Cancer Revealed: How the Immune System Sees and Destroys Tumors, with Jeffrey Weber

no therapy today's date is Tuesday June 16 2015 the title for today's webinar is cancer revealed how our immune system sees and destroys tumors today's webinar is made possible through the generous support of amgen M gen focuses on areas of high unmet medical need and leverages its biologics manufacturing expertise to strive for solutions that improve health outcomes and dramatically improve people's lives a biotechnology pioneer since 1980 Amgen has grown to be one of the world's leading independent biotechnology companies has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential my name is brian brewer and i'm director of marketing and communications at the Cancer Research Institute Cancer Research Institute is the world's only nonprofit organization dedicated exclusively to harnessing the immune systems power to conquer cancer we fund scientists around the world whose work has led to significant breakthroughs in treating cancer with immunotherapy over the next 45 minutes you'll have an opportunity to hear first-hand from an immunotherapy expert how cancer treatment today is undergoing a revolution thanks to these breakthroughs after a 25 minute presentation from our speaker we will open the discussion to questions submitted by you you can pose your question at any time throughout the presentation by typing in the Q&A box on your screen we're also will be live tweeting this webinar so you can tweet your comments and questions to us at at cancer research and be sure to use the hashtag CRI webinar today's webinar is being recorded and will be made available for viewing on the CRI website and on our youtube channel now it's my distinct pleasure to welcome today's expert speaker dr. Jeffrey Weber is a senior member director of the Donald a Adam comprehensive melanoma Research Center of Excellence and professor in the Department of on collage excitement at cancer center as a tumor immunologist and immunotherapy he focuses on translational clinical trials including the development of novel trials in melanoma Dr Weber earned his PhD in molecular cell biology from the Rockefeller University and his MD from New York University Medical Center he has published more than 100 articles in the top peer-reviewed journals in his field it's an honor to have you here Dr Weber welcome thank you very much Brian that kind introduction so today we're going to talk about the concept of anti-tumor immunity and hopefully at the end of this perhaps 25 30 minute session I'll convince you that the immune system does play an extraordinarily important role in potentially mediating the regression of established cancers I just have to show my disclosures and let's get on to the meat of the matter so first what are the players or who are the players in the immune system keep in mind the immune system is broadly divided into two arms there's the so-called innate immune system which is really our first line of defense innate immunity is pre-existing it's ready to respond to it infection inflammation or cancer it's essentially a booby trap examples of innate immune cells are macrophages neutrophils it is not an educated immune system nor is it very selective essentially the innate immune cells kill first can ask questions later the flip side of the coin from innate immunity is the adaptive immunity adaptive immune cells are called B cells or T cells and they're educated in the sense that they can learn they have memory and they can recall prior exposure to bacteria viruses tumors or other stimuli and they're very specific and they have a very selective not a general action it's not a shotgun as much as it's think of it as a sniper rifle and again if you compare the innate and the adaptive immune cells for example if you look at the innate immune receptors they're encoded in the germline in all of our cells whereas adaptive immune cells are in the somatic cells if you look at the receptors the innate immune receptors are not clonal they're not specific they're general adaptive immune receptors on the b-cells and t-cells they're clonal they're very specific the repertoire of receptors in a b-cell or a t-cell my god it's it's dozens of thousands literally whereas it's very limited in innate immune cells the targets are very specific for the innate immune cells it could be virtually anything for a b-cell or a t-cell b-cells and t-cells can even destroy normal tissue they can destroy tumors viruses bacteria in flight you name it recognition of the innate immune cell is perfect but it's not quite perfect for adaptive immune cells and you want your innate immune system to work really fast it's the first line of defense adaptive immunity takes time so it's slow it takes weeks to develop and you have memory the hallmark of the adaptive immune system of the t-cell and the B cell it remembers it can recall that doesn't happen with the innate immune system so here are the players and if you look at the left side you can see the adaptive immune cells pardon me the innate immune cells mast cells which make histamines cause us to have allergic reactions macrophages natural killer cells basophils eosinophils neutrophils neutrophils that's your first line of defense against infection and then there's kind of the cells in between natural killer cells are sort of when they're called a natural killer t-cell they're sort of on the fringe between innate and adaptive but if you look at the adaptive immune cells there's your b-cell making antibodies and on the right there's the t-cell and that can mature into either a helper cell called a cd4 cell or a killer cell call it a cd8 T cell and those T cells well I think of myself as a T cell chauvinist those T cells are are very important and if you look at the T cells the first signal they get to do anything comes when a piece of a protein so-called peptide binds to a MHC a major histocompatibility molecule and when that T cell receptor on the T cell binds it has the capacity to recognize but it's not very strong and you need something called a second signal and that second signal is something on the T cell which is called cd28 binding to something on well it could be a dendritic cell a macrophage ironically that's an innate immune cell it binds to b7 one or b7 to that's another signal another we call it a ligand receptor interaction strengthens the interaction of those two cells and then there are multiple potential we call them agonists or antagonists all pairs of a receptor that meets a ligand that can interact to regulate the T cells and release substances from the T cells that's called cytokine release that's the third signal and one T cell by the way can just cruise around the body interrogating targets it feels its way along a tissue it encounters a cell and if it has good recognition wow it stays there and starts to differentiate and get activated if it doesn't recognize just moves on there are actually pretty promiscuous little critters one T cell could literally interrogate thousands of targets in one day and then here's the picture it shows you the different signals so again signal one is when the T cell receptor on the t cell recognizes the MHC molecule with that little green guy that's the peptide that's the piece of protein that's the target second signal two is cd28 meets up with so-called