so this year's laureate, Tasuku Honjo, was born in Kyoto in 1942. This was during World War II, so these were really difficult times. The family moved around quite a lot, but Honjo managed to make it through. In the 1960s, he started medicine at Kyoto University and became MD in 1966. He spent the next years in the Graduate School at the same University. After that, he went to the US. During 1971-72, he was a fellow at the Carnegie Institution of Washington in Baltimore, and later he worked at NIH. In 1979, he became a professor at Osaka University, and thereafter at the Department of Medical Chemistry, Kyoto University, where he later served as Dean. Currently, he is a distinguished professor at the Kyoto University Institute for Advanced Study, and from this year, he is also the deputy director-general. When I first met with Tasuku Honjo many years ago, he was interested in working on class switch recombination in B lymphocytes and trying to understand the process.

succeeded in finding the reason, and he identified the new protein. This protein was named activation-induced cytidine deaminase, and this crucial enzyme was not only important for switching the clause, but it also causes somatic hypermutation. And this is important to make antibodies work really well. I also remember listening to seminar in the 1990s when he mentioned about PD one, the importance of which was not at award understood at that time. His discoveries related to PD one originate from its identification and all the way through the understanding of its role as a checkpoint inhibitor. And of course, antibodies directed against this molecule have become highly important cancer drugs. Dr. Hondo has received many awards, and I will mention a few. He has received the imperial price and the Japan Academy prize. He's a foreign associate of the US National Academy of Sciences and member of the German academy of natural scientists. In 2012, he received the Robert Koch price. He has received the order of Culture Japan, the tank prize, and in 2016, the Kyoto prize. He has also

received the ko medical science prize and the Warren Alpert foundation price. Tosca Anjou likes music and painting. He has tells me that he always tries to visit museums and go to concerts when traveling. He made an attempt to play the flute but it didn't really work out so you gave it up but tasks evangelized essentially all types of exercise such as tennis baseball basketball table tennis and golf. He takes golf quite seriously and his handicap is 14. He told me yesterday that he every year he plays a few times with Shinya Yamanaka Nobel laureate in 2012. When his father was also doctor similar to Allison's he was a surgeon. He was a good painter and played tennis and golf very well similar to Jim Allison. There were things happening in during also during Hondo's school period. In Honda's case as a child his teachers did not perceive him as a good obedient pupil. This was because he often asked very difficult questions since reading regular textbooks never really satisfied him. One day a young

female teacher even began to cry when he pointed out that she might be wrong. Since then, he stopped asking questions in school and instead he decided to read books other than textbooks by himself. And of course, today we are the ones that read about Tosca Honda's discoveries. Please welcome this year's laureate, Tuscany. [Applause] [Music] [Applause] Thank You, professor Aerosmith's, for your kind introduction, distinguished guests, ladies and gentlemen. I'm extremely honored and humbled to have the opportunity to give Noble another lecture at the current Square Institute. For this, I had free appreciate the enormous efforts of the novel Assembly of the current sky Institute. The title of my talk, Serendipity's of acquired immunity, as your meaning a represent not only my contribution to cancer is rather for teachers, but also all human beings fortunate to have acquired immunity aquatic immunity. Otherwise, Ken Simon therapy must have been impossible. I was born in Kyoto in 1942. My family has generated many

medical doctors. My surgeon, my father, was a surgeon and had a rather strict educator. On the other hand, my mother is so beautiful and always warm-hearted. She has been my guardian goddess until she passed away five five years. The first incidence when I was charmed by a natural science took place at the playground of the elementary school. Then I watched this tiny tiny ring of Sodom through the telescope. The picture you recently see is more fantastic and likely you can see even the earth from sudden through the recent technical development by Cassini. I was very much fascinated by astronomy and I read many books and see very what seriously wanted to become astronomer. I read many books but my enthusiasm gradually faded away when my mother kept a book of biography of Noguchi Hideo now, which she is kind of self-educated doctor. He moved United States at age of 23 or so and hired as a professor in Rockefeller University and identified syphilis vaccine as a cause of progressive paralysis. Unfortunately, he

