 It's certainly my pleasure to be here, and I don't know if you were in the other thing, but I grew up, you know, I was born in Pasek, New Jersey, and grew up in Clifton, so, though no one from Philadelphia recognized that until I say quaffee and becosse. And then they say, okay, I know where you're from. Anyway, I'm gonna try to go move things along and primarily talk about the cool stuff. The multiple myeloma is characterized by significant immune dysfunction, right? Abnormal cytokine profiles, defective T-cell activation, increased expression of PD1 and TGF beta, down-regulation of NKG2D, decreased immune surveillance, you know, screwed up antigen presenting cells, aberrant support cells like myeloid-derived suppressor cells. In fact, we have a cool study where we're using monoclonal antibodies to attack those things. So it's a screwed up immune system. And so how do we sort of bolster the immune system in myeloma? As you know, the number one thing that we've been doing for many years is the immunomodulatory agents, right? You know, pomalidomide and lentilidomide, they truly are immune modulators. And then, of course, the new monoclonal antibodies that I'll talk very briefly about because I think you've heard about it three times already, the daratumumab and the ilotuzumab. And then what I want to focus most on are the cellular therapies that are being developed, both the tumor infiltrating lymphocytes, the CAR T-cells and the T-cell receptor-engineered T-cells. So immunotherapy for myeloma, currently available, are the imids. The monoclonal antibodies, the anti-CD38, anti-slam F7 CS1, ilotuzumab and daratumumab. And then immune checkpoint inhibitors, pembrolizumab and nevolumab. And then the future science fiction soon to be available are the cellular immunotherapies. So the monoclonal antibodies, again, you've heard 100 times about this. So ilotuzumab anti-seems to natural killer cells and myeloma cells have the slam F7, the CS1 on their surface. And so we think that the way this monoclonal antibody works is by both putting a flag in a myeloma cell and activating the T-cells to then attack a plasmacel. And you know the studies of Lendex versus elolendex showing the benefit of elolendex in terms of response rate, in terms of duration of response, with very little toxicity increase, 10% infusion reactions with pre-medications, et cetera. Daratumumab we've heard about with the anti-CD38 direct anti-tumor effect. Most if not all myeloma cells have CD38 on the surface, but it also has immune mediated activity as well as immunomodulation. And you know the studies, the original study, it's really sort of interesting how they were so nervous about the development of this antibody because CD38 is on many more things than just plasmacels that they started with homeopathic doses of this in Scandinavia, as Dr. Sonnenfeld was talking about. And once they finally got to about four milligrams per kilogram, they started seeing responses. And so this is just a recent report from the last ASH where they combined the patients in the phase two trial which was a New England Journal of Medicine article as well as the ones who got the 16 milligrams per kilogram which is sort of the standard dose of Daratumab from the phase one trial and just demonstrated that as we know when used it as a single agent about a third of the patients respond. But I think what is sometimes forgotten is that somewhere in the neighborhood of another 50% of those patients had stabilization of their disease. And so even as a single agent we're seeing some real clinical benefit. With you know this one of course has more of the infusion reactions and it sounds like you guys do the same thing we do which is our referring physicians tend to send for the first dose or two the Daratumab to our center because we have a staffing that's long enough to do a potential eight hour infusion with this. And then usually after the second infusion the toxicities and the duration of infusions are so much less that they can do it in their local thing. What I learned today actually which had never really occurred to me was there are two twin trials that were done, Caster and Pollux which are of course the Gemini constellation, the main stars in Gemini and also you know are the twins from mythology. And I'm a Gemini so I should have known this but I guess my parents should have called me Caster. But anyway so there are now two twin studies, so this was the combination or the comparison of DVD versus VD you know of course when we think DVD we think of an antherocycline but it's a Daratumumab and as you've seen 25 times today significant improvement with the inclusion of this monoclonal antibody without really causing a lot more toxicity though there may be a little extra infections maybe a little extra cytopenias and then it's twin the Pollux study show was DRD to Dararevdex versus Revdex and also showed let's see do I have it oh I guess I don't have that but also showed a very significant benefit by the addition of this monoclonal antibody so and you know the only the cool thing which I don't know if it came up yet but you know the cool thing about Daratumumab is that monoclonal antibody is number one screws up your ability to make a CR because the the antibody it shows up on your S-pepsin so you you have sometimes a little bit measurable or near CR but sometimes it's of a different IG class so that's how you sort of figure it out and the other is it mucks up blood you know typing and so it's always what we do and I'm sure what you do is that we always do red blood cell typing before we start the Daratumumab so at least we have a good sense of what the ABO will be and so when we get a positive Coombs test we can get the best-matched blood if the patient really needs it and there are ways of getting out the Daratumumab and then of course there's the checkpoint inhibitors the Pembrolizumab etc. and the rationale for targeting PD1 and PDL1 is that PDL1 is expressed on plasma cells in an increased way and this this allows these plasma cells to evade the immune system and proliferate and and also the T and NK cells from myeloma patients have functional defects that decrease their activation so the hypothesis is if you use a PD1 blockade that this will activate the myeloma specific cytotoxic T cells so it will stimulate the immune system and and interestingly if you use as a single agent both either Pembrolizumab or Nevolomab in myeloma there was actually very little evidence of a response at all so single agent doesn't seem to be sufficient however again there was a stabilization of disease in a good portion of these patients so maybe there was a little bit more activity than what we initially thought but Bob Drose and others at the University of Maryland went the next step and said all right well why don't we add to this checkpoint inhibitors that's stimulating the T cells an immunomodulatory agent Pembrol in this case pomalidomide and there's also been studies with linalidomide which I don't remember whether I have for you and so using Pembrolizumab in an every two-week dosing similar to what what is given in a lung cancer every three weeks pomalidomide in the standard way four milligrams three out of every four weeks in dex given weekly and they took patients but in this case they took patients who had greater than two prior therapies and they all had been exposed to a