A few months back, I entered an international medical competition centered in the UK called the Unofficial Guide to Medicine Essay Contest. For secondary school students, or high school students, there were two prompts to choose from. The first read “Learning from the past: What do you think has been the most important medical discovery in the last 10 years and why?” while the second read “Anticipating the future: What do you think will be the greatest challenge modern medicine will face in our lifetime?” Upon reading these prompts, I immediately knew I wanted to do the former. Furthermore, I knew that I wanted to do it on cancer immunotherapy, which I had read a little on recently and knew was something that had profoundly changed cancer therapy in the past decade. Here is my entry for the competition that was awarded a highly commended distinction on the topic of cancer immunotherapy.
Learning from the past: What do you think has been the most important medical discovery in the last 10 years and why?
At the Winship Cancer Institute in Atlanta, Georgia, a 91-year-old man was suffering from metastatic melanoma that first spread to his liver and soon after reached his brain. He was former US president Jimmy Carter, and he rightly believed at the time that he had months to live as no patient with the same initial metastases for Stage IV melanoma survived even a year (Figure #1). However, the doctors came to him with a treatment plan, combining radiation therapy and surgery with a new drug, pembrolizumab, which was approved less than a year earlier by the FDA for the treatment of metastatic melanoma. The drug worked by preventing the cancer’s evasion of President Carter’s immune system, allowing the body’s natural anti-tumor response to fight the cancer. Within months, he was entirely cancer free. As President Carter stated, his “key to success” was cancer immunotherapy.
The human body’s immune system prevents infirmity through a two-pronged response. The first response, known as the innate immunity, uses non-specific physical and chemical barriers to prevent the entry of offending agents. If the threat bypasses or is not subdued by these barriers, the more specific and efficient second response, known as the adaptive immunity, rounds up and eliminates the offending agent through antibodies and cell-mediated pathways. Cancers are sometimes not stopped by either the innate or adaptive immunity though. In part, this is due to their origin as an abnormal growth of the body’s very own cells, growing with the upregulation of the cell cycle “accelerator,” oncogenes, or the downregulation of the cell cycle “brakes,” tumor suppressors. Checkpoints meant to prohibit unrestrained cell growth fail. Then, the cancer further evades the immune system by reducing its own antigen expression to make itself less detectable or by deactivating the immune cells through targeting receptors like PD-1. Thus, the cancer is able to immortally proliferate, dividing at an immense rate for a considerable amount of time. With the immune system not functioning as it should, the human body is defenseless against the cancer.
What if you could prevent the cancer from evading and deactivating the immune system in the first place? In seeking an answer to this question, Dr. William B. Coley utilized the power of the immune system to fight cancer in 1891. By injecting cultures of the bacteria to cause erysipelas, an infection of the surface of the skin, Dr. Coley discovered that patients with cancers like sarcomas and lymphomas could achieve full remission. However, the significance of “Coley’s Toxins” was not understood at the time and ultimately dismissed by his contemporaries. Only after a century of tireless work has the field of immunology unveiled the key to potentiating the body’s own defenses in fighting otherwise fatal cancers. The culmination of the last ten years of work with the discovery of new mechanisms and ways of treating various cancers has made cancer immunotherapy worthy of the title of the “breakthrough of the year” in 2013 by Science, one of the leading journals in the US. Researchers predicted that with its successes in recent years, immunotherapy will form the backbone of 60% of cancer treatment in a decade. Given its excellent track record in clinical trials thus far, immunotherapy may reach that milestone much sooner.
Enthusiasm for cancer immunotherapy drugs flooding the field is justified when one examines what they have to offer. Take for example pembrolizumab, a monoclonal antibody, which has been significantly more effective than traditional chemotherapy in treating non-small-cell lung cancer, extending survival rates by nearly 75% in one study. The drug works by specifically targeting the PD-1 checkpoint protein, which is located on the surface of immune T cells, and its complementary PD-L1 ligand, which is located on host cells (Figure #2). As a self-protective mechanism, the physical interaction between the two acts as an “off-switch” for T-cells, aborting an immune attack. However, certain tumors, in order to evade this immune attack, upregulate their PD-L1 expression, which causes T cells to have “reduced proliferation, reduced cytokine secretion, and reduced survival,” essentially inactivating them. Additionally, the PD-1 and PD-L1 interaction triggers the increase of regulatory T cells (Tregs) function, further suppressing the immune system to the advantage of the cancer. Pembrolizumab, a PD-1 inhibitor, occupies and blocks the PD-1 receptor on the T-cell, preventing this interaction with PD-L1 and thus exposing the cancer to a T-cell attack. As a testament to its enormous potential for transforming cancer therapy, the FDA, the US federal agency in charge of regulating drugs, recently approved pembrolizumab to treat all types of cancer for patients with one of two biomarkers—mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H)—after a clinical trial representing fifteen different types of cancers found that 40% of patients positively responded to the drug. No longer is it a question of where the cancer is located. It is a question of what biomarker the cancer has; one immunotherapy drug can be used treat a myriad of cancer types.
Chemotherapy, radiotherapy, and surgery have traditionally been the three pillars of treating cancer. However, there are inherent limitations to each of them that do not apply to immunotherapy. Surgery is not always feasible for cancers which have undergone widespread metastases as it is nearly impossible to excise all of the tumors. Likewise, chemotherapy and radiotherapy are toxic and not entirely selective since they affect normal cells as well as cancerous cells. At some point in the cancer progression, these treatments cannot do enough to stop the growth of tumors. All of these pillars are typically solely effective for cancers that are diagnosed in their earliest stages. For fast-progressing cancers like pancreatic and esophageal cancer, this failure of the traditional treatment regimen is put into clear focus as a vast majority of patients die within five years.
For patients with advanced cancer, hope is something that they covet and so desperately need. Immunotherapy is there to provide that hope. It is not limited by cancer type nor its progression. As mentioned before with pembrolizumab, what works for one cancer works for another as long as the cancer shares the same biomarker. Moreover, successful therapy can happen at any time during the course of the cancer progression. Once a drug has activated and mobilized the immune system, then theoretically no matter how far the cancer has spread, the immune system can get to it and kill it with impressive precision and speed. Scientists are now adapting and tailoring immunotherapy to cancer with chimeric antigen receptor (CAR) T-cell therapy by infusing genetically modified T-cells, designed to recognize and destroy particular cancer cells by binding to cancer-specific antigens (Figure #3). The ability to flood a patient with personalized white blood cell soldiers not only solves the immediate cancer problem but also is able to prevent the cancer from recurring since these cells will continue to multiply and will circulate in the bloodstream indefinitely. Transformative advances such as CAR T-cell therapy, which has been approved by the FDA and widely utilized recently, is what makes cancer immunotherapy so promising.
In the past decade, cancer immunotherapy has treated rare cancers, like acute lymphoblastic leukemia with an 83% remission rate, and especially lethal cancers, like Merkel cell carcinoma with a 73% response rate with only one immunotherapy drug., These numbers are highly encouraging and are a testament to the fact that immunotherapy is becoming the fourth pillar of cancer treatment. Additionally, if only one immunotherapy drug can yield such high response rates, then we may see nearly 100% remission rates when immunotherapy drugs are combined with one another or with other traditional forms of cancer treatment. With over 3400 cancer immunotherapy clinical trials on the horizon, these combinations will likely be found and will likely revolutionize cancer treatment forever. If so, cancer immunotherapy will be the vanguard of the silver bullet that destroys cancer once and for all.
Bucco, Danielle. “Immunotherapy Offers New Optimism for Patients with Merkel Cell Carcinoma.” Cure. Last modified October 20, 2017. Accessed February 10, 2018. https://www.curetoday.com/conferences/smr-2017/immunotherapy-offers-new-optimism-for-patients-with-merkel-cell-carcinoma.
Buchbinder, Elizabeth, and Anupam Desai. “CTLA-4 and PD-1 Pathways.” American Journal of Clinical Oncology, February 3, 2016, 98-106. Accessed February 10, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892769/.
Buechner, Jochen, Stephan Grupp, Shannon Maude, Michael Boyer, Henrique Bittencourt, Theodore Laetsch, Peter Bader, Michael Verneris, Heather Stefanski, Gary Myers, Muna Qayed, Michael Pulsipher, Barbara Moerloose, Hidefumi Hiramatsu, Krysta Schlis, Kara Davis, Paul Martin, Eneida Nemecek, Christina Peters, Patricia Woods, Tetiana Taran, Karen Mueller, Yiyun Zhang, and Susana Rives. “Global Registration Trial of Efficacy and Safety of CTL019 in Pediatric and Young Adult Patients with Relapse/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL): Update to the Interim Analysis.” European Hematology Association, June 14, 2017. Accessed February 10, 2018. https://learningcenter.ehaweb.org/eha/2017/22nd/181763/stephan.a.grupp.global.registration.trial.of.efficacy.and.safety.of.ctl019.in.html?f=topic=1574*media=3.