died in Ghana during pursuit of arrow fever pathogens, but I'm very much impressed his strong spirits and hiring activities. So, I went to medical school in Kyoto. There, I'm a game very fortunate to meet or some Hayashi, my mentor, who discovered the gas oxygen can be directly in cope into organic organic compounds by the enzyme oxidase. He spent nine years in United States and came back establish the Department of Biochemistry, which is well I kept it, and also he provided very international atmosphere. Thanks to that, I had an occasion to discuss with Jack mano in very early stage in my career. I was also very fortunate as soon after I went in the graduate course. I picked up the interesting paper by John career. He says Geoff theory toxin in activates protein synthesis elongation factor ef-2, and this reaction requires respiratory coenzyme nad. I was very much fascinated and tried find out what's a mechanism of nad. I was very fortunate Nishioka at that time in high reaches love later she found the protein c kinase. He made lots of nad derivatives.

with radio-labeled compounds, and I found, actually, Jeff theory toxin is the enzyme that catalyzes ATP ribosomal transfer to elongation factor 2. And this way, the enzyme is inactivated. With this very fortunate start of my career, I'm also very fortunate to meet Donna Braun in Carnegie Institution. Wasn't an embodiment. He is a person who opened my eyes to the molecular immunology. He explained to me their long history, not only immunology but biology. Antibody diversity is now on the table. We can now tackle this big question by modern molecular balance called technology like reverse transcriptase. The mystery of immune response around 1970 is very attractive to everybody. The question is how can animals generate antibodies specific to almost infinite number of antigens, including artificial chemicals. Like Karl Landsteiner, he took any compounds on his shelf, conjugated with protein, inject animals, and then he could prove animals can generate antibody against the chemicals, so-called hapten with high specificity. So, people thought, wow, animal may have endless number of immunoglobulin genes.

obviously impossible. The structure of antibody, which was originally identified from varying and Sheba Sbrocco Sato, are gradually becoming clear. A number of scientists involved. Paul Ehrlich also studied a lot. And most directory Gerald Edelman, Rodney Potter found antibodies composed to heavy chain to light chain. They are linked by disulphide bond. Hirshman and Craig, and also Putnam discovered light chain is composed and a terminal variable and c-terminal concern region. And obviously the variable region is responsible for antigen recognition and concern region responsible various activity of antibody to process the capture of the antigens. So the question is how many regions, how many seasons the dawn gave very attractive idea of multiple V and market the C. But obviously this is the hypothesis. So I was very fortunate don't introduce me to fill leaders laboratory in NIH. And he hired me as a postdoc. I moved there and worked very hard. And after few years we reached the conclusion immunoglobin light chain either Kappa or lambda has

only one at most of your genes the results ironically suggest Don's idea is wrong. There must be a limited number of the C region and therefore another indication is to explain the large number with a variable region expression. Animal should have genetic alteration either somatic hypermutation or recombination or both. Ensure enough four years later Susumu Tonegawa found to generate a larger repertoire of a maneuver even the four light chain VJ4 heavy chain DJ components were assembled during differentiation and by combinatorial mechanism they generate enormous diversity. He was awarded Nobel Prize 87 I believe. Meantime I decided to go back to Japan and got a position in University of Tokyo. Thereafter long thinking I decided to pick up a different project but still I wanted to understand the immunoglobulin diversification as my serious question. Instead of continuing the same series of study using a light chain I switched to the heavy chain which has obviously different questions. This is related repeated immunization so-called vaccination so people already knew after repeated immunization there are two interesting of the vision. One is

