The 2018 Nobel Prize in Physiology Or Medicine
Journal of Young Investigators SCIENCE NEWS ARTICLE
Check it Before you Wreck it: the 2018 Nobel Prize in Physiology or Medicine
Tina Xiwen Zhou
The Nobel Prize in Medicine and Physiology for 2018 was award- ed to Dr. James P. Allison and Dr. Tasuku Honjo for making break- through discoveries on strategies for treating cancer by preventing the “ignorance” of tumors by the immune system. Developing can- cer cells are normally detected by surveying white blood cells, or T-lymphocytes, that recognize the tumor progenitors as abnormal and target the abnormal cells for destruction. However, as a tumor develops, the cancer cells of the tumor begin to send inhibitory signals to immune cells, causing them to “ignore” the growing tu- mor until it is virtually invisible to the immune system. The igno- rance, or immunotolerance, of these tumors is caused by cellular “brakes” placed on the immune cells. Dr. Allison’s and Dr. Honjo’s research focuses on two of these cellular brakes and how their in- fluence can be lifted to induce the body to attack cancer. In the 1990s, Dr. James P. Allison studied the function of a Dr. Tasuku Honjo (left) and Dr. James P. Allison (right), win- T-cell receptor called CTLA-4, a down-regulator of immune ac- ners of the Nobel Prize in Medicine and Physiology this year. tivity. The CTLA-4 receptor inhibits T-cell activity by blocking Cartoon and graphic by Tina Zhou activating signals that come from other cells. Its function is like telling the T-cell to ignore a blaring cellular alarm that says “at- tack”. While other researchers sought to use CTLA-4 as a target for treating autoimmune disorders, Dr. Allison explored the pos- sibility of targeting this protein to treat cancer. He developed an antibody that could bind to CTLA-4, called anti-CTLA-4, and block its function, thus preventing the inhibition of T-cell activ- ity. Testing his hypothesis on mice yielded promising results; mice treated with the antibodies unlocked the devastating cancer-killing abilities of T-cells, effectively decreasing the size of their tumors. These results pushed the study forward to clinical trials, in which patients with skin cancer, called melanoma, showed drastic reduc- tion in tumor advancement. Advanced-melanoma patients treated with the anti-CTLA4 therapy showed persistent responses, some lasting 10 years. In a subset of other patients treated with the ther- ficacy in treating a variety of cancers--patients showed dramatic apy, all signs of any remaining cancer had disappeared. Seeing the improvement and long-term remission. The therapy was even ef- success of anti-CTLA-4 is baffling for researchers in the field; its fective in patients with severe metastatic cancers that had spread to success is shared with another therapy targeting a similar cellular multiple parts of the body, a feat that was previously unthinkable. brake known as PD-1. Current research is moving forward with further characterization PD-1 was discovered by Dr. Tasuku Honjo in 1992. Like of how exactly these cellular mechanisms allow for T-cells to infil- CTLA-4, PD-1 is a surface protein found on T-cells that acts as a trate the cancer and destroy tumors, as well as methods for increas- cellular brake. PD-1 and its associated proteins are generally in- ing the likelihood of therapy success. volved in protecting the body’s own cells from immune attack, but The discovery and targeting of both CTLA-4 and PD-1 led to they are also responsible for helping tumors and other infectious the development of what is now called immune checkpoint inhibi- agents gain immunity against the body’s defenses. Dr. Honjo’s tion therapy. Cancer is one of the top causes of death worldwide team characterized PD-1 in a series of elegant experiments and and conventional pillars of treatment include radiotherapy, sur- showed that blocking PD-1 by using an antibody called anti-PD-1 gery, and chemotherapy, each with its own drawbacks. Dr. Honjo’s can be effective in treating cancer in mice. Following this success, and Dr. Allison’s research, along with many other researchers’ dis- clinical trials proceeded. The anti-PD-1 therapy clearly showed ef- coveries, have led to the substantial emergence of a new pillar,
JYI | December 2018 | Vol. 35 Issue 6 Journal of Young Investigators SCIENCE NEWS ARTICLE
termed immunotherapy. Earlier in 2017, two different treatments of this category, called Chimeric Antigen Receptor T-cell therapies (CAR-T) were approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia. Similar to anti- CTLA-4 and anti-PD-1 antibodies, CAR-T therapy involves the manipulating the body’s own T-cells for attacking and destroying cancerous cells. Immunology is now a growing field of interest in targeting a variety of diseases aside from cancer, despite having only been heavily studied in recent years. The clinical proficiency of CAR-T and anti-CTLA-4/anti-PD-1 therapies in treating a mul- titude of cancers in a variety of patients is groundbreaking and extremely promising for doctors, researchers, and patients alike. These bright spots of hope for those receiving the devastating di- agnosis of cancer would not be possible without the hard work, dedication, and scientific intuition of scientists and doctors like Dr. Allison and Dr. Honjo.
REFERENCES “CAR T Cells: Engineering Immune Cells to Treat Cancer.” National Cancer Insti tute, www.cancer.gov/about-cancer/treatment/research/car-t-cells. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 107(9):4275- 80, 2010. e-Pub 2010. PMID: 20160101 Ishida, Y., Agata, Y., Shibahara, K., & Honjo, T. (1992). Induced expression of PD- 1, a novel member of the immunoglobulin gene superfamily, upon pro grammed cell death. EMBO J., 11(11), 3887–3895. Jin HT, Ahmed R, Okazaki T. Role of PD-1 in regulating T-cell immunity. Curr Top Microbiol Immunol.2011;350:17-37. doi: 10.1007/82_2010_116. The Nobel Prize in Physiology or Medicine 2018. NobelPrize.org. Nobel Media AB 2018. Fri. 2 Nov 2018.
JYI | December 2018 | Vol. 35 Issue 6