The 2018 Nobel Prize in Physiology or Medicine: An exemplar of bench to bedside in immunology

The catchphrase “from the bench to the bedside” has certainly been hackneyed and attained a cliché status. The 2018 Nobel Prize in Physiology or Medicine should re-energize this approach (https://www.nobelprize.org/prizes/medicine/2018/press-release/). The science for which it has been awarded is the epitome of the progression of basic scientific observations that were initially undertaken for their own sake through the scientific discovery process ultimately leading to life-saving therapeutic approaches. The 2 awardees, Drs James Allison and Tasuku Honjo, took complementary and equally outstanding approaches to elucidate how immune responses are regulated, checked, or terminated. Harnessing the immune system for tumor control has been the holy grail of immunologists for more than a century. In the late 1800s, William Coley noticed that one of his patients with cancer had a miraculous recovery after a severe bacterial infection. He developed what is known as “Coley's toxin,” which is believed to have been a mixture of bacterial products with the idea that this stimulated the patient's immune system. This led to the report by Krieg et al1Krieg A.M. Yi A.K. Matson S. Waldschmidt T.J. Bishop G.A. Teasdale R. et al.CpG motifs in bacterial DNA trigger direct B-cell activation.Nature. 1995; 374: 546-549Crossref PubMed Scopus (3097) Google Scholar in 1995 showing that bacterial DNA (CpG motif) can be a potent stimulator of the immune system. CpG oligomers have been and continue to be tested in patients with several immunologic diseases, including tumor immunotherapy. Since Coley's observation, the emerging concept has been that the immune system should be able to recognize any given tumor cell as “non-self” and should be able to reject it. The immune system's inability to do so might be either due to some processes that selectively inhibit immune response to tumors or due to the ability of tumor cells to inactivate the immune cells trying to destroy them. Basic research on the fundamental mechanisms controlling the interface of the immune system and cancers has led to the breakthroughs by Drs Allison and Honjo in cancer immunotherapy by targeting checkpoint inhibitor immune pathways. The 1980s and 1990s witnessed major advances in our understanding of lymphocyte activation. This led to our current understanding of the need for 2 signals for T-cell activation: the first signal occurs when the T-cell receptor (TCR) binds to the MHC-antigen complex on the surface of antigen-presenting cells, and the second signal occurs when CD28, which is constitutively expressed on T cells, engages CD80/CD86 on antigen-presenting cells. Binding of the TCR in the absence of the CD28 signal leads to anergy, whereas binding of the TCR and CD28 leads to T-cell activation. As T cells are activated, they begin to express cytotoxic T lymphocyte—associated antigen 4 (CTLA-4) on their surfaces. CD28 and CTLA-4 bind the same ligand (CD80/CD86), but CTLA-4 binds with a much greater affinity. Binding of CD80/CD86 by CTLA-4 suppresses T-cell activation by making CD80/CD86 less available to CD28, thereby preventing further T-cell activation.2Sharpe A.H. Mechanisms of costimulation.Immunol Rev. 2009; 229: 5-11Crossref PubMed Scopus (242) Google Scholar In 1995, Waterhouse et al3Waterhouse P. Penninger J.M. Timms E. Wakeham A. Shahinian A. Lee K.P. et al.Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4.Science. 1995; 270: 985-988Crossref PubMed Scopus (2385) Google Scholar and Tivol et al4Tivol E.A. Borriello F. Schweitzer A.N. Lynch W.P. Bluestone J.A. Sharpe A.H. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.Immunity. 1995; 3: 541-547Abstract Full Text PDF PubMed Scopus (2402) Google Scholar reported that CTLA-4–deficient mice manifested expansion of activated CD4 cells, resulting in massive lymphoproliferation and death of the animals at 3 to 4 weeks of age. These findings suggested that blocking CTLA-4 could be harnessed to prevent termination of an immune response and that this might be useful for tumor immunotherapy. In 1996, Leach et al5Leach D.R. Krummel M.F. Allison J.P. Enhancement of antitumor immunity by CTLA-4 blockade.Science. 