the change of the title affinity to the antigen, and this is due to the somatic hypermutation. The B-cell change the variable region rather randomly, and one of the highest affinity expressing these cells selected by antigen, and this is the mechanism of antigen-induced high affinity maturation. The Alpha mechanism is class switching. The initial antibody generated memory IgM, but after repeated injections, IgG become dominant. The cloths, which is a change of the concentration rather than V region, and that produced from IgM to IgA, IgG, IgE, and each has different function and different location. The V region surprisingly remain constant. How this captain and both are antigen-driven, so we decided pick up this question, and we are very fortunate to find to make class switching big chunk of DNA on the chromosome deleted to express one particular C gene from IgM, IgG to a you have to delete a big DNA, and that intervening segment is grouped out, and this was done with the help of bright medical student in Korea University Toru kataoka and Akira see Meisel, and we also

determined the order of the CH Dean along the chromosome, which we hypothesized soon after we came to Sweden and met Unum. You're the food Mattias wobble many others who compete each other for cloning amino group in lockers and found almost simultaneously reached a similar conclusion, but still we have many questions we haven't solved mechanism for somatic hypermutation. And also, most importantly, what the enzyme to mediate such interesting genetic alteration. And we also fortunate to obtain original say trova cell, which can be stimulated from IgM to IG a with CD40 lion art for TV of bitter. And Masamichi Mohammed's came and try to see the difference between stimulated not stimulated, and they found new gene called activation in decided in the army needs a ID, which is specifically expressed Germany center b-cells involved for class switch recombination probably. And we made a knockout, and the knockout animals showed strong induction of IgM by immunization, but IgG showing a blue is totally absent.

in air D-deficient animals. In addition, hypermutation is also disproved in air D-deficient animals, and no hypermutation as compared to heterozygote AI D animals. Our collaborator in France, and Ronnie and Aaron Fisher, also found in any human cohort patient of hyper IGM syndrome type 2. They all had a mutation in the same gene AI D, and we published the paper on side by side and together. A ID is the enzyme that engraves antigen memory in the antibody gene, and this is the mechanistic basis for vaccination. So taken together, Susumu Tonegawa showed the rabbit of a generation by putting vdj together and mature B so my greater periphery and see the pathogen induce a ID and that mediate have a mutation and class rating well occasionally here it is apparently induced and cause tumor and this is very rare because most of the immunology told immune activation rather suppress tumor growth. The idea of cancer immunotherapy dates back to the last century, but the very hypothetical backbone of can't immunotherapy immune surveillance was

proposed by Sir Frank MacFarlane Burnet 1970. And because of this very strong hypothetical background, large number of people try to demonstrate by activating immune system. Tumor can be suppressed or treated. And unfortunately, as you heard from Jim, it was very difficult. The trial includes many different types. First, many people isolated and purified cancer-specific proteins called neoantigens and produced in abundance. Injected as a vaccine. Another trials in which reactivation of T lymphocyte using IL-2 and putting back to the same patient. Also worth injection of cytokines like interferon gamma, IL-2, IL-12. Or failure retrospectively. All these trial or to push axial. And unfortunately, immune system was totally under the strong break induced by tumor growth. To identify the immune system break came only 1995 when Jim Allison showed CTL for is kind of the parking brake paired with CD28 is ignition molecule. And I think this is a comparing like parking brake and directs on/off rather drastic regulation. We identify the PD-1 as a brake and accelerator.

cause pairing and rather mild smooth regulation of the immune system. The moment we encounter the PD one was very fortunate. I'm very fortunate or over so yes Massa Ishida came to my department what it identified thymus selection mechanism namely something involved cell death and he actually cloned the cDNA by subtraction and found this surface molecule hydrophobic regions and intracellular domain contains highly conserved tyrosine molecules and to tyrosine is a very well known at that time for activation signaling molecules but these two titles in MPD one are different the distance between two a double compare the rest of the known activation molecule so we are convinced there are something different interesting but I don't know so we decided to make knockout and knockout done by Nishimura and others and that's the beginning of the law struggle first knockout born rather soon but couldn't see any phenotypic change dr. Minato advised to back rows to the homozygote again no phenotypic change we.

