Immunotherapy is a novel treatment that involves activating the immune system to attack foreign and invasive cells. This type of treatment specifically targets cancer cells, whereas traditional treatments such as chemotherapy and radiation do not specifically target cancer cells. As a result, immunotherapy may be extremely effective in terms of survival and remission rates. However, many immunotherapy treatments are still in clinical trial.
Despite the novelty of immunotherapy, there have already been four FDA- approved immunotherapy treatments for colorectal cancer: Bevacizumab, Cetuximab, Ramucirumab, and Panitumumab (“Colorectal Cancer”). Coincidentally, all four of these treatments are monoclonal antibodies. Monoclonal antibodies are mass-produced antibodies that can initiate the immune response against cancer cells. To clarify, antibodies, produced by B cells, are molecules that target antigens (markers that can indicate a foreign cell). An antibody can only recognize one specific epitope (the part of the antigen that binds to the antibody), allowing for a specific response against that antigen. Thus, there are many different antibody molecules in our bodies.
Because cancer cells often appear as normal cells to the immune system (since cancer cells develop from normal cells), antibodies against their antigens may not be sufficient. With monoclonal antibodies, our immune systems can recognize cancer cells and, thus, initiate a destructive response. Monoclonal antibodies can target receptors to prevent the activation of a cancer cell, tag a foreign antigen in order to signal for destruction, and stop cancer cells from proliferating through blocking molecules such as checkpoints. As for the treatments for colorectal cancer, they target receptors, specifically VEGFR, EGFR, and VEGFR-2, that allow the cancer cells to proliferate (Francoso).
Bevacizumab and Ramucirumab bind to VEGF, which is a receptor on the inside of the cell membrane that works with the extracellular matrix (the extracellular matrix relays cell messages to other cells and molecules). By binding to VEGF (vascular endothelial growth factor), Bevacizumab prevents VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) from interacting with this protein. To clarify, VEGF is a growth factor that provides blood supply to cells and promotes angiogenesis, a process in which blood vessels are created in order for endothelial cells (cells that line the insides of blood vessels) to develop. This drug prevents the cancer cell from continuing to proliferate by inhibiting VEGF and, thus, inhibiting angiogenesis (Francoso). This action is essential, since angiogenesis allows for the tumor to metastasize and survive.
Panitumumab and Cetuximab bind to EGFR (epidermal growth factor receptor), a receptor that signals to the cell to continue developing and growing. By blocking this receptor, the cell cannot proliferate, since it is not signaled to do so. Thus, blocking EGFR can cause cancer cell death and inhibition of cancer cell rapid development and division (Markman). It is important to note that cancer cells cannot survive either or rapidly develop, without interleukin-8 and VEGF, both of which are produced in response to EGFR activation (Francoso).
While monoclonal antibodies are a type of targeted therapy, they can still affect healthy cells. When this action occurs, toxicities (harmful side effects) happen. For example, Ramucirumab can cause hemorrhages, Bevacizumab bleeding of the tumor and hypertension, Cetuximab heart attacks (if using chemotherapy or radiation with the drug) and severe allergies, and Panitumumab moderate to severe headaches and high blood pressure (Francoso). Perhaps these toxicities are due to the immune system believing the monoclonal antibodies to be invaders or the monoclonal antibodies attacking healthy cells that look similar to cancer cells. Although monoclonal antibodies are humanized after being produced in a lab, they can still pose a threat to the immune system by triggering the immune system to attack them. Because of the mild to severe toxicities associated with monoclonal antibodies, especially if they are used with chemotherapy or radiation, it is essential to consult with your doctor concerning the appropriateness of the drug therapy and your responses to treatments such as chemotherapy.
Interestingly, monoclonal antibodies are often used together with a traditional treatment, such as chemotherapy or radiation. One of the reasons they are used together is to limit cancer cell resistance: if the monoclonal antibodies do not completely eliminate cancer cells, then the chemotherapy can get rid of the rest. Also, monoclonal antibodies can directly carry the chemotherapy/radiation drug to the tumor and deliver it (“Monoclonal Antibodies”). However, monoclonal antibodies may be used as the treatment if the first-line treatment, which is usually chemotherapy or radiation, does not work.
In the future, researchers could potentially develop monoclonal antibodies to be even more targeted toward specifically cancer cells. While there will always be a risk of the monoclonal antibodies harming normal, healthy cells, there is always room for improvement. Perhaps one way to go would be to utilize nanoparticles (very small particles that are constructed in the laboratory from various materials ranging from gold to lipids) to introduce monoclonal antibodies to the specific region of the body, since nanoparticles can reach tumor cells (Turner).
“Colorectal Cancer.” Cancer Research Institute, Cancer Research Institute, 2017, www.cancerresearch.org/we-are-cri/home/cancer-types/colorectal-cancer.
Françoso, Alex, and Patricia Ucelli Simioni. “Immunotherapy for the Treatment of Colorectal Tumors: Focus on Approved and in-Clinical-Trial Monoclonal Antibodies.” Drug Design, Development and Therapy, U.S. National Library of Medicine, 11 Jan. 2017, www.ncbi.nlm.nih.gov/pmc/articles/PMC5241129/.
Markman, B, et al. “EGFR and KRAS in Colorectal Cancer.” Advances in Clinical Chemistry., U.S. National Library of Medicine, 2010, www.ncbi.nlm.nih.gov/pubmed/20857619.
“Monoclonal Antibodies (MABs).” Cancer Research UK, Cancer Research UK , 1 Nov. 2017, www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/biological-therapy/types/monoclonal-antibodies.
Turner, Christopher T., et al. “Therapeutic Potential of Inorganic Nanoparticles for the Delivery of Monoclonal Antibodies.” Journal of Nanomaterials, Hindawi, 1 June 2015, www.hindawi.com/journals/jnm/2015/309602/.