cdat or cd8 e6 and this here this is your innate immune cell that's your dendritic cell it has one job and one job only and that job is to show things to the immune system and then the third signal comes when either the dendritic cell or the t-cell itself starts making cytokines and those cytokines have the capacity to stimulate lots of other T cells and then you develop into a helper cell and there are different types of helper cells T helper 1 cells T helper 2 cells so once you get that third signal everything starts rolling very quickly on the other hand what are the impediments to the immune system working against tumors well as you know we get cancers there are you know hundreds of thousands of cancers diagnosed each year in the United States it's between 500,000 and a million and obviously it works but it doesn't work perfectly and there are many problems or many impediments to successful anti-tumor immunity most of the antigens the things that could be recognized by your immune T cells are self related meaning they're very similar to what would be on a normal cell because after all that's - Marcel as it develops from a normal cell so most of the proteins the potential targets were tolerant to them we have to be or else we'd all develop autoimmunity if we develop two T cells that could recognize self antigens they get to lead in an embryonic life they're gone we need to do that to protect ourselves so those T cells that could recognize tumour related proteins they may be gone and when you treat patients with chemotherapy which even today we do very often for many different types of tumors that really weakens the immune system and the tumor microenvironment boy it has many influences that suppress the immune system it is incredible to witness how many different ways the tumor has of suppressing immunity it's an amazing defensive system in the tumor you have suppressive cytokines substances that in normal life are our feedback negative regulators of immunity after all we don't want to have the immune system get activated forever you have to have a yin and a yang but there are high levels of those suppressor cytokines and tumors there are even T regulatory cells which are T cells that shut off the immune system and not they don't activate it they turn it out we have myeloid derived suppressor cells which are related to some of those innate immune cells like the macrophage and they also have the flip side of the coin they suppress community sometimes the tumors modulate off MHC molecules or the very antigens that could be recognized that means they're like a stealth cell they don't get recognized at all or they could directly suppress the immune system by expressing something called PDL one which we'll hear about a little while and the immune cells get stimulated to express their own negative molecules and that's very important for cancer therapy they are called checkpoint proteins because for every yen there's a yang every time you activate a t cell you need a way to turn it off or else we'll all die of autoimmunity well there are these checkpoint proteins those are the brakes every car needs a break but it needs an accelerator now what do those t-cells recognize well the tumor antigens are the targets of the immune cells and they come in different categories the best-possible antigen is right here on the left hand side and that's a antigen that is the that develops as a result of a mute so that only would occur in the tumor would never occur in normal tissue and as a very specific tumor specific antigen and then there are a whole bunch of different proteins that are relatively expressed in the tumor the tumor specific but they're not absolutely tumor specific for example many of them are expressed in embryonic life and they're shut off by a process called methylation which is these little lollipops here if you unmethylated expressed it sort of wakens these antigens that were present during embryonic life and they don't really belong in an adult and the tumor can show them to the immune system and sometimes the tumor can recognize those and then there are a whole bunch of other antigens that are relatively expressed on tumors but not on many normal tissues in melanoma those are the so called melanocytes antigens and finally there's the rare antigen that could be recognized by the immune system that's over expressed simply a huge amount of it allows it to be recognized by the immune system that's pretty rare one of them would be called p53 which is a very common antigen and finally relatively few tumors are virally related but the virus is foreign so if there's a viral antigen made by the tumor that should definitely be recognized as foreign by the immune system so there's a lot of direct evidence that immunity is very important for treating cancer for example immune deficient mice are more susceptible to spontaneous and carcinogen derived tumors a cytokine made by t-cells called interleukin 2 has anti-tumor activity it works terrifically in mice it works not as well in people that it definitely can work in people it was the first true immunotherapy approved for melanoma and that was back in 1985 it was first shown in the New England Journal by my old boss Steve Rosenberg and that was ultimately approved in 1998 by the FDA for melanoma and kidney cancer checkpoint proteins those are the brakes on the immune system they can be blocked and the first time that was shown to effectively work in cancer was in 2010 when Steve Audia colleague published in the New England Journal an article showing benefit for patients who got an anti ctla-4 antibody called a polymer map that's now an fda-approved drug since 2011 and definitely has benefited melanoma other tumors and finally you can purify those adaptive immune cells those are the t-cells they call them T il tumor infiltrating lymphocytes and if you grow them and then transfer them to patients with melanoma they can make sure those tumors will shrink there's a lot of indirect evidence that the immune system is important for example in certain histologies for example colon cancer the presence of a t-cell infiltrate in the primary tumor is a positive factor and that's called the immuno score and that was first put forward by a guy from Paris called Jehovah alone and that was published in science almost 10 years ago in melanoma there are certain factors associated with a good outcome and one of those factors is whether there are T cells in the tumor that's a good thing and if there's PDL when staining on the tumor that's also important that's a reflection of what we call an immuno genic tumor microenvironment finally in ovarian cancer if you have a lot of T regulatory cells they are associated with a poor outcome so again having lots of the bad guys the T regulatory cells not a good thing in most cancers so is there an immune response to cancer heck yes can the immune system reject cancer absolutely but as we stated there are many impediments to having effective anti-tumor immunity for example there are many mechanisms of immune suppression just take a look go from left to right in the normal situation here's your activated T cell T cell meets up with its target the antigen presenting cell there's a little antigen there the T cell receptor recognizes the antigen and you have all these other positive interactions that activate the cell those are