the immune system has the ability to search out and kill tumor cells. One hypothesis is the immune system becomes activated in a way that leads to the recognition of nonself proteins, which can be targeted and killed. The strongest evidence of this phenomenon has been in T-cell responses associated with immune response in spontaneous regression of melanoma. Although we’ve learned a lot about immune responses, there is still a long way to go.
In the middle of the 20th century, the immunologists Lewis Thomas and F. Macfarlane Burnet termed the concept “immune surveillance.” Please speak a bit about this process.
The primary cells that are capable of searching out and killing cancers are T cells and natural killer (NK) cells, and the concept of immune surveillance is based on the idea that these cells patrol the body, looking for nonself signals to attack and kill. The immunologists Dr. Thomas and Sir Burnet coined the term “immune surveillance” in which normal cells could recognize and block cancerous development. There is also evidence the immune system mounts an attack against established cancers although it often fails.
In a way, we are making precancer cells all the time in our body, and our immune system is capable of either killing those precancerous cells directly or keeping them under control. This is a process called “immunoediting.” Data from lung computed tomography scans in smokers show that small nodules are often found to have cancerous cells that have been held in equilibrium. In other words, the immune system is killing the cancer cells at basically the same rate in which they are growing. It’s as if the cancer cells are under control, but the immune system is struggling to maintain stasis. However, the problem comes during the next phase of immunoediting, often referred to as malignancy. When there are further mutations and metabolic changes in the stable-sized tumor, which can evolve to evade the immune system’s check on growth, a process called immune escape occurs, allowing the malignant clones to have a survival advantage.
Therefore, immune surveillance is extremely important to kill and keep tumor cells in check, but eventually cancer mutations can lead to many survival-beneficial traits, and they then become deadly malignancies. When this occurs, the immune system often has been neutralized, and it is no longer successful in blocking the growth of a malignant tumor clone. Death from cancer is due to the mass action of cancer cells on vital organs.
Please explain the role of checkpoint inhibitors in immune surveillance.
What I just described is the clonal development of cancer cells, which is important in understanding the immune system because these malignant clones often develop cloaking proteins on their cell surface that signal the immune system to “turn off.” Programmed cell death ligand 1 (PD-L1) is the prime example of a protein expressed on cancer cell surfaces that binds to programmed cell death protein 1 (PD-1) on cytotoxic T cells and signals to these immune cells approaching the cancer cell to wind down and turn off.
Think of it this way: If you get a splinter that infects and fills with pus, it goes away within 7 to 10 days because the immune system has developed the mechanisms to “turn off” the immune reaction. PD-L1 is one of about 20 proteins now known to be part of the checkpoint system. It appears that upregulation of PD-L1 may allow cancers to evade (via spurious expression) the host’s immune system via normal immune signaling. When PD-L1 binds to PD-1, an inhibitory signal is transmitted into the T cell, which reduces cytokine production and in turn suppresses T-cell proliferation. Therein lies the excitement over checkpoint inhibitor research.
Thymus in Immune Surveillance
Please briefly discuss the role of the thymus in immune surveillance.
PD-L1 is expressed within the thymus, as other normal tissue antigens are. Two things occur within the thymus and also within the periphery. The T cells make random rearrangements within their actual genes in the T-cell receptor. The T-cell receptors in the thymus are sorted about between those that are against “self” and those that are against nonself pathogens. T cells that are against “self” can either be killed in the thymus by apoptosis or can be downregulated or checked by the immune system, so they don’t act against normal tissues.
In the periphery, PD-L1 and PD-1 serve as the mechanism by which T cells are kept in check. The newly rearranged positively selected T cells then exit the thymus and circulate via the blood and lymphatic system, patrolling for nonself cells, such as those from tumors.
As we age, the thymus shrinks and becomes a less nurturing environment for T cells. How does this affect our immune system’s ability to fight cancer?
In fact, the thymus does shrink with age, but that process can be reversed. If an overwhelming immune response is required and new T cells are needed, the thymus can restore itself. We’re just beginning to help this process along with the administration of various cytokines and other immune chemicals. This is important because of the correlation between cancer, increasing age, and decreasing immune function. This is an exciting and important area of research, and I suspect within the next several years, we’ll have a better understanding of how to restore this selection of T cells and the management within the thymus.
‘Cloaking’ of Cancer Cells
In a nutshell, please describe how cancer cells “cloak” themselves against the immune system.
Cancer cells can cloak themselves in fake checkpoint proteins, such as PD-L1. And when a T cell recognizes an abnormal protein on the surface of the cancer cell that it would otherwise kill, another part of the T cell attaches to the PD-L1, and the killing reaction gets “turned off.” That is a powerful survival mechanism cancer cells have developed to be able to check the immune system. Moreover, cancer cells are constantly making mutations that allow their clones to survive. If a cancer cell happens to make a mutation that allows PD-L1 to be transferred and transcribed to express on the cell surface, that clone now has a survival advantage against T cells.
Clonal theory and the immune system are in play, in that the immune system gets tricked into not attacking foreign proteins. As the T cells become activated in the lymph nodes, they make more and more PD-1, so the early cells can actually kill the cancer cells; however, there may not be enough of them and as time goes on, if the tumor has PD-L1, T cells may get shut down. This is sometimes referred to as T-cell exhaustion.
Could you offer some closing thoughts on the future of immunotherapy in oncology?
Therapies that blockade tumor cells’ immune checkpoint mechanisms have proved to be successful in reversing the inhibitory immune reactions engendered by tumors, which have achieved immune escape. There is no single drug or radiation therapy that can normally cure cancer cells that are mutated sufficiently to have significant survival traits, including immune escape mechanisms. If you look at the cancers that we do cure, such as testicular and childhood acute lymphoblastic leukemia (ALL), they are treated with combination therapies. But host immune system cells are needed to clean up the last cancer cells, and the combinations of the future are going to be therapies that are specific against the mutation plus activation of the immune system. ■
DISCLOSURE: Dr. Messerschmidt reported no conflicts of interest.