History of Immunotherapy by James Allison at PMWC 2017 Silicon Valley

[Music] so why I mean to therapy I think for for decades the issues have been pretty apparent one is particularly with t-cells and specificity I think everybody knows that t-cells recognized peptides in the context of MHC molecules they're displayed to let the body know what's going on in the cells and we know now increasingly that in cancer the intercept seems to be focused on neo antigens generated by mutations not just the driver mutations which is what precision medicine has been about but also all the many of the passenger mutations if they meet certain minimum qualities they can be presented to the immune system and second is memory once you've got t-cells you've got them for the rest of your life and they can be reawakened if a cancer occurs and attack it again unlike any other drug and finally there's adaptability you probably have about a hundred million t-cells with different set receptors going around the body and I would argue and it can change with time and I would argue that that's that's a match for the for the genomic instability and mutability and evolution of the tumors that plagues more conventional types of cancer therapy and so just to show you where you where we are in 2011 drug I helped developed in hip elumen lab with meta racks approved for melon for melanoma 2014 there were two pd-1 drugs and another checkpoint I'll talk about also for melanoma in 2015 there was an avalanche of approvals at lung Agilent melanoma renal carcinoma and then last year their approvals of Hodgkin's lymphoma bladder head neck and non small cell lung cancer so you can see that this this field is growing at a really geometric rate and has been years down and many different types of cancer we're beginning to understand the rules of it and I'll get to that later for some of the capsules that don't respond what is this well it's kind of a strange cancer therapy because it doesn't involve the cancer cells at all we ignore the cancer cells we don't sequence it or try to find drugs that inhibit an enzyme so anything like that doesn't involve the present point at least using vaccines are to target the immune system of cytokines to turn them on what involves is it works about just removing inhibitory circuits to unleash the immune system to do what it was doing anyway so people say we've learned how to harness the immune system to attack cancer well that's true some types of immunotherapy but not checkpoint blockade check for blockade is merely unleashing it or helping it in the case of some positive checkpoints to do a better job of what it's doing anyway and so how do we get here a kid got here again just mentioned earlier and I like to point this out by just fundamental research I'm trying to understand how t cells work just basic science without basic science we're not gonna have anything to translate for the sermon so I would urge us to really keep that in mind this early funding decisions are made by the NIH notice so this looks complicated but it's really not that complicated when when the t-cell antigen was discovered we work out the structure of that in 1982 it was thought that that was the single single that signal single signal is enough to get T cells activated but quickly it became apparent that that wasn't correct that there are other signals consummatory signals that could only be provided by very specialized cells dendritic cells which Ralph Steinman run Nobel Prize a few years ago and when T cells got contemporaneous antigen receptor signals and custom Ettore signals T cells take take off anyway we showed about 1988 Jane gross and Fiona Harding of lab showed that the main receptor for stimulatory signals on T cells will cd28 which is constitutively expressed when a t-cell gets both those two things happened one the first one is that a go program is launched with all that green stuff happening the T cells go to cell cycle and just let it take off because you need to if you're going to fight a virus infection go from a few dozen cells perhaps the hundreds of thousands in a matter of a few days and so this is a really amazing for a while see cells are dividing about every four to six hours but in the mid nineties we discovered along with JetBlue so there's now UCSF that is an off program is also initiated when the t-cell gets those two signals what happens is a gene of a molecule is very homologous to cd28 called ctla-4 gets induced with time C to look for accumulates in the cell and it has the ability to out-compete because of its affinity for the exactly the same ligands at cd28 users can stop co-stimulation and ended immune response it's important because you have to stop that proliferative phase your immune system will kill you we are and other labs knocked out the gene for CDC play for and the mice dive and about three weeks old from Olympic proliferation and so what does if do is cancer well we sure don't we on that solid tumors don't have the co-stimulatory ligands so they're invisible to the municipal the only way the immune system because they don't have a score similar story signals they're visible immune system until they die cause inflammation these specific cells have been picking the tumor beds displays pick up the tumor that's displayed to in the context of the co stimulatory signals and then you get by this cross priming and immune response started but also turns on the off signal and the other we had in the 1994 was if the officer gets turned on before you kill all the tumor cells the tumor wins the race because it has an inherent head start so we had the idea to just block seats like for and tumors can get rejected and this is one of the first mouse experiments that we did it shows that just covering up that single molecules enough to get the tumor rejected and give you a permanent immunity so we teamed up with meta racks and subsequently bristol-myers Squibb to make this if you live a mam it's a fully human antibody to see play florida but over seventy thousand patients treated with this objective responses and many types of cancers we would have predicted in the original formulation of the idea there are adverse events colitis hepatitis a lot of viruses but their inflammatory just dupe laboratory conditions generally and can be handled with steroids and they don't come back this actually is what our favorite side this will make Sharon lived in Santa Monica California when you played a lot of tennis was out in the Sun got melanoma and you could see the metastasis in her lung in 2001 she was on the phase one trial she got a single dose of three MiG's per kig