could see some over response to antigen stimulation. Maybe some negative regulator, but not so clear. But it took almost six-seven years until we find clear nephritis of arthritis by crossing with LPR air pure background, which is all immune prong five weeks after. In case of CT a four by four weeks, every single animal died. So, this is a very mild and chronic and clear at immunity in PD one knockout by only 14 months. So, I don't know whether Nishimura watched every day. I don't think so. She left the mice for months, and one day she found this. So, anyway, we found PD one knockout in blood mice shows nephritis arthritis white mouse called the myopathy and crossed with the odium from background and OD MLL all XS a very, very severe phenotype. We are very much convinced this is the negative regulator because we release the break immune system goes up Taku Okazaki photo showed the mechanism by crossing PD one with T cell receptor signal induced by antigen.

recognition. It's force waited, and PD1 also get phosphorylated and recruit phosphatase that defaults for it one by one. So, this way the reaction is reduced. Now, we find all this mechanism obvious thing is immune system in balance with accelerator and brake. And no Murray if it's a balance, it's okay if it goes to the hyper amina activity, it's good for infectious diseases treatment and cancer treatment, but risk of autoimmunity. So, if we push broke the brake and push the axle, we have a chance to cure the cancer. So, we try this. The first experiment I asked Yoshikawa is to compare PD one deficient animal and while animal see whether Timo can grow differently. The reason I chose this instead of antibody is because I don't trust the antibody because there are many antibodies. I trust the genetics. So, what we found sorry is here compared the wild-type PD one deficiency. Well, this is the last published data, but anyway, the first error she showed was convincing, and we think PD one the efficiency or

blockade is good for suppressing tumor growth so I doctor minato and he already started making antibody against the PDL-1 and also PD-1 but PD-L1 is the best antibody available and he could clearly demonstrate antibody blockade also suppress tumor growth and even prolong the survival our new Yoshio I further went on to show the metastasis of the melanoma injection into spleen to liver and liver this is rather normal and this is metastatic liver and you can say by weight and color under PD untreated animal shows much less metastatic liver so both PD-1 blockade or PDL-1 blockade we can cure the cancer and the mechanism we still don't know some people claim tumor Express Ligon and we block here but PDL-1 is expressed everywhere almost all ABC Express so how the CTL become suppressed we still don't know but anyway the key molecule is PD-1 and either Ligon or receptive blockade can cure the cancer so we wanted put this into the clinic and we

need lots of money and lots of the technologies. We are very fortunate medics found our published patent and approached us and studied generate anti-PD one human antibody. The product is IgG for and point mutation to prevent antibody-dependent survey, etcetera basicity and named Neve Oman. This antibody was approved by FDA investigation new drug was first to 2006 and then we can start crink trial about that time. I met a famous scientist rock this guy and you know so this was a very unfortunate incident and then the animal our clinical trial went on rather smoothly and the first report was published 2012 by Susan - partying and result was amazing. This was all spread all over the world newing Journal Medicine paper came out and Wall Street Journal and Frankfurt argument are all the front line of first page so basic message to one all the patient recruited to a terminal stage patient with solid tumor big tumor melanoma lung cancer renal cancer and surprisingly twenty to eight twenty to thirty percent patient.

responded, complete or partial. On top of that, those who once responded still respond years. The treatment stopped after two years but still they respond continued to stay. We did our own clinical trial in small scale in Kyoto in collaboration John ecology department and patient or Platon resistant ovarian cancer. And here again, if we include stable disease as a disease control rate, it reached to the 40 to 50 percent and among them we are very much impressed. The lady for responded very quickly and become a completely tumor free. And this lady even after we stopped the treatment after one year remain tumor-free more than four years. And another case more than 3.5 years tumor free. So without treatment this can last there is very very ideal. The most impressive quicker trial using me Bowman published 2015 by international collaboration many European countries Australia Canada. And they showed comparison of NIMH ovum and chemo typical chemo dacarbazine. It's a random trial so it's a blind test and patient who received Nouveau mom almost 70%.

survived after year and a half. On the other hand, chemo-treated patient less than 20%. So though it's a drastic difference, the huge number of clinical trials. I don't have time to mention, but because of this, the PD one locate therapy is now approved over dozen type of cancers, even this year cervical cancer and primary mediastinal large B-cell lymphoma. And as Jim mentioned, striking all highly mutated cancers. It can detect easily by microsatellite or the deficiency of mismatch repair enzyme, regardless the origin of tumor tissues. This is very, very important. So taking together the PD one treatment opinion treatment brought paradigm shift in cancer therapy. First, less adverse effects because normal cells are almost untouched. Second, effective for wide range of tumors. More than thousand clinical trials are still ongoing. Thirdly, it shows durable effects. You can stop the treatment and they can last at least four to five years. Why this is so effective, we already heard enormous amount of investigators sequenced the cancer genome. The published studying melanoma to breast cancer or thyroid.

cancer. All of them accumulate mutations. Each spot is one sample. So, this is a log scale plot of coding mutation, and normal cell has no mutation. So, all tumors has either thousand times or 10,000 times higher mutation in coding region that leads to the expression of new antigen. We call new antigen, and those new antigen are different from our original protein, and that is recognized by immune system. So, what we learn is this cancer cell mutate and make new antigen. Secondary mutations are so frequent, it's very difficult to pinpoint what is dominant mutations or what is a secondary mutation, and because of this cancer cell continuously mutate and you give the chemo, they change and give rise to resistant Crohn's, another drug, another resistant Crohn's. And fortunately, lymphocyte can recognize all these resistant mutants and can attack them. This is the big advantage. Now, I told you very, very promising outcome, but this is not the end of the story. You know we have many, many problems. First of all, clearly only 20 to 30 percent patient respond so we

have to distinguish responders from non-responders. How can we do it? One is high mutagenesis in tumors, which I mentioned, but this is also not always. Most important point is potency of individual's immunity. Some puke when flu virus you get, some people sneeze and that's all, others get 48 very high fever and almost die. So, enormous variation among individuals, and this is very difficult because it's not just MHC gene, there are hundreds genes involved in immune power. We also have to deal with improvement of immunotherapy or free not 20 to 30% of free to 80 to 90 percent. And actually, there are two aspects. One is access severity of killer T-cell to tumor site, the other is potency of carousel function itself. I'd like to briefly mention about the first aspect. Candy Tamata in my lab found that tumor cell first attacked by resident Kiera T so by PD one blockade and this stimulation give the gamma interferon and tumor cell itself secrete some chemical and this also leaves activated T's in lymph node.

migrate to the tumor site so PT one blockade takes place. To position one in tumor site but its number is very limited. But most important is activation of karate so in lymph node that activate chemical receptor and also differentiation. And this is very important process so often surgeon removes many lymph node sounding lymph tumor but that's not good idea you have to keep intact. If not and he showed in animal experiment if you remove draining lymph node even if we inject anti PD-1 that tumor cannot be reduced. Tumor keep growing now as Jim said now many people trying to combine with PD one with CT four and chemo radiotherapy and BGF a and Okun combination so thousand combinatorial trial going on. And we hope there will be something very promising come out in a few years. We also try new approach in our case we know that T lymphocyte 1 get activated needs lots of energy and lots of compounds energy depends on mitochondria. And so we screened chemicals which might be able

to boost my country, and it may attack the tumor more efficiently. We and others showed P DC 1 alpha co-transcription factor couple ways people are signaling activates essential step in mitochondria activation, oxidative phosphorylation, and fatty acid consumption. In fact, better fit braids together with anti-PDL one antibody in animal tumor model. The effect of the antibody is further enhanced synergistically. So, this is promising. So, we now on clinical trial in Japan Kyushu University and the common water university and high. We hope the results relatively soon. The mechanism, the two whole one is the better fit a paper signaling promote increased proliferation generation effect a killer T cells and also they enhance the perforation into memory generation instead of exhaustion and service by these two mechanisms pres afib rate combination PD one blockade increase number of killer T cells in tumor site. So, I'd like to add a little bit of wallet adverse effect of the PD want efficiency. Sidonia Fidelis on in weekend together with the from each Komatsu that showed.