called the co-stimulatory molecules that's what we call signal to for what if the T cell can't get to where the antigen is what if there's an anatomic barrier it ain't going to happen what if when you have the T cell meet the antigen there's a substance that kills the cell that's called fast or fast ligand if there's fast on the T cell and it meets up with fast ligand on the antigen presenting cell it's going to be dead that's called apoptosis program cell death or what if it meets up with the antigen but there's something that turns off the second signal that's ctla-4 well you have an ignorant t-cell there's no activation or if a regulatory t-cell comes up and makes immunosuppressive cytokine il-10 or tgf-beta you'll have an ignorant t-cell no activation so they're an awful lot of ways to go wrong and not too many ways to go right in cancer and look at this if you look at this diagram here's your t-cell there are many accelerators on these t-cells and think of the agonistic molecules as it's like a car here's the Azhar all accelerators the problem is these are all the brakes and if you have more brakes and the brakes are working more rapidly than the accelerators the t-cell is going to get turned off and that's what happens in the tumor microenvironment you have a lot of ways to accelerate the t-cell the problem is you have probably have more ways to put the brakes on so it's a assessment of what's the dynamic interplay between the accelerators here and the brakes here and every accelerator and every brake has something to interact with either on the tumor cell or on the antigen presenting cell so if you have lots of things interacting with the accelerator you're going to activate the t-cell it's going to be like a car moving forward if you have a lot of things that interact with the brakes you're just going to be permanently on the brakes and that cars going nowhere so that's you look at that dynamic interplay within the tumor and the big question is okay well the immune system can recognize cancer is it doing it actively do we have immune surveillance against cancer and this was proposed by Louis Thomas and MacFarlane Burnet and actually MacFarlane Burnet in part got the Nobel Prize for this something like 30 years ago but it was proposed literally 40 years ago 20 years ago there was a lot of skepticism and there are those who thought it was disproved but thank god and it's to the credit of many scientists including Bob Schreiber and Jim Allison and many others that this whole idea of immune surveillance has been resurrected and there's now a clear concept of immune surveillance that is the immune system constantly on the watch against cancer trying to eliminate it when it arises obviously that doesn't always work but there three phases there's an elimination phase where both our innate and adaptive friends work together to recognize and destroy a tumor that's trying to develop before it becomes clinically apparent then you reach an equilibrium you're occasionally going to throw up some tumor cells and their residual occult or hidden tumor cells sometimes they're not destroyed in the elimination phase and they're kind of held in a state of dormancy or suspended animation and why because there's an adaptive immune response that's ongoing and as long as that immune response is ongoing the tumor cells aren't going anywhere they're just going to be held in dormancy the problem comes when something changes application immunosuppressive influence whatever it is that somehow the tumor cells get editing and they are no longer recognized or destroyed by the adaptive and innate immune system they grow and in a diabolical manner they actually induce an immune suppressant microenvironment within the tumor and then they become clinically apparent so again three steps three phases and here's a picture here's your normal cells and this goes counter clock or pardon me clockwise so up top you have your normal cells and eventually you know the tumors are going to get they're going to try to grow the cells become transformed but you go down here they'll summon up your innate and adaptive immune cells which are the multicolored cells and you're going to get rid of these red tumor cells eliminate them and you're protected so a small number of cells may pop up boom recognized by the immune system eliminated you're in great shape the problem is over time there's this genetic instability and you select the tumor cells for their ability to evade and avoid the immune system so eventually you reach this difficult equilibrium where some of the tumor cells will grow some of them will be recognized some others will evade and you'll just sort of sit there for a while with a few tumor cells just hanging out the problem is something will then change and eventually they'll escape and now you get lots of tumor cells begin to grow they're all going to evade and avoid the immune system and not only that in this amazingly diabolical matter they'll summon to t-regulatory cells so one thing piles up on another you get a snowball effect the tumors grow they bring in the regulatory cells suppresses immunity they bring in the myeloid direct suppressors suppresses the innate immune cells now you got a tumor and that's a real problem and is there evidence for this in an animal well here's an interesting experiment and it's easy to understand so what you do is you actually raise tumors in in an environment where there's no immune cells in a mouse and that mouse has a name it's called a rag tumor and you let tumors grow in the rag mouse and then you transplant them out of this rag mouse which stands for recombination deficiency and you transfer them from the immunosuppressed Mouse to another Mouse who also has no immune system guess what's going to happen the tumors are going to grow nothing is getting rid they're not being eliminated etc but what happens you have now the ability to take the tumors that grow in the immunosuppressed mouths put them back into a normal Mouse it's called WT wild-type wild-type just means normal immune system now all the sudden some of them are getting rejected they stop growing so look down here so isn't that interesting so it says during the process by which they're actually in the immune suppressed Mouse they're able to grow once you put them into the wild-type Mouse all of a sudden the tumor system immune system becomes awakened and now they can recognize the tumor and again going clockwise so we're always going to go clockwise and all these fancy cartoon diagrams there is always an inhibitory influence and a stimulating influence there's a yin and a yang every step of the way so there's the elimination but there's the editing so you have the accelerator and you have the brake so the story of immunity against tumors is there's always this this pushing and this pulling that's going on so if you start at the very beginning releasing the antigens sometimes there will be tumor cell death that's immuno genic the tumor cell will die and can be recognized by release of antigens other times the tumors are diabolical they die in a way that hides them from immune system and then you'll take those antigens the little red guys and you'll try to have them recognized by the immune system well that's great if the green guys the immune stimulating cytokines are around they'll be recognized but if the immune