proteasome inhibitor an immunomodulatory agent but they were naive to pomalidomide but nevertheless in this setting where we would expect you know from the phase two trials and phase three trials maybe a third of these patients would respond to to this just from pomalidomide and decadron they got they got a 70% of the patients responding the overall response rate was 66% in 43 patients that were treated and 70% of the patients who had double refractory disease meaning that they were refractory to proteasome inhibitor and a little and linalidomide responded to this therapy there was some increased toxicity maybe a 15% pneumonitis and some and some of the patients had a GI inflammatory thing but but a very high response rate in the progression free survival in this small group of patients 33 patients with something like 14 months we actually have done a similar retrospective analysis we didn't do it as a prospective study just of 10 we have 10 patients now who are pomalidomide resistant or pomalidomide exposed patients where we gave them pembro pomdex and we're gonna where we have a poster at ash that shows also a similarly very high response rate so it's pretty cool all right but the main thing I want to talk to you about is the cellular therapy so remember the rationale for cellular hemotherapy myeloma is we're not fixing people yet with myeloma despite all the stuff that we've been doing that the T cells and the NK cells from myeloma patients have been shown to kill autologous myeloma cells and you know and we've done allotransplants as your center has done and and it does look like there's a subset of patients at least to our long-term relapse free survivors when we've infused the donor T cells but of course there's a high morbidity and mortality and it's usually associated with a graft versus host disease when you get this graft versus tumor effect and so you're sometimes just substituting one chronic illness for another chronic illness so well you know so the philosophy of using autologous engineered T cells is perhaps if we could engineer our own immune cells to specifically attack myeloma we could get the good graft versus myeloma effect without the bad graft versus host disease and every all of these T cell adoptive T cell therapies really have the same process where what you do is you take a person's own T cells in the case of of the car T cells and the T cell receptor engineered cells you take it from the blood a simple steady-state lympho pheresis in the case of the tumor infiltrating lymphocytes which is what the guys at Johns Hopkins have done they actually go in and suck out bone marrow from the myeloma filled bone marrow and then tweeze out the T cells that are infiltrating that area and then these and in the case of the Tils those cells are expanded ex vivo and in the case of the engineered T cells those T cells have are injected with a virus that that carries with it genetic material to infect these T cells and put on their surface these new T cell receptors then these patients ex and then these cells ex vivo are expanded and then are infused into the patient as a therapy as a drug right and and and we keep talking about so what is a chimeric antigen receptor what it is is simply a sort of an antibody receptor that that is engineered so it's an it can and it's a chimeric because it has both that receptor area as well as an intracellular domain that stimulates the cell so it's got a sort of a standard antibody receptor it has this hinge region has a transmembrane domain that is a CD 28 usually a piece of of protein and then inside the cell are co-stimulatory molecules the magic is which ones are the best ones and it looks like the four one BB as a co-stimulatory molecule as well as a system illatory molecule of CD 3 zeta chain of is tends to be the the pieces that are inside the cell and so basically when the cell when when the receptor latches on to something it entered it energized that cell to proliferate and become more active so it's very cool technology my son who's a biology major in college a senior when he took molecular biology they actually use this it was sort of cool they use this in the first lecture of why you should learn molecular biology because there's actually and he started dad and yeah now he thinks I might know something anyway the so this these are the three major technologies that required that were required to have this occur number one is the creation of the genetic material that would code for this chimeric antigen receptor the number two was the development of a lentiviral vector so the so you actually put this genetic material into a lentivirus and then that and then infect the T cells and and that's what gives this genetic material and then an artificial dendritic cell which is a magnetic bead that has on its surface two antibodies CD 3 and CD 28 that that make the T cells think that they're getting in that in infections there and activates them to do something right and this is a cartoon that just shows how they infect the cell you know the it puts on its surface the warhead and the warhead finds a the antigen on the tumor cell to kill it so and this is sort of the the the diagram of how all of these cellulotherapies occur you first have to luciferise the appropriate patient and get these T cells out ex vivo you insert the magnetic beads and the virus and you infect the cells and this whole process takes about five to twelve days and and then you cook up you expand these cells meanwhile the patient has to have some lympho depleting therapy so so that their immune their T cells are lower so you can squirt in these cells so they can proliferate into the patient so the number one target that has been used to so the chimeric antigen that receptor that it they've been directed against is CD 19 that has been the number one one that that has been used and that's because that's on the surface of most of the malignant B cell diseases like non-Hochkins lymphoma B cell ALL chronic lymphocytic leukemia there are over 27 trials that have gone on in numerous centers throughout the world the responses in heavily pre-treated chronic lymphocytic leukemia acute lymphocytic leukemia B cell non-Hochkins lymphoma have been impressive about 50% of the patients who've received these cells have have had a nice response about a quarter of the patients with CLL are long-term remissions are our best patient was our second patient treated who is now six years from the infusion just of these cells and it's still in complete remission as no evidence of CLL for ALL it's even better I think I'm going to show you that in a second something like 90% of the patients many of them children with ALL who've just received these cells went into complete remission and and many of them are years three four years out from that and follicular lymphoma the the low-grade non-Hochkins lymphomas also have it this is not something though without toxicity and the number the two toxicities of these people have lots of disease in their system so tumor lysis syndrome but we know how to deal with that number two this stuff is indiscriminate if it's a CD 19 positive cell it will blow them up and so normal lymphocytes are that and so they get a B cell aplasia and some of these patients need to get continued intravenous gamma-globulin and then cytokine release syndrome which is the new syndrome that's been developