Cancer kills millions of people every year, making it one of humanity's greatest health challenges. Several older family members of mine have recently passed away from various forms of cancer, prompting me to think more about the illness as well as what treatments are being utilized as potential cures. In my preliminary research, I learned about one relatively new technique, immunotherapy, that is currently being used to treat forms of lung cancer and lymphatic cancer. Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. I discovered that in their establishment of this cancer therapy, 2018 Nobel Laureates, James P. Allison and Tasuku Honjo, have constituted a major breakthrough in our world’s fight against cancer and I was curious to learn more.
Throughout this project, I researched the topic of immunotherapy. Without much prior knowledge, I began by learning to understand the basic mechanisms used by this medical technology -- how immunotherapy uses one’s own immune system to fight cancer. I continued my research reading three articles. The first article, titled Development of New Immunotherapy Treatments in Different Cancer Types, gave me a general understanding of how the use of different therapeutic treatments can lead to a manipulation of the immune system. And how these manipulations can stimulate immune agents such as cytokines, vaccines, cell therapies, and humoral, transfection agents in order to target cancer cells. The second article titled, A Guide to Cancer Immunotherapy: From T cell Basic Science to Clinical Practice, focused more specifically on T cells and T cell therapy and its role in immune responses to cancer. As T cells are a crucial component of immunotherapy, learning how to harness T cells to fight cancer proved to be very important. According to the method called adoptive T cell transfer, T cells are removed from the patient, genetically modified, or treated with chemicals that enhance their activity, and re-introduced into the patient. There are several trials using adoptive T cell transfer techniques that are currently enrolling patients with cancer. Finally, in order to understand the effectiveness and success of immunotherapy in living organisms, I read a third article, titled Combination Immunotherapy of Primary Prostate Cancer in a Transgenic Mouse Model Using CTLA-4 Blockade. This article demonstrates that an effective immune response against primary prostate tumors in transgenic mice can be elicited using a strategy that combines CTLA-4 blockade and an irradiated tumor cell vaccine. Importantly, this article found that treatment of transgenic mice using immunotherapy at 14 weeks of age resulted in a significant reduction in tumor incidence (15% versus control, 75%), as assessed 2 months after treatment. This article also required me to learn about T cell inhibitor proteins, CTLA-4 and PD-1, which I explain in the immune defense graphic on the website. Ultimately, after reading these three articles, I formed a greater understanding of how immunotherapy works to target cancer cells and its effectiveness in living organisms.
Modern medicine has allowed scientists to develop new technologies to treat types of cancer that were previously thought to be incurable. For over a century, scientists have attempted to understand how to engage the immune system in the fight against cancer. The discovery and establishment of immunotherapy has now revolutionized cancer treatment and has fundamentally changed the way we view approaches to cancer management. Immunotherapy provides a new class of drugs for cancer therapy. Today, scientists understand that tumors mediate immunosuppression through cellular mechanisms, which protects tumors from immune system recognition and elimination. In time, immunotherapy combined with other forms of target therapy will lead to advances in personalized medicine, greatly increasing the overall survival rate for patients with cancer and helping doctors to achieve success in fighting one of humanity’s most dreaded diseases.
FIGURE CAPTION:
Upper left & right: CTLA-4 and PD-1 are T-cell brakes that inhibit T-cell activation.
Lower left & right: Antibodies against CTLA-4 and PD-1 inhibit the function of the brake leading to activation of T cells and highly efficient attack on cancer cells. PD-1 has proven more effective immune responses and results.
SOURCE: The Nobel Committee for Physiology or Medicine. Illustrator: Mattias Karlén
IMMUNE DEFENSE:
The activation of the immune system is one strategy for attacking tumor cells. The figure to the left details the specific pathway utilized by immunotherapy. The effects of proteins CTLA-4 and PD-1 blockade have been developed into a treatment referred to as "immuno checkpoint therapy".
ACCELERATORS AND BRAKES:
The fundamental purpose of our immune system is to separate "self" from "non-self" so that invading bacteria/viruses can be attacked and eliminated from the body. T cells are central to this defense mechanism. T cells have receptors that bind to structures on "invaders" and trigger the immune system to engage in defense. There are other proteins called T cell accelerators that lead to a fuller immune response. It was found that other proteins serve as brakes on the T cells, inhibiting immune system activation. The balance between accelerators and brakes is essential for control of the immune system.