pd-1 deficient animals show serum level reduction of treat for metabolism method mitochondria activation-related compounds so it grows so rapidly they consume essential amino acid and madcon you're turning on very rapidly they can monitored in serum an actually this enormous expansion and consumption metabolites effects even the brain neurotransmitter level like serotonin and dopamine and induce behavior change and she fathers showed this is related with gut bacteria change earlier Ferguson's group showed PD one deficiency reduce high affinity iga production IG a that combined good bacteria mean efficient for symbiosis and they lose such a iga production and change microbiota spectrum in the gut less anaerobic bacteria and increase the Enterobacter like e-coli and this will in turn stimulate host immune system an actually to make high affinity IgA you need a ID another my favorite molecule in germinal center cut germinal center PD one on t-cell interact with PD lichen on bezel and if P cell can capture good antigen and presents strong stimuli to

t-cell. They cannot proliferate. They can offer the help to be so produce good antibody so only P cell which can produce high affinity iga get this selection by T so in germinal Center and that good for controlling gut Mac bacteria in fact pack 2002 so Nia Vardalos on showed first time added efficiency skewed gut micro micro buta and expansion segmented favored 5:5 filamentous bacteria like this and this course an almost expansion of the power patch on the gut and even the spleen is enlarged so gut microbiota is very critical to control the level of the host immune system so we asked the question PD one deficiency definitely have hyper team activity how about air D deficiency the result just pd-1 deficiency air D deficiency has strong anti-tumor activity even without pd-1 blockade this is just straight animal and this separation of tumor grows in air the deficiency is bacteria dependent because in germ free condition they don't show any difference so what's happening is

pd-1 and air D should collaborate to produce appropriate IgA to control gut microbiota, and this balance is important to maintain in intolerance and homeostatic balance of metabolome improbably brain condition. But once this balance is destroyed, either pd-1 deficiency or AI D deficiency, they cannot produce appropriate IgA to control microbiota, and it may enhance the anti-tumor activity. But on the other side, they cause some emotional or behavioral defect and also Ottoman diseases, so we clearly don't know much about the whole body regulation, and we have to learn more and more. 2016 an equivalent code it don't chain saying we just discovered cancer equivalent penicillin, although the penicillin itself couldn't cure all infections, it gave rise to a whole generation of antibiotics that change the medicine forever, consigning most previously fatal infections to history. So I hope this will be true currently, they still immunotherapy is a minor fraction of the cancer treatment, but because of enormous efforts of the number of the people, it will eventually.

grow and more and more cancers may be treated by immunotherapy, and someday, I don't know whether it's 2030 or not, cancer may not completely disappear but be controlled by immunotherapy. Cancer may become one of the chronic diseases. If you still have a tumor but no growth, that's okay, especially for elderly people. You can keep your quality of life. Now, last century, we eradicated infectious diseases by vaccination and antibiotics, and this century, I hope cancer we control by immunotherapy. Its improvement, including as I mentioned, microbiome manipulation, had said at the beginning, our quail immunity is critical. A quite immunity evolved in vertebrates as a defense system against the pathogens. Consequently, the lifespan of the vertebrates expanded dramatically. That's why we are here. Fortunately, cancer cells are cumulative adhesions and express new antigens, which can also be recognized by acquired immunity. So, this must be the bonus of evolution. Finally, I'd like to thank my collaborators. I cannot mention all of the people involved. Some people, well, I think it's

too much because there are more people than I could list. I leave the so long so I I also many people, and this is the also the list of the funding agency who support me for a long term. Well, thank you for your attention. [Music] [Applause]

Nobel Lecture: Tasuku Honjo, Nobel Prize in Physiology or Medicine 2018

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