标题: 2018 Nobel Prize in Medicine [打印本页] 作者: choi 时间: 10-1-2018 13:21 标题: 2018 Nobel Prize in Medicine 本帖最后由 choi 于 10-1-2018 14:31 编辑
(1) Press release: The Nobel Assembly at Karolinska Institute Has Today Decided to Award the 2018 Nobel Prize in Physiology or Medicine jointly to James P. Allison and Tasuku Honjo for their discovery of cancer therapy by inhibition of negative immune regulation. Oct 1, 2018 https://www.nobelprize.org/uploads/2018/10/press-medicine2018.pdf
Quote:
"During the 1990s, in his laboratory at the University of California, Berkeley, James P Allison studied the T-cell protein CTLA-4. He was one of several scientists who had made the observation that CTLA-4 functions as a brake on T cells. Other research teams exploited the mechanism as a target in the treatment of autoimmune disease [in which it is believed, but not proven, that human immune cells attack one's own cells for reasons unknown]. Allison, however, had an entirely different idea. He had already developed an antibody that could bind to CTLA-4 and block its function (see Figure). He now set out to investigate if CTLA-4 blockade could
disengage the T-cell brake and unleash the immune system to attack cancer cells." Allison succeeded in his experiments.
"In 1992, a few years before Allison's discovery, Tasuku HONJO 本庶 佑 ['at Kyoto University'] discovered PD-1 [Programed Cell Death Protein 1], another protein expressed on the surface of T-cells. * * * The results [of his lab] showed that PD-1, similar to CTLA-4, functions as a T-cell brake, but operates by a different mechanism (see Figure).
"Of the two treatment strategies, checkpoint therapy against PD-1 has proven more effective and positive results are being observed in several types of cancer, including lung cancer, renal cancer, lymphoma and melanoma. New clinical studies indicate that combination therapy, targeting both CTLA-4 and PD-1, can be even more effective, as demonstrated in patients with melanoma.
Note:
(a) If you are not a biologist, the quotation is all you need to know.
(b) Alison (given name) https://en.wikipedia.org/wiki/Alison_(given_name)
(c) CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 (cluster of differentiation 152)
(d) "He [Allison] had already developed an antibody that could bind to CTLA-4 and block its function"
(i) An antibody that can bind to a certain surface protein (say, receptor) of a cell is easy to develop; conceptually, its binding block that protein from interaction with its ligand (the latter in a key-and-lock manner). It is also possible to develop an antibody that ACTIVATES the receptor, much lie its (receptor's) ligand
(ii) What this quotation in (b) says is that Allson wanted to inhibit CTLA-4 receptor and see what happened, whereas other scientists wanted to ENHANCE (by whatever means; unsuccessfully it turns out) to suppress immunity(because autoimmune diseases are reportedly due to overreaction of immunity).
(e) Reference ("Key Publication") 1 of the press release explained the name PD-1 (that is Honjo had a wrong idea of PD-1 function when he cloned the gene -- under wrong assumption and in the wrong direction: he thought at the time activation of PD-1 protein CAUSED programed cell death), whose full article is available to the public for free. https://www.ncbi.nlm.nih.gov/pubmed/1396582
View only Figure 1 where APC is short for antigen-presenting cell. A cancer cells )as well as many other types of normal cells) also expresses PD-L1.
(3) PD-1, PD-L1, CTLA-4 and the latter's ligand (CD80)all belong to immunoglobulin superfamily. The binding of PD-1 and PD-L1 is shown in Figure 1 (with two nearly identical images to be viewed with a 3-D glasss) of
Zak KM at al, Structure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1. Cell, 23: P2341-2348 (2015). https://www.cell.com/structure/fulltext/S0969-2126(15)00402-5
My comment:
(a) President Jimmy Carter announced in summer 2015 that he had terminal melanoma with metastasis to brain and liver. He received surgery, radiation and checkpoint immunotherapy (with monoclonal antibody against PD-1: pembrolizumab (Keytruda®); order of different modes of treatment unclear) but no chemotherapy. On Dec 7 of that year, he announced he was cancer-free; he has remained so. A Dutch company invented the medicine in the first decade of this century; Merck bought the right.
(b) I has expressed doubt about PD-1 inhibition to treat cancers: Why most human cancers are not susceptible? In those cancer types that do respond favorably, why do many patient do not while some do? Why do some cancer patients respond favorably initially, then relapse beyond control?