suppressive cytokines are around they'll be ignored and then again you deliver these antigens to the lymph node here's your lymph node and things will go really well in the lymph node if you have the right priming and activating substances present but if the immune cells Express too much of the break like these things ctla4 pd-1 PDL one nothing's going to happen and then you'll get them out of the lymph node you try to traffic them into the bloodstream and generally things will go well they'll get into the bloodstream but now they'll try to get into the tumor and if and here this is out of the blood vessel in red into the tumor in white they have to squeeze through the walls and if you're expressing immunosuppressive influences here they're not getting into the tumor if you're expressing these things on your blood vessels well then they will squeeze through the wall and get into the tumor and finally you're actually at the tumor if the tumor cell doesn't have that which could be recognized it's ignored it's like a stealth bomber but if it does have that which could be recognized the t-cell could destroy the tumor and then if in the tumor you express the suppressive influences you're in big trouble unless you express high levels of the immuno activating substances like interferon gamma so at every point to the way there's a push in a pole and it's very complicated because there are plenty of bad guys hanging around and there's one of the big bad guys the regulatory t-cells and they can inhibit immune responses in many different ways so again this time we're going to go clockwise so inhibitory cytokines these regulatory t-cells make these cytokines that suppress immunity they can directly kill the t-cell they can actually secrete these things called grants I'm which latch on to the t-cells that kills him or they can metabolically disrupt the t-cells by certain cytokine secretion or they can actually target the antigen presenting cells right so here here's your reg Ettore t-cell it'll put the kibosh on the antigen-presenting cell or it'll convince it to send off cytokines that suppress the immune cell so it's amazing how many ways you can go wrong and that was the adaptive regulatory suppressive cell there's also an innate suppressive cell called a myeloid derived suppressor cell because it's derived from the myeloid cells which are the neutrophils of macrophages the monocytes so it's just kind of this big blobby cell which can specifically present antigens to the immune t-cell but it does the double whammy it shows at the antigen the t-cell starts to get activated then it starts secreting all kinds of nasty things like our Gen ace or reactive oxygen species which absolutely puts down the t-cell and then when it and that's in the peripheral lymphoid organs in the lymph nodes once it gets into the tumor oh man it starts making all this stuff nitric oxide Arjun ace you name it and it converts the macrophages from attacking cells into something called a tumor associated macrophage which means they're useless cells not only are they useless they're actually making cytokines that suppress immunity so it's amazing how many ways you can go wrong in a few ways you can go right and this just again shows it graphically here you are in the primary site of the melanoma if there's a barrier and the immune cells can't get into that tumor they're going nowhere in the lymph node and here down at the center it shows the actual lymph node and if we pull our arrow down you'll see here in the lymph node you can go wrong if the T cell makes ctla4 in the turquoise because it then is going to latch onto the antigen presenting cell it's going to suppress it alternatively once you get into the tumor so you went from the primary to the lymph node now you're hit sitting in the tumor if the tumor makes PDL one it's going to bind to PD one on the t cell what do you think happens there it acts as a break it's going to shut off the T cell so you got a real problem and those problems occur anywhere along the pathway so it sounds pretty pessimistic but the amazing thing is for each way that the tumor tries to suppress immunity there's a vulnerability and if there's a vulnerability you can attack it and one of the most successful ways we've been able to attack it is with something called checkpoint protein inhibition a concept originated by Jim Allison and Jeff bluestone and many others that has borne terrific clinical group that I'll show you in a few moments you can also try to vaccinate patients and although that's kind of the holy grail of tumor immunity I regret to say there's not a lot of evidence that you can successfully achieve clinical benefit by vaccinating patients against cancer coming up the road is a whole series of experiments and trials where we can actually pull T cells out of the patients and instead of them hanging out in the immunosuppressive environment of the tumor we grow them outside the body and we transfer them in those are till tumor infiltrating lymphocytes clonal T cells we can genetically transduce T cells and then we have these chimeric antigen receptor T cells we call them car and T cells and you're going to hear an awful lot about those car T cells in the future so cancer vaccines I'm going to dismiss it in one slide there have been hundreds of trials of cancer vaccines only one cancer vaccine ever approved it's called Provenge for prostate cancer it's a cell product made from live cells and it shows survival os's overall survival prolongation has been shown in a randomized trial with this vaccine it's not very toxic but it does not shrink any tumors it does not prolong progression so it doesn't change the progression-free survival and to be honest it's not widely used in practice in oncology in fact in my own Hospital they don't even have it on the formulary so what does that say yes there is some evidence of benefit to this vaccine but there's not a lot of belief that it really does much good and that's really sad the best antigen in the world and I'll very briefly spend the time here would be what we call a neo antigen so here is a tumor and in that tumor you're going to see mutations in a few of the cells and you can actually isolate those mutated proteins and you can actually synthesize proteins and peptides pieces of proteins that are from those ant we call them neo antigens because they're normal proteins but they're mutated and then they become recognized by the immune system even though the parent molecule cannot and it turns out that in cd8 t-cells that recognize these things the only a very small proportion of these are proteins that are on kinetic proteins the rest of them are just normal proteins they're called passengers and it turns out that we can actually recognize many of these so-called passenger mutations very interesting so what about checkpoint proteins that's where all the hot action is in oncology in fact that this most recent ASCO meeting our big cancer meeting in Chicago someone told me this was the immunotherapy ASCO because this is where all the excitement was and let me tell you why checkpoint proteins are the brakes on the immune system the agonistic molecules are the accelerators so if your immune system is a car you got to brake and you got an accelerator one set of proteins limits immunity to avoid autoimmunity and the other enhances immunity and the