Throughout my first few articles, beginning April 11, I discussed how alterations at the DNA level can at times cause cells to evade normal regulation, as well as their own death, and become cancerous. Scientists, however, have learned how to exploit some of these genetic differences in order to develop cancer therapies such as PARP inhibitors. While genetic mutations such as those in the BRCA1 or BRCA2 genes do not directly cause cancer, they can lead to physical changes in a cell's properties that allow the cell to continue growing, despite signals to stop. Scientists have also learned how to take advantage of these physical changes in cancer cells to develop targeted therapies. One rapidly growing technology takes advantage of the specialized mechanisms that our own bodies use to defend against disease and harmful pathogens. This technological advancement, called immunotherapy, takes the components of our own immune systems and trains them to detect cancer.
Cells constantly send and receive signals, both within their local environment (i.e. tissue) and throughout the body. Communication between our cells is essential to the proper functioning of our bodies and processes like thinking, moving muscles, and digesting food. Recognition of these signals occurs through proteins that sit on the outer surface of cells, like antennae. When cells have the wrong types of proteins on their surfaces, however, they receive incorrect signals which can lead to growth at the wrong times. When these cells grow at the wrong time as a result of incorrect signals they can develop into cancer.
Similar to how we can distinguish FedEx from UPS drivers based on their uniforms and branded trucks, the combination of proteins on the outside of a cell acts like a uniform that helps our bodies identify which cells belong to us and which belong to foreign organisms. Cells in different tissues in our bodies have unique protein uniforms that allow them to have different functions. Cells in our livers, for instance, have a different set of proteins than cells in our hearts. By detecting these protein uniforms, our immune systems can determine whether a particular cell is a part of our own body or from a foreign invader. Cancer cells are a unique class of cells in that they contain the same proteins normally found in the cells that comprise our bodies, but have combinations of proteins that differ from the patterns seen in our normal cells.
Despite these nuanced differences between the protein combinations of cancerous and non-cancerous cells, scientists believe that under certain circumstances our immune systems are able to identify and fight off cancer. This concept of "immunological surveillance" was proposed over 50 years ago and is supported by a number of observations. Certain types of cells that comprise the immune system, for instance, are often detected within the tumors of cancers including breast cancer. Suppressing the response of the immune system, either through certain drugs or as a result of diseases such as HIV and AIDS, can lead to elevated risk for cancer. Despite its best efforts, however, our immune systems are not perfect at eliminating cancer because cancer can evade detection.
The ability of cancer to dodge detection by the immune system is similar to the way BRCA1- and BRCA2-mutated cancer cells acquire resistance to PARP inhibitors, as discussed in my previous article, The Power of PARP Inhibition. That article addressed how cancer cells can acquire secondary DNA mutations that bypass the DNA repair mechanism being targeted by PARPi. When cancer cells evade detection by the immune system, they similarly acquire DNA mutations. These mutations change the way protein uniform looks, like painting the FedEX logo a new color. This new uniform, as a result, cannot be detected by the immune system. Scientists are utilizing our knowledge about the connection between the immune system and cancer to target cancer cells, specifically, as a treatment.
Although scientists are still trying to figure out how the complex immune system works and interacts with the other cells in our bodies, we do know that the immune system is comprised of two primary parts. The innate immune system is the first defense against intruders. Each cell in the innate immune system has a specialized role but cannot easily adapt to unique threats. Like the military, it has different branches of cells that each specialize in attacking different enemies through different mechanisms. The second part of the immune response is the adaptive immune system. These cells, like the Navy SEAL special operations forces, take time to mount a specialized attack on the invaders. The innate and adaptive immune systems often work together, combining their specialties to attack pathogens that enter our bodies.
One branch of the adaptive immune system's special forces is the B cells. These cells create specialized proteins called antibodies that specifically bind to proteins from pathogenic invaders. B cells can detect proteins from invaders through a receptor on the surface of their cells. Once a B cell detects a foreign protein it hones its antibodies until they become highly specific for the target protein through a series of mutations in the DNA sequences that code for the antibody. It is estimated that through different combinations of antibody genes and mutations, the human body can create upward of one trillion different antibodies! Once an antibody becomes specialized and interacts only with the target protein as a result of these mutations, B cells can create large amounts of this same antibody. The cells then send them like arrows throughout the body to hit their targets.