“Cancer and the Cell Cycle.” Khan Academy. Accessed February 10, 2018.https://www.khanacademy.org/science/biology/cellular-molecular-biology/stem-cells-and-cancer/a/cancer.
“Cancer Facts and Figures.” American Cancer Society. Last modified 2017. Accessed February 10, 2018. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf.
CAR T-cell Therapy. Image. Accessed February 10, 2018. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy
Couzin-Frankel, Jennifer. “Cancer Immunotherapy.” Science, December 20, 2013, 1432-33. Accessed February 10, 2018. http://science.sciencemag.org/content/342/6165/1432.
“Definition of CAR T-cell Therapy.” National Cancer Institute. Accessed February 10, 2018. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy.
Dong, Yinan, Qian Sun, and Xinwei Zhang. “PD-1 and Its Ligands Are Important Immune Checkpoints in Cancer.” Oncotarget, December 10, 2016, 2171-86. Accessed February 10, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356790/.
FDA Approves First Cancer Treatment for Any Solid Tumor with a Specific Genetic Feature. May 23, 2017. Accessed February 10, 2018. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm560167.htm.
Gangadhar, Tara, and April Salama. “Clinical Applications of PD-1-based Therapy: A Focus on Pembrolizumab (MK-3475) in the Management of Melanoma and Other Tumor Types.” Onco Targets and Therapy, April 22, 2015, 929-37. Accessed February 10, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410900/.
———Overview of the PD-1 Pathway. Image. Accessed February 10, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410900/.
Howard, Jacqueline. “Hope and Hype around Cancer Immunotherapy.” Last modified September 27, 2017. Accessed February 10, 2018. http://www.cnn.com/2017/06/02/health/immunotherapy-cancer-debate-explainer/index.html.
“The Immune System and Cancer.” Cancer Australia. Accessed February 10, 2018. http://edcan.org.au/edcan-learning-resources/supporting-resources/biology-of-cancer/defining-cancer/immune-system.
Park, Alice. “What If Your Immune System Could Be Taught to Kill Cancer?” Time. Last modified March 23, 2016. Accessed February 10, 2018. http://time.com/4270345/immunotherapy-pembro-clinical-trials-cancer/.
“The Promise and Pitfalls of Cancer Immunotherapy.” Stanford Medicine. Last modified 2016. Accessed February 10, 2018. http://stanfordmedicine.org/communitynews/2016fall/immunotherapy.html.
Reck, Martin, Delvys Rodríguez-Abreu, Andrew Robinson, Rina Hui, Tibor Csu0151szi, Andrea Fülöp, Maya Gottfried, Nir Peled, Ali Tafreshi, Sinead Cuffe, Mary O’Brien, Suman Rao, Katsuyuki Hotta, Melanie Leiby, Gregory Lubiniecki, Yue Shentu, Reshma Rangwala, and Julie Brahmer. “Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer.” The New England Journal of Medicine, November 10, 2016. Accessed February 10, 2018. http://www.nejm.org/doi/full/10.1056/NEJMoa1606774.
Sandru, A., S. Voinea, E. Panaitescu, and A. Blidaru. Overall Survival for Stage IV Patients According to First Metastatic Site. Image. National Center for Biotechnology Information. 2014. Accessed February 10, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4316142/table/T1/.
———“Survival Rates of Patients with Metastatic Malignant Melanoma.” Journal of Medicine and Life, October-December 2014, 572-76. Accessed February 10, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4316142/.
Schmidt, Charles. “The Benefits of Immunotherapy Combinations.” Nature. Last modified December 20, 2017. Accessed February 10, 2018. https://www.nature.com/articles/d41586-017-08702-7.
Steenhuysen, Julie, and Deena Beasley. “Immunotherapy Is Not Just for Melanoma Anymore.” Reuters. Last modified May 31, 2013. Accessed February 10, 2018. https://www.reuters.com/article/us-cancer-immunotherapy/immunotherapy-is-not-just-for-melanoma-anymore-idUSBRE94U05P20130531.
“Timeline of Progress in Immunotherapy.” Cancer Research Institute. Accessed February 10, 2018. https://www.cancerresearch.org/cri-impact/timeline-of-progress.
Tontonoz, Matthew. “Understanding Jimmy Carter’s Surprise Cancer Turnaround: A Conversation with Jedd Wolchok.” Memorial Sloan Kettering Cancer Center. Last modified December 9, 2015. Accessed February 10, 2018. https://www.mskcc.org/blog/understanding-jimmy-carter-s-surprise-turnaround-conversation-jedd-wolchok.