problem is in the cancer bearing state you got too much break and not enough accelerator so what are you going to do well you could hit the accelerator or you can cut the brake and hit the limo mab is a drug that cuts the brake it's a ctla-4 activating antibody and that was first approved in 2011 and definitely benefits those with melanoma pd-1 is probably a more important brake on the immune system so if you block pd-1 it turns out you can generate significant clinical benefit and Pember ilysm a band d'Avola member to pd-1 blocking antibodies both approved at the end of 2014 and I'm going to show you quickly some data that I hope will convince you that these antibodies against pd-1 had dramatic benefit in melanoma now it's many other tumors they are beneficial or have been shown to have benefit in lung cancer head neck cancer ovarian cancer certain types of colon cancer Hodgkin's disease you name it almost almost any cancer will show benefit when you block pd-1 and this just shows the cartoon on the T cell you got all those breaks and all those accelerators the accelerators are in green the Blake brakes are in red you got lots of pd-1 on the T cell and guess what it recognizes PDL 1 on the macrophage you can recognize PDL 1 on the tumor so the tumor itself makes the very substance that binds to PD 1 and blocks immunity very diabolical even the dendritic cell that shows the antigens to the immune system makes PDL 1 it makes a lot of other things but blocking the interaction between PD 1 and PDL 1 particularly in the tumor microenvironment turns out to be extraordinarily important why well here's the evidence this was a trial of a PD one antibody it's called member lizmac and it was tested in patients who had seen ctla-4 antibody hipolito map they were refractory they had melanoma and it was a trial which randomly compared Pember liz' map to chemotherapy who is a randomized we call a phase 2 study and look at the progression free survival that is the time that it took the patients to start growing after an initial response I think you'll agree that at the doses of pemrose deer in green and red there's no question that they literally look identical and they are clearly superior to the chemotherapy which is shown here at the bottom that's in blue and the difference in time what we call the progression free survival clearly superior in Pember lism at either dose to chemotherapy alone so no question in one of its first tests when you do a head-to-head trial PT when antibody beats chemotherapy nine ways to Sunday and then if you look at the other NT body called Ebola map and again there are two antibodies out there and this time these are previously untreated patients here the response rate with nivolumab is forty percent versus 13.9% with chemo boy that's a lot better that's an easy one but look at the survival this is the survival in sort of a brick red color of the patients who got Nivola map who previously had no other therapy we call this first-line therapy and this is the survival with dacarbazine chemotherapy it splits apart very early at three months and it stays apart and what is almost certainly going to happen is this is going to continue continue and continue and continue and a lot of these patients are going to be alive five years later of the patients with chemo almost everybody is eventually going to die so now in first or second line we have antibodies that clearly provide benefit and if you look at combining these drugs together than the rola map and the a polymer map again this is taken out of a manuscript that was just published a month or two ago if you put both drugs together so you hit two breaks so you cut two brake cables at the same time clearly superior and blue for what we call progression free survival compared to just the of aluminum atoms so again very impressive difference in both response rate and progression free survival for the combination of killing the brakes twice you block ctla-4 and you block D d1 beats the heck out of blocking ctla-4 alone and then if you compare pd12 if a limo map and again here is Pember ilysm ab and we're looking at two different doses or two different schedules member liz amass every two weeks and every three weeks this is a survival curve and as you can tell it really doesn't make a difference the tube femoral is a map schedules identical clearly superior to the limo map so again in patients who were previously untreated you're better off getting the PD one antibody and getting the ctla4 antibody ctla4 antibody still works but the PD one antibody where it's better suggesting with PD one is a more important break than a ctla4 these drugs are now being tested in my god 20 different histologies there are thousands of patients being evaluated it's already approved in lung cancer it's going to get approved in head neck cancer bladder cancer kidney cancer Hodgkin's disease you name it very promising and that's just the beginning I told you there were 10 or 15 breaks and 10 or 15 accelerators that's only two out of about 30 think of all the other antibodies that we're going to be able to test now that's checkpoint protein inhibition let's finish up by talking about cell therapy cell therapy is where you actually take the T cells out of the immunosuppressive milieu of the body and you expand them to huge numbers and you give them back to the patients sometimes with interleukin 2 to make them grow better sometimes you get rid of all the t-cells by giving chemotherapy we call that lympho depletion and here it just shows different strategies if you look at TI l these are tumor infiltrating lymphocytes that you just grow out of the tumor you can actually take lymphocytes and put a new t-cell receptor gene into them shown here in red so that you redirect them so previously these would be directed against nothing in particular if you isolate the T cell receptor you want and genetically transfect it you'll make them all into specific t-cells directed against whatever that t-cell receptor recognizes and finally you can graft a hybrid molecule that kind of looks on the outside like a b-cell antibody but on the inside it's like a t-cell receptor that's called a chimeric antigen receptor and that's another way to redirect those lymphocytes to kill that which you want to target so again do t IL work well here's a group of 91 patients and 20 of them were complete responders and it showed if you have a complete response which occurs it's about 20 percent of the time with these tumor infiltrating lymphocytes with il-2 look how far out we are this is almost 10 years out these patients are almost surely cured so if you get a complete response to this tumor infiltrating lymphocytes you may well be cured of melanoma and for someone who's out eight or nine years without progression I'd say they're in pretty good shape to be cured you can even grow these T il and grow them so that they recognize mutations specific antigens from a tumor so this is a cholangiocarcinoma gall bladder origin tumor and these are tumor infiltrating lymphocytes so T il and they were grown because they were stimulated specifically against one protein called herb b2 and this just shows that these T cells only recognize the mutated herb b2 and they don't recognize the wild-type the normal that's why it's called a neo antigen the neo antigen is a mutated protein that's normal but it becomes