1996; 271: 1734-1736Crossref PubMed Scopus (2752) Google Scholar reported that injecting anti–CTLA-4 antibodies in tumor-bearing mice prevented the establishment of melanoma and induced regression of pre-established tumors. This was followed by development of a human antibody against CTLA-4 (ipilimumab), which was used in clinical trials, with the first report showing miraculous responses in some of the patients with melanoma.6Hodi F.S. O'Day S.J. McDermott D.F. Weber R.W. Sosman J.A. Haanen J.B. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (11264) Google Scholar This antibody has since been used in many trials of tumor immunotherapy alone or in combination with chemotherapy or radiation therapy.5Leach D.R. Krummel M.F. Allison J.P. Enhancement of antitumor immunity by CTLA-4 blockade.Science. 1996; 271: 1734-1736Crossref PubMed Scopus (2752) Google Scholar In 1992, Ishida et al7Ishida Y. Agata Y. Shibahara K. Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death.EMBO J. 1992; 11: 3887-3895Crossref PubMed Scopus (2192) Google Scholar identified a protein called programmed cell death protein 1 (PD-1), which was expressed on cells undergoing programmed cell death or apoptosis. Some mutant mouse strains that were deficient in PD-1 expression had autoimmune disease.8Nishimura H. Nose M. Hiai H. Minato N. Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor.Immunity. 1999; 11: 141-151Abstract Full Text Full Text PDF PubMed Scopus (2048) Google Scholar This finding suggested that inhibition of this pathway might result in sustained immune responses (foreshadowing one of the major side effects of checkpoint blockade therapy, which is the development or exacerbation of various autoimmune diseases). PD-1 binds one of 2 ligands (programmed death ligand [PD-L] 1 or PD-L2) that can be expressed on tumor cells; this binding results in attenuation of immune responses against the tumor. It is now established that PD-1 is expressed on exhausted effector T cells and that such “exhaustion” can be rescued by inhibiting this pathway. Following the natural progression of science, these investigations led to the development of various antibodies against either PD-1 or PD-L1, which resulted in hitherto unprecedented tumor regression. In contrast to other forms of immunotherapy, which usually work in immunogenic tumors (eg, melanoma or renal cell carcinoma), checkpoint blockade therapy seems to work in a spectrum of tumors, with many other tumors currently under investigation.9Gettinger S.N. Horn L. Gandhi L. Spigel D.R. Antonia S.J. Rizvi N.A. et al.Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer.J Clin Oncol. 2015; 33: 2004-2012Crossref PubMed Scopus (938) Google Scholar The detailed history of this line of immunologic research and the detailed mechanisms of action were covered in detail in the November 2018 issue of the Journal.10Wieder T. Eigentler T. Brenner E. Röcken M. Immune checkpoint blockade therapy.J Allergy Clin Immunol. 2018; 142: 1403-1414Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar This editorial celebrates the role of immunology in a wide spectrum of diseases. Modifying an immune response to restore immune homeostasis holds promise not only for patients with cancer but also for those with many other organ-based diseases with immune abnormalities that continue to be uncovered. Many lessons can be drawn from the progression from the first discovery of the role of CTLA-4 and PD-1 in immune responses to the initiation of clinical trials. This basic research was started as one of many approaches seeking to understand the immune system. As is usually the case in basic research, the results led to new insights that might not have been considered at the outset. The field of immunology celebrates the accomplishments of Nobel Laureates Drs Alisson and Honjo and their colleagues. Their achievements illustrate the need to invest in such research because our understanding of the immune system remains rudimentary. These advances also illustrate the importance of patience in the support of biomedical research because these fundamental immune discoveries took more than 2 decades before they came to clinical fruition. Further investment in our current young investigators might lead to even greater achievements 2 or 3 decades hence.