event acetylated for you know within about six months of tumors went away she told Tony Reba's her doctor she just want to live long enough to see her son's graduate from high school I visited in 2011 and that was her cat scan in 2011 ten years later with no treatment in between just that one injection she's still doing fine today she's almost 16 years out now she's probably the oldest survivor on appeal of a man so anyway I was approved by the FDA in 2011 this is a retrospective study of almost 5,000 patients was done a couple years ago and it shows about three years there's an inflection point in space flat for ten years so about about 22 percent the survival curve flattens out in these patients who are still a lot nobody dies after about three years or so and patients fraction of them are alive again for ten years but why not more why is it just 20% was a number of reasons for that but could be but one obvious was maybe there are other checkpoints and so this is the clinical data started coming in on C delayed for a group at Harvard working with Tosca Hangzhou in Japan showed that pd-1 which is a molecule that really had no known function a clear functional then was shown to be another Kotori molecule like C play for it has two ligands on APCs we don't know exactly what those do yet but unlike C play for one of its ligands PDL one can be induced on tumor cells by tumor specific t-cells that are making gamma interferon the tumor puts up the PDL one to engage the P one molecule and stop that it stops the function of the C cells and so antibodies to PD run and PDL wound where develop this is the first PD one antibody phase one trial in 2012 and you can see a melanoma again there's better there's a 20% almost 30 percent response rate non-small-cell lung cancer a very significant needle cell cancer again very good response rate not in colorectal cancer in this trial the system has been found that there is a subset of colorectal cancer with a high mutation rate as microsatellite instability and those do respond and castrate-resistant prostate cancer also didn't respond and the time to talk about it I think we've figured that out my colleagues at MD Anderson anyway here's a survival curve for PD one it's not clear that there's a tail on it because it just hasn't been around enough it looks like there probably is and at least some patients have very durable responses so where do you go you've got these two things that both work on a fraction of patients and because they have different mechanisms the PD one works at the level of T cell antigen receptor we did some Mouse studies and show that the combination of P D 1 and C 24 was better than either alone and so from here well that slide got somehow going to lead but anyway the combination results in responses in about two-thirds of patients who get both the antibodies there was a phase 3 trial a couple of years ago whether it was a 50 percent objective response rate but 60 percent of patients we know now are alive two years later and so it may be that those patients if they make it too much further will will have a decade long response rate and so where we are now is we really need to know the mechanisms of these what we're finding is the clinical data is coming in so fast its overtaking the list the science we know that those little cartoons I showed you are really not all that correct once we got deeply into what's going on in the tumor a key should be some antibodies would be really great to have predicted prognostic or pharmacodynamic markers you're going to hear about that from the speakers today partly new molecules to improve advocacies this molecule high cost that was identified by patent sharma to play a role in too many as if you're going to hear about some Debbie writer and also we need to know how these things work so we can combine the best out of care there appease now we've got these two but they're really different as I said C plate 4 is hardwired p1 is induced resistance CGA like for target co-stimulation p1 the t-cell and receptor seek ty for work priming pd-1 works on exhausted t-cells and just lose function ctla-4 blockade can expand foam diversity they bring new t-cells into the mix p1 expands the key cells of our you there so you play for primarily works on cd4 cells we know now cd8 T or P one primarily works on cd8 cells ctla-4 can move t-cells into some tumors prostate cancer notably pd-1 does not appear to be able to do that number big differences is the disease recurrence after response is really low with c24 and typically focal in nature whereas the the relapse after responses with p p1 is significant it's about 25% in melanoma about 35% in lung cancer and so anyway that difference is a little worrisome but the rest of them really explaining why these two things work so well together as new molecules come we've got to figure out you know how they work this is kind of where we are this is a chart showing the range of mutational burden and a variety of types of tumor cells what's obvious is that the high end those that have high mutation burden the Box all of those have been approved for mono therapy or combination therapy kidney as a lower button for the stands out among those with moderate levels of mutational load but there's other it's like pancreatic cancer and glioblastoma that we need to really get working on there's also problems of getting T cells into tumors that new electrical desert so we could didn't worry about checkpoints but we know how to do it a lot more molecules to work on they're constantly being discovered I'm sure your health a lot more at this meeting now this close by saying this is where we where have been in cancer for a long time therapy that's treating a lot of patients with a drug and it's statistically determining if we move the medium survival with C play for we know we could do that we could also get a flat survival tale of a fraction of patients between 20 and 30% and this is a aspirational goal that is we know with a combination of PD - before we can get about 50% our goal now is to move that tail up not so much to worry my opinion about about moving the median over but to raise the tail as high as we can get it as many cancers as we can and the good news is I think that we know the basics there's a lot more work to do but I think we can get there at least to a degree cure certain kinds of cancer so thank you for your patience [Applause]

Channel: PMWCintl

Views: 20,433

Rating: 4.9093852 out of 5

Keywords: James Allison, PMWC, Precision Medicine, MD Anderson Cancer Center

Id: PphTL6vY4W4

Length: 13min 46sec (826 seconds)

Published: Thu Jun 15 2017