mutated it can be recognized or unmasked by the immune system and here it shows the tumor burden this was traditional lymphocytes the so-called regular till the tumor grows it shrinks but then it starts to grow again and each one of these lines is an individual tumor but if you give the cells directed against this neo antigen or B - whoa everything starts to come down and if you continue this all these go down almost to zero and this particular patient is a near-complete responder with tumor infiltrating lymphocytes grown from a cholangiocarcinoma patient that only recognize one neo antigen incredible there are many ways to skin that cat as I said you can have normal t-cells and this simply shows this is a normal t-cell receptor what if you genetically modify it and put in a new one well you just have to change these alpha beta chains and now you have a transgenic t-cell receptor that may be of a tumor specific variety but you can put the gene encoding these new t-cell receptor genes into virtually every T cell in the body and they'll be redirected and here's the chimeric antigen receptor this is the top of an antibody which is shaped like a Y you'll delete out the rest of the antibody and your graft in the transmembrane sequence from the t-cell receptor genes so it kind of fakes the t-cell into thinking it's got a t-cell receptor but at the surface it's not the t-cell receptor it's the antibody so again a chimeric antigen receptor and they work incredibly well in hematologic or blood malignancies I'll just point you to some nice pictures showing bone marrow taken over with chronic lymphocytic leukemia so this is a bone marrow pack with tumor cells after you treat with these chimeric antigen receptor bearing t-cells the tumor starts to clear away and then it's almost completely gone by six months after treatment and it shows that the tumors themselves can disappear so it's truly amazing that simply by taking a antibody against the substance called cd19 making it into what's called this chimeric receptor sticking it into the immune cells and transferring them back intravenously you can make many leukemia patients completely free of disease so there are 27 trials now going on in which these chimeric antigen receptor cars are being used against cd19 which is a molecule on b-cells and B lymphocytes and thus on b-cell leukemias and the response rates are very high in chronic lymphocytic leukemia CLL adult leukemia and pediatric leukemia and it turns out the longer the cells hang out in the body big surprise the better they work and the downside is you can get something called a cytokine storm so when you transfer the cells they are so active they work so well they secrete all kinds of nasty cytokines which cause side effects you can get CNS symptoms you can get high fevers and low blood pressure from the release of all these cytokines so the good news is that many patients go into remission stay there the bad news is there are some side effects you're going to hear an awful lot more about these cars because there are folks developing cars for solid tumors not just for the so-called hematologic malignancies so what's the conclusion to all this mostly good news see I told you the bad news in the beginning I told you what all the potential downsides were but now I'm giving you the good news tumor immune surveillance is a real phenomena tumor immunity admittedly faces many hurdles due to the escape from elimination of many tumors and tumor antigens these mutated neo antigens as I showed you for that one cholangiocarcinoma patient and viral antigens and by the way an increasing number of tumors have a viral etiology they may be the best antigens to generate potent unity nonetheless we've had spectacular success in many tumors with checkpoint protein inhibition especially with PD one blockade the immune suppressive mechanisms that are the impediments to successful anti-tumor immunity that exist in cancer can be overcome and the rationale or the evidence that you can overcome them we've shown by those outstanding slides showing clear benefits to checkpoint protein inhibition that I showed you the success of these new adaptive cell therapies with till with the chimeric antigen receptor t-cells the car t-cells clearly shows that immune tolerance to cancer can be overcome and the thought I'll leave you with is a thought that I left the audience with a couple years back at ASCO when I gave a talk and the line is the best is yet to come so I think if your attention and I think we have time for questions that's great thank you so much dr. Webber it's very exciting to see all the different stop signals and the different go signals and while that poses a lot of complications it also provides what looks like to be many many opportunities for developing therapeutics that take advantage of what we now know about how the immune system sees cancer and how it interacts with cancer so thank you very much for walking us through that I'd like to remind everyone who is watching the webinar that the QA pod is now open and you can submit your questions by typing into that Q&A pod I will go through the questions and feel them for dr. Webber in the meantime we do have a few questions that were submitted in advance of the webinar the first one dr. Webber is our immunotherapies intended to replace the current standard of care or are they to be added on top of the current standard of care well as as we all know there are many histologies where chemotherapy can induce either complete responses potential cures or certainly clinical benefit in prolonged survival those therapies aren't going to go away in the front line therapy with those of the standard of care you know the simple-minded way to look at it is we're going to add immunotherapy to the chemotherapy which surprisingly you can do many chemo therapies are not that immunosuppressive so you can add chemotherapy to them classic example is non-small-cell lung cancer so chemotherapy is not going to go away anytime soon although from melanoma chemotherapy was never particularly promising and I think that will as I have said in the past go the way of the dodo but for lung cancer breast cancer many other common histology chemotherapy is going to stay for a while we'll need radiotherapy for localized disease for symptomatic disease and as a primary modality at head neck cancer and lung cancer interestingly little sidelight radiation followed by immunotherapy can lead to spectacular responses and that's because there's some how the radiation sets up the immune system it Prime's it to work better so we're not going to see these drugs go away anytime soon so you spoke a lot about the the important critical step in the immune response to cancer where the marker or the antigen or the protein that alerts the immune system to the presence of danger or cancer but that's that's that's key to getting to initiating the immunity cycle so I've heard that one way to do that is with cytotoxic therapies like chemotherapy and radiation where you go in and you kill those cancer cells quickly they release their antigens to the immune system that then pick it up and trigger further responses is that is that what you've seen or is that what you believe well the urban legend is that if you get some evidence of tumor destruction you will effectively prime the immune system if you have an