The 2018 Nobel Prize in Physiology or Medicine

Contributed by Jane Naberhuis, Ph.D.

The Nobel Prize in Physiology or Medicine has been awarded multiple times for work related to cancer therapy. In 1966, it was awarded to Charles Huggins “for his discoveries concerning hormonal treatment of prostatic cancer.” In 1988, Gertrude Elion and George Hitchings secured the prize “for their discoveries of important principles for drug treatment,” which included chemotherapy.  Joseph Murray and E. Donnall Thomas won the award in 1990 “for their discoveries concerning organ and cell transplantation in the treatment of human disease,” which included bone marrow transplant for leukemia.1 Most recently, in 2018, it was awarded to James Allison and Tasuku Honjo “for their discovery of cancer therapy by inhibition of negative immune regulation.”1

The idea of harnessing the immune system for management of cancer is not a novel one,2 but the endeavor to develop widely applicable immunotherapies against cancer has been challenging.  Immunotherapies shift the focus of treatment toward the patient’s immune system, which fundamentally has the ability to recognize “self” from “non-self.”3 Critical to this action are T cells, which recognize “non-self” and induce defense against invading pathogens. T cells do not act alone, however, as additional proteins are capable of either accelerating or inhibiting T cell activation. This balance between activation and inhibition must be carefully maintained so as to effectively destroy invading pathogens, while simultaneously preventing autoimmunity.3

By the 1990s, James Allison had developed an antibody that could bind cytotoxic T-lymphocyte associated protein 4 (CTLA-4), an immune checkpoint protein which functions as a brake on T cell activation. Binding of this antibody to CTLA-4 blocked its function, and resulted in tumor rejection in a mouse model of cancer. Furthermore, tumor rejection resulted in immunity to a secondary exposure to tumor cells in these animals.4 These discoveries spurred other groups to investigate anti-CTLA-4 therapy, and in 2010, a landmark clinical trial demonstrated robust results with antibody treatment in patients with advanced melanoma.5

Also in the 1990s, Tasuku Honjo discovered programmed cell death protein 1 (PD-1), a protein expressed on the surface of T cells. Through a series of experiments, Dr. Honjo elucidated that similar to CTLA-4, PD-1 acts as a brake on T cells, though the two proteins act through different mechanisms.6,7 Also similar to CTLA-4, anti-PD-1 treatment was demonstrated to be a promising anticancer treatment in animal models, and in 2012 proved to be efficacious in patients with various types of cancer.8 Significantly, results of this trial showed that long-term remission of patients with metastatic cancer was possible.

Since these early studies, cancer treatment using antibodies against CTLA-4 and PD-1 has come to be known as immune checkpoint therapy. Antibodies against both CTLA-4 and PD-1 have been approved by the US Food and Drug Administration, which has dramatically improved prognosis for certain patients with cancer.9 The development of immune checkpoint therapy continues to evolve as these therapies, their combination, and other immune checkpoint inhibitors are investigated in clinical trials. Immune checkpoint therapy has significantly transformed cancer treatment, the progress of which was significantly furthered by recipients of the 2018 Nobel Prize in Physiology or Medicine, James Allison and Tasuku Honjo.

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References

1. The Nobel Prize. All Nobel Prizes in Physiology or Medicine. Available from https://www.nobelprize.org/prizes/lists/all-nobel-laureates-in-physiology-or-medicine/. Accessed January 20, 2019.

2. Coley WB. 1910. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc R Soc Med. 1910;3:1-48.

3. Parkin J, Cohen B. 2001. An overview of the immune system. Lancet. Jun;357(9270):1777-89.

4. Leach DR, Krummel MF, Allison JP. 1996. Enhancement of antitumor immunity by CTLA-4 blockade. Science. Mar;271(5256):1734-6.

5. Hodi FS, O'Day SJ, McDermott DF, et al. 2010. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. Aug;363:711-23.

6. Ishida Y, Agata Y, Shibahara K, et al. 1992. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. Nov;11(11):3887-95.

7. Freeman GJ, Long AJ, Iwai Y, et al. 2000. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. Oct;192(7):1027-34.

8. Topalian SL, Hodi FS, Brahmer JR, et al. 2012. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. Jun;366(26):2443-54.

9. Chae YK, Arya A, Iams W, et al. 2018. Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC). J Immunother Cancer. May;6:39.