One of the most exciting areas of cancer research being done today is the study of immunotherapy. It is a big focus in the Cancer Moonshot Initiative precisely because it offers so much promise as a more effective treatment – and possibly a cure – for cancer. This potential extends to mesothelioma as well, which is historically very difficult to treat and generally has a poor prognosis.
The Development of Immunotherapy
Immunotherapy is a form of treatment that activates or enhances the immune system’s response to an illness. Cancer immunotherapy specifically refers to treatments that enable to immune system to target and eliminate cancer cells.
People have been interested in this topic as early as 460 BCE when a Greek historian named Thucydides discovered that people that survived the plague were immune to future outbreaks. The first attempt at cancer immunotherapy in recent history occurred in the 1890s. A surgeon named William Coley observed that a cancer patient went into remission after surviving two infections by the bacteria Streptococcus pyogenes. To determine whether the remission and infections were linked, Dr. Coley injected the bacteria into cancer patients and found that in some cases (approximately 10%), the treated patients went into remission as well. It was this discovery that led to the most effective treatment against superficial bladder cancer today.
Jump forward to the early 1950s, when researcher Dr. Frank Medawar and his colleagues verified a hypothesis developed by Dr. Burnet that immune cells (lymphocytes) that recognize and attack host cells are destroyed prior to birth so it is not possible for these cells to distinguish between normal and cancerous cells that arise in the same host. This hypothesis was known as immunological intolerance. However, it was later determined that cells from tumors caused by carcinogens, called transplantable tumors, could be distinguished from healthy cells.
Studies showed that when a tumor was removed from an animal with cancer and then injected back into the same animal, the body was then able to reject it. This result suggested that tumor cells are associated with antigens (known as tumor-associated antigens, or TAAs) – that is, markers on cells that identify them as host cells or foreign cells – and it led Dr. Burnet to revise his hypothesis about cancer immunotherapy. He began to suspect that the immune system could eliminate cancer cells, and he hypothesized that one function of lymphocytes was to find and destroy cancer cells in the body using a process called immunosurveillance. Unfortunately, Dr. Burnet was unable to support his theories, and interest in immunotherapy waned.
Then, in the mid-1980s, interest in cancer immunotherapy began to pick up again due to three discoveries. First, it was determined that not all host attacking lymphocytes are destroyed during tumor development, and meaning they could attack host cells that have become cancerous. Many studies also identified TAAs in humans. The greatest evidence was the discovery that cancerous tumors are genetically unstable and lead to the presentation of many TAAs.
However, even though TAAs were present, the tumor cells did not themselves induce a tumor response. Normally, molecules on foreign cells and lymphocytes interact in order to initiate an immune response once a lymphocyte recognizes a foreign antigen. Evidence discovered in the late 1990s and early 2000s found that antitumor immune responses can be induced by cells presenting tumor-derived molecules. In addition, evidence for Dr. Burnet’s decades-old theory of immunosurveillance surfaced. Based on these discoveries, cancer immunotherapy has accelerated and resulted in the development of several effective and promising therapies for multiple forms of cancer.
Immunotherapy for Mesothelioma
There are currently several types of immunotherapy showing potential for treating mesothelioma. All of these are in various stages of clinical trials, and depending on the results of those studies, they could become mainline treatments for mesothelioma.
Tremelimumab is a monoclonal antibody – that is, a drug that targets specific proteins or processes involved in tumor development, maintenance, or progression. Specifically, tremelimumab targets the protein CTLA-4. Studies have shown disease control in as much as 31% of patients. However, many patients experienced side effects such as gastrointestinal issues and rashes. It is currently being tested in a clinical trial in combination with a checkpoint inhibitor for non-small cell lung cancer.
Another monoclonal antibody is bevacizumab, which is a drug that helps to block the formation of new blood vessels that support cancerous tumors. In recent studies, bevacizumab has been shown to be useful in treating mesothelioma. In fact, the National Comprehensive Cancer Network – a network of 27 of the world’s leading cancer centers – recently updated their guidelines to include bevacizumab as part of a first-line treatment for unresectable mesothelioma in combination with chemotherapy.
Perhaps the most promising immunotherapy for mesothelioma is pembrolizumab, which is a checkpoint inhibitor. Checkpoint inhibitors work by blocking molecules interaction between immune cells and tumor cells that would otherwise identify the tumor cell as normal. As a result, the immune cell will attack and kill the cancer cell. Pembrolizumab has been studied for a wide variety of cancers, and has already been approved by the FDA for treatment of non-small-cell lung cancer and head and neck squamous cell carcinoma. Studies have indicated that pembrolizumab may be effective against mesothelioma as well, and a number of mesothelioma patients have had near-miraculous remissions of their cancer after taking the drug.
The development of immunotherapy has been centuries in the making. Now, with the current immunology knowledge and biomedical technology, cancer immunotherapy has become a reality. Several immunotherapies are FDA approved and many more are in development. With more research and time, immunotherapy may make mesothelioma – and hopefully, all forms of cancer – a thing of the past.