Scientists have taken advantage of this highly specialized nature of antibodies in order to target cancer. They have developed antibodies that can detect proteins which are characteristic of certain types of cancer cells. Expression of the protein Human Epidermal Growth-factor Receptor 2 (HER2), for instance, occurs in approximately 25% of breast cancers. HER2 is a protein that resides on the surface of cells and receives signals instructing cells to grow. HER2 is an oncogene which, when mutated, can cause too much protein to be made. You may recall the discussion in The Double-Edged Sword of Mutation about how too much protein function can cause cells to divide uncontrollably by making cells more sensitive to the growth signals. Similarly, while HER2 can be found in many cells, some cancer cells actually overproduce HER2. Two therapies, trastuzumab and pertuzumab, have been developed to treat cancers that over-produce HER2, including breast cancer. Both of these drugs consist of antibodies designed to bind to HER2 and render it non-functional; this, in turn, results in HER2 no longer being able to receive growth signals.
These antibody therapies are often used in conjunction with other types of treatments, such as chemotherapy. Using multiple approaches makes treatment more effective and reduces the likelihood of developing resistance to the treatments. Importantly, chemotherapies do not work in a targeted manner and affect both cancerous and non-cancerous cells; scientists, however, have figured out a way to target chemotherapies to cancerous cells by attaching the drugs to antibodies. The therapy ado-trastuzumab emtansine, for instance, consists of the HER2-targeting antibody that is linked to a chemotherapy drug. In addition to preventing the growth of the cancer cells by blocking function of HER2, the chemotherapy drug infiltrates the cancer cell and kills it. This particular chemotherapeutic drug, emtansine, destroys the machinery that helps properly segregate DNA during cell division. By attaching the chemotherapeutic drug to the antibody, the drug is localized to the cancer cells, allowing more of the drug to get into the cell and thereby making it more effective. Additionally, attaching emtansine to an antibody targets it specifically to the cancer cell, which lowers the potential harm to healthy cells. Utilizing both methods of preventing the growth of cells, therefore, makes the treatment more effective. These HER2-targeting antibody-based therapies rely on creation of the antibodies in the laboratory, which are then administered to patients.
Scientists, however, are also developing ways to utilize our own immune systems to more effectively fight off cancer. This concept of cancer vaccines trains our immune systems to fight off cancer similar to the way flu vaccines ward off influenza. The vaccines we are familiar with that prevent the flu or chicken pox stimulate the production of antibodies against specific pieces of these pathogens. Rather than prevent cancer by predisposing the immune system to potential cancer markers in order to make antibodies that target those markers, cancer vaccines train the immune system to attack specific cells.
One method being explored for cancer vaccines is to present proteins from the cancer to specific immune cells, called cytotoxic T cells, which then seek out the cells with the matching protein. Cytotoxic T cells, which are another arm of the specialized adaptive immune system, can then kill the cancer cells they identify. This process is similar to training a search and rescue dog to find a missing person by providing them with the scent of the missing person. One therapeutic vaccine for cancer is currently approved by the FDA. This therapeutic, sipuleucel-T, treats metastatic prostate cancer by taking advantage of dendritic cells, which are part of the innate immune system. These cells help activate the cytotoxic T cells by "eating" pathogens, digesting their proteins, and then displaying fragments of those proteins on the cell surface. Presenting these digested fragments acts as a "be-on-the-look-out" sign to T cells, allows for a larger attack to then be mounted against the pathogens. The sipuleucel-T vaccine cuts out the step in which dendritic cells detect and eat pathogenic cells, and instead, directly provides the cancer-specific proteins to the cells.
Sipuleucel-T is a cocktail of prostate cancer proteins that get introduced to the dendritic cells, which are taken from the patient. Once the dendritic cells have been activated, they are infused back into the patient, to activate the T cell response. As sipuleucel-T is effective in treating prostate cancers that do not respond to other chemotherapies, many additional therapeutic vaccines are being developed including one, currently in clinical trials, that targets the HER2 protein and is showing promise in treating certain types of breast cancer.
One of the advantages of this "search and destroy" aspect of immunotherapies is that targeting unique protein markers on cells allows for the treatment of cancer cells that have spread from the primary tumor site. Targeted therapies can also be used across different types of cancers that share some of these markers. I previously discussed that PARP inhibitors, another targeted therapy, have the same advantage of treating cancers throughout the body that all have the same molecular identifier. PARP inhibitors, however, target cancer cells based on their genetic differences. The antibody therapies I discussed in this article distinguish cancers based on the protein identifiers present on the outer surfaces of the cells.
In summary, our immune systems are highly specialized in the detection of protein identifiers in order to determine what is a part of our bodies and what is not. The ability of our immune systems to create specialized antibody proteins is, in part, one reason our bodies are capable of such nuanced responses. While this article only scratches the surface of how the immune system works and both naturally and synthetically detects cancer, the ability to harness the power of the immune system as a means of targeting cancer cells has revolutionized cancer treatment. In my next article I will expand on these promising technologies, as I will discuss chimeric antigen receptor T cell (CAR-T) therapy, which also utilizes T cells to fight cancer.