effective way of completely destroying a tumor and it dies in a mutagenic cell death and the answer is yes that's not always going to be the case the AB scope will affect at least in melanoma where you radiate and give it the Limor map and in the face of it balloon will map progression then see responses is pretty rare it happens so it's kind of the exception that proves the rule but um I think that we're going to see this more and more in other histologies I think the AB skull effect will happen in breast cancer so when you have a really sensitive histology like breast cancer lung cancer sensitive to radiation and you get complete near complete destruction with an immuno genic cell death yeah I think that these things allow us together no question okay and you reported some depressing results I mean uh negative results are good in terms of they at least teach us what doesn't work but I'm speaking of your slides on vachs and how there really hasn't been despite many many trials of different types of vaccines very little evidence of real clinical benefit for patients now that checkpoint inhibitors have kind of they're on the ascendancy and we're finding that there are ways to combine those with other forms of therapy for benefit to patients do you see vaccines perhaps enjoying a renaissance or soon to be a renaissance when used in combination with checkpoint inhibitors I still see issues with the vaccine field having a potent checkpoint protein inhibitor will not make a bad antigen into a better vaccine I think that when we begin to understand how to use the neo antigens viral antigens and the potent antigens that are truly immuno genic combining that with the proper combination of agonistic antibodies or substances and checkpoint protein blockade will generate a successful anti tumour response where the vaccine will be part of that combination vaccines alone for cancer I don't see ok question about side-effects what are the typical side-effects of immunotherapy you mentioned with vaccines for instance that there really aren't or in provenza's case you don't have very many side effects but what about with things like checkpoint inhibitors well checkpoint inhibitors like a blue mona and prim realism AB and d'Avola map as I tell patients it's easy to discuss the side effects of the different drugs because they're all pretty much similar types of side effects we call those immune related adverse events and they tend to be organ specific they are associated with the action of the drug sometimes there's some feeling that they're associated with benefit from the drugs but for example you can see rashes caused by a inflammatory infiltrate in the skin you can see colitis inflammation of the colon you can see hepatitis inflammation of the liver pancreatitis which is information the pain Cree's you can see pneumonitis which is inflammation of the lungs and these are often asymptomatic amazingly you can see sky-high abnormalities of the liver which in a hepatitis patient would make them really sick but in a patient getting saying tuvalu maverick embolism em they'd have no symptoms which is backlund you can see abnormalities of the pancreas functions the amylase and lipase and the patient will feel happy as a clam whereas if that patient had pancreatitis from a gallstone or alcoholism they'd be writhing on the floor in pain so it's you see these characteristic inflammatory changes in individual organs for example you can see nephritis and you can see clear inflammatory changes on even on a cat scan of the kidneys but the small bowel that moves right next to the kidneys perfectly fine so these are bizarre drugs and explaining this to patients is not an easy thing to do and then the patients will say well doc why is it that way and you don't have a good answer why does uh in one patient the liver get amazingly inflamed and in the next patient it's the pancreas or the colon sometimes you see multiple organs involved but thank goodness mostly its individual organs and we don't know yet I think when you're when you're dealing with individual immune systems you are and individual people you are likely to see the quite a diverse range of responses so yeah it's it's a thrill a minute trust me it's never-ending excitement and then there are other amazing things that we discover like ctla4 can be expressed on the pituitary the pituitary that's this little gland at the base of your brain why is it expressing an immune marker and that's perhaps why if a little map can induce inflammation of the pituitary which prior to maybe 2002 would have been a reportable episode that you could publish so it's it's actually very baffling that under some of the side effects of these drugs here's a question about kind of the the order of therapy that patient might receive so for instance if bulimia mad nivolumab and Pemberley Zoom AB are all FDA approved now but can a melanoma patient start with a PD one therapy or does that patient have to first fail anti ctla-4 therapy well if you go by the package insert niebo as we call it and PEM bro are approved for those who failed epilim lab or if there be rep mutated a b rep inhibitor in it in fact the National Comprehensive Cancer Centers network or NCCN which helps to set guidelines for the treatment of cancer patients and is recognized as such as an authority in this country and abroad has recommended with its highest level of recommendation that you can use the pd-1 antibodies in front-line before at the limo mat and I absolutely agree with that and there was a discussion at the plenary session of ASCO by Mike Adkins who's a terrific guy from Georgetown and he basically told the audience that he thinks that the limo map is now a second-line drug which I think it is pd-1 or PDL one antibodies are the first choice in melanoma and you don't have to have failed at the liberal a Barbie rep inhibitor to go on a PD one blocking antibody these are very good drugs and the issue is when should you actually combine them not not when you should sequence and when should you combine them and the answer to that question is the jury is still out but at the plenary of course we heard Jed wallchuck presenting some terrific data showing major-league increased responses prolonged progression-free survival and improve response rate in those patients with melanoma who got the combo of it via Nebo compared to either drug alone so on the other hand the toxicity rate was almost as high as the response rate so there are issues with with these drugs but still the benefit was very striking something that I don't think you touched on in your presentation was uncle lytic viral virus therapy in cancer and this is an area that's received a bit of attention with the high-profile television spot I believe it was viral therapy for a form of brain cancer that had some dramatic results what can you tell us about acha lytic viral therapy yes the I guess it was a 60 minutes episode at Duke in their brain tumor center with a relatively small number of patients who had an ankh oolitic directly I believe was directly injected into the tumor bed those patients have had fantastic survival much better than you would have expected all very encouraging the most mature data we have for the oncolytic virus is with something called T Beck which is a genetically inactivated herpes virus that can't replicate but can express some legal gm-csf to boost the immune system it's had some promising results when directly inject a tumor the virus will spread pretty much within the tumor itself and result in a significant immunogenic cell kill it's the perfect engine priming to combine with checkpoint protein inhibition and right now there's some very impressive data with that combination suggesting that patients who get an initial treatment with this T back into the tumors you kill tumors develop immunogenic dead cells it acts to prime the immune system and if you then follow up with hippy limo map or Kember lism every d'Avola map you might get some very impressive results so that's that's where I think it has some utility alright great well thanks for that we are almost out of time so we'll wrap up with one last question in your view dr. Webber where do you see immunotherapy going over the next five years what what can patients expect well I think that the drugs that were approved in melanoma and lung cancer will be expanded to many other histologies you're going to see large randomized trials you're going to see new drugs come along things like CD 137 antibody ox40 you'll see antibodies now prepared against other checkpoint proteins like Vista BTL a CD 244 so there are at least eight potential targets for antibodies that just kill the brakes there are another eight or ten potential antibodies or small molecules that hit the accelerator so you're going to see increasingly complex combinations you know we're into double double combos but then you're going to see armed triple combinations or quadruple combinations and sequential therapy so it's going to get pretty complicated but I think things for the patients are only going to get better and better and we'll be able to derive a profile for a patient where prior to treatment you're going to do some either gene profiling of the patient or profiling of the tumor and I think we'll be able to predict in advance which group of any individual patient should get so for example you'll you'll do a tumor biopsy and maybe do a blood test and the amalgamation of those two will tell you oh no this is a patient we're PD anti-bot PD one antibody would work you should do the liver map plus X Y Z or will now come up with new ideas to alter the immune microenvironment so that that patient that wouldn't have responded to PD one antibody would so that's the that's the future the future is combinations and expansion of this type of therapy to the major histologies you know the epithelial astrology is like breast a prostate colon and lung which accounts for a huge chunk of all cancer patients around the world a gastric which interestingly is the most common GI cancer around the world probably more than colon although not so in the US and really the the tumors that provide major morbidity and death around the world you're going to see immunotherapy being applied to them that being said you're going to have to train an entire generation of oncologists to deal with these drugs and their unique side effects so I don't I don't anticipate losing my job anytime soon I hope not because this has been very very fascinating and I'm sure that the people that you work with also appreciate your you're very charming personality when you talk about you know combinations of things of course where you're combining two three possibly four drugs this is certainly going to raise some questions about affordability and cost which we don't need to get into today that's not the topic of today's webinar but that I think is also going to be another issue going forward as we as the science tells us that these combinations are more effective we'll have to sort out those issues when we cross those bridges so you are absolutely correct it is something that weighs on the minds of all the investigators it is something that weighs on the collective consciousness of many of the pharma biotech companies they're all thinking about this because let's face it there's only so much money in the world and there are limits to what proportion of the u.s. GNP can be devoted to health care we have other things to spend the money on too and ideas on cost-effectiveness and things like being reimbursed for example only if you get a response paying a certain amount of money up front and then subsequent treatment is free there are all kinds of creative models that I think will be out there and you know in this country there has been much research done by pharmaco economics experts and there's a there are a few people who are really standout around the country there's one guy who I think at Hopkins at Hopkins I believe named Smith and he's published extensively on this and Americans are willing to pay a certain amount of money per year of life prolonged and pd1 antibodies because their median survivals are turning out to be very long probably well over two years in front-line just for a single antibody clearly provide benefit and the question is how much are you willing to pay and it turns out Americans are willing to pay between fifteen hundred and fifty thousand dollars per year of life saved and I think if we stay in that ballpark hopefully we won't break the bank and we'll we'll stay within a rational range but when it gets above that the question becomes how we can afford that so that's that's I'm not an economist but that's a question that weighs on our minds well with that I'd like to begin our conclusion so once again I thank our very generous sponsor and Jen for supporting today's webinar also would like to let you know that we have two more webinars coming up on the 23rd and 25th of June one is about immunotherapy and brain cancer with dr. David Reardon and the other is a more of a prospective look at what's going to come down the road over the next five years elaborating probably a dr. Webber on what you just said that's with dr. Jed wallchuck on the 25th all of our webinars you can register for all of them at cancer research or forward slash webinars you can also view previous webinars there and if you're a cancer patient or someone who is caring for a cancer patient and you're interested in learning more about immunotherapy or if you are healthcare professional dr. Webber you mentioned that we there will need to be an effort undertaken to train a generation of oncologists and not just oncologists but also oncology nurses and pharmacists as as cancer treatment develops thanks to breakthroughs in immunotherapy resources like I'm the answer to cancer which you can get at the answer to cancer org can be very helpful for helping to explain some of the very basic concepts that we are seeing in immunotherapy and we also provide information on clinical trials there for patients who are looking to connect with an immunotherapy clinical trial so once again that's the answer to cancer org finally if you'd like to learn more about the Cancer Research Institute and our research funding programs or if you'd like to support our mission you can visit us at cancer research org we have a lot of resources there as well and with that I thank you all again dr. Webber for this very excellent webinar and all those who attended and we look forward to seeing you all at our next webinar thanks very much

Channel: Cancer Research Institute

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Length: 62min 36sec (3756 seconds)

Published: Wed Jun 17 2015