June is Cancer Immunotherapy Awareness Month!
Despite receiving less funding per patient than breast, colon or prostate, lung cancer research has been instrumental in bringing immunotherapy into the realm of accepted therapies for cancer. Immunotherapy has revolutionized cancer treatment and is the reason James Allison and Tasuku Honjo won the 2018 Nobel Prize in Physiology or Medicine.
Broadly speaking, immunotherapy describes the use of any part of the immune system in combatting cancer. The immune system is a complicated system of specialized cells tasked with defending the entire body from the constant onslaught of foreign invaders such as bacteria, viruses and even cancer. It is typically easy for the immune system to recognize bacteria and viruses as foreign because they do not share the same genetic makeup of the human body. In other words, bacteria and viruses are not you and the immune system is pretty good at differentiating you from everything else.
However, cancer cells arise from the body’s own cells and are very similar to the normal cells of the person. This makes immunotherapy a difficult but not impossible venture. What researchers have long looked for are unique parts of cancer cells that set them apart from the normal cells. These unique parts of a cell are called antigens. When an antigen is also part of normal cells, we call them Tumor-Associated Antigens. When they are unique to the cancer, we call them Tumor-Specific Antigens. It is these tumor-specific antigens that hold the most promise.
Some of these tumor-specific antigens come from a class of viruses known as oncogenic viruses. Oncogenic viruses can cause cancer after infection by inserting their genes into a normal cell and taking over. These viral genes are therefore unique to the cancer and are considered tumor-specific antigens. Examples of oncogenic viruses include certain subtypes of the Human Papillomavirus (HPV) that can cause cervical cancer and is the reason HPV vaccines and cervical cancer screenings are critically important.
Most cancers are not driven by viruses and make discovery of tumor-specific antigens difficult. However, a key characteristic of cancer cells is their ability to mutate. Although an increased ability to mutate can lead to advanced metastatic disease, it also produces small changes in normal proteins that are unique to the cancer cell and create tumor-specific antigens. These newly created tumor-specific antigens (known also as neoantigens) are recognized by the immune system as foreign in a similar way as the immune system recognizes a virus. These neoantigens are the target of anti-cancer immune responses. These anti-cancer immune responses are highly effective and prevent the cancer that we are projected to get every day.
So then why do some cancers escape the immune system and become clinical disease?
A cancer is made up of many cells that although they originated from one cell, they are now a collection of many cells each with slightly different genes due to their constant ability to mutate. These new mutations give the different cancer cells new abilities. One new ability some cancer cells develop is the ability to block anti-cancer immune responses. If there is a potent anti-cancer immune response then the immune cells will kill all of the cancer cells except for the ones that are impervious to the immune response. This allows those cells that block the immune response to become the dominant cell type because they are the only cancer cells to survive.
The cancer cells capable of blocking the immune response tend to produce proteins that lie on the cell surface that interact with the immune cells called T cells aimed at killing the cancer cells. On the cancer cell surface, they produce a protein called Programmed Death Ligand-1 (PDL1). PDL1 interacts with a protein on the T cells called Programmed cell Death protein 1 (PD1). When PDL1 interacts with PD1, the T cell is stopped from working and the cancer grows. This interaction forms a checkpoint that classically directs the immune system to only attack the appropriate foreign targets. But in this case, cancer cells with PDL1 disallow the immune system from removing the damaging cancerous cell.
Checkpoint Inhibitors are a powerful class of immunotherapy that prevent the cancer cell from blocking the anti-tumor immune responses from doing their job. Checkpoint inhibitors are antibodies that block either PDL1 on cancer cells or PD1 on T cells from interacting. Blocking the interaction of PD1 and PDL1 unleashes the anti-tumor immune response and has cured ~20% of advanced lung cancer patients.
More to come on this blog about immunotherapy as it’s a major interest of the kilt wearing founder. But hats off to the dedicated researchers who continue to advance this science.
‘Cause no one should die of Lung Cancer.