DISCOVERY OF PD-1:
PD-1 (similar to protein CTLA-4) is a protein expressed on the surface of T cells, that functions as a T cell brake. Scientist James Allison developed an antibody that could bind to PD-1 and block its function. The PD-1 protein was then tested to understand if a PD-1 blockade could disengage the T cell brake and unleash the immune system to attack cancer cells. This mechanism was made into a treatment (immunotherapy) in which utilizes antibodies that inhibit the brake and unlock anti-tumor T cell activity.
Cancer immunotherapy involves the use of different therapeutic treatments that lead to a manipulation of the immune system. These manipulations utilize and stimulate immune agents such as cytokines, vaccines, cell therapies, and humoral, transfection agents in order to target cancer cells.
T cells play a central role in immune responses to cancer. In this guide to cancer immunotherapy, the authors provide a comprehensive historical and biology al perspective on cancer immunotherapy, with a focus on current and emerging therapeutic approaches that harness T cells to fight cancer.
In this study, scientists demonstrate that an effective immune response against primary prostate tumors in transgenic (TRAMP) mice can be elicited using a strategy that combines CTLA-4 blockade and an irradiated tumor cell vaccine
Global Head of Translational Clinical Oncology at Novartis
Immunotherapy has been established as a treatment for patients with many types of cancer, including patients with lung cancer, which is the leading cause of cancer-related mortality in both men and women worldwide. Despite this new medical practice, the survival rate of patients with lung cancer remains relatively low. Interestingly, scientists have found that the process of evolution has improved the ability of tumors to adapt to immunotherapy. Several studies have focused on applying the concept of evolution to tumors in order to improve clinical outcomes.
Tumors evolve through genetic changes and respond to changing environments, including environments altered using immunotherapy. Tumors can produce new mutations that lead to selective growth advantages at any time. Immunotherapy has been widely used as a new model for tumor treatment. However, the greatest problem with this approach is that over time, patients develop immune drug resistance: the manifestation of tumor evolution under treatment pressure. The study of tumor evolution has helped scientists to reveal mechanisms of tumor drug resistance and propose solutions to this problem.
The principle of Darwin’s Theory of Evolution is natural selection. Natural selection is defined as the process whereby organisms better adapted to their environment tend to survive and produce more offspring. Within tumor cell populations, tumor cells that genetically mutated to have drug-resistance survive at higher-rates than tumor cells without this mutation. Further, drug-resistant tumor cells are able to produce more drug-resistant cells as they are not being targeted and eliminated in the body. Within this environment, there is also competition for resources among tumor cells. This competition works to rid the body of genetically mutated cells and keep the number of drug-resistant tumor cells low.
Anti-tumor therapies, such as immunotherapy, work effectively to kill sensitive tumor cells, but they allow drug-resistant cancer cells to continue to grow. In patients whose cells may have high drug resistance, the drug therapy works less effectively, leaving the patient with many drug-resistant, cancerous cells. In this way, the treatment results in the breaking of the competitive balance of the types of tumor cells. Now, the drug-resistant tumor cell subgroup becomes the new dominant subgroup, shifting the competitive balance.
Current evolutionary cancer researchers are looking to find in what ways can we achieve the goal of treating tumors by controlling the evolutionary process of tumor cells? Scientists using immunotherapy are working to answer the questions: 1) What mechanisms/methods can we use to maintain the competitive balance of tumor cell populations that occurs naturally due to tumor cell evolution? 2) Can the competition balance of tumor cells be regulated using a combination of treatments: chemotherapy, targeted therapy, and immunotherapy?
Ultimately, our immune systems are constantly changing with cancer cells mutating continuously. Thus, working to better understand the process of tumor evolution, specifically, how physical intervention in the evolutionary process of tumor cells can decrease tumor drug resistance and lead to improved cancer treatment outcomes.
Hurwitz AA, Foster BA, Kwon ED, Truong T, Choi EM, Greenberg NM, Burg MB, Allison JP. Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res. 2000 May 1;60(9):2444-8. PMID: 10811122.
Stanculeanu, D L, et al. “Development of New Immunotherapy Treatments in Different Cancer Types.” Journal of Medicine and Life, Carol Davila University Press, 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC5154307/.
“The Nobel Prize in Physiology or Medicine 2018.” NobelPrize.org, www.nobelprize.org/prizes/medicine/2018/press-release/
Waldman, Alex D., et al. “A Guide to Cancer Immunotherapy: from T Cell Basic Science to Clinical Practice.” Nature News, Nature Publishing Group, 20 May 2020, www.nature.com/articles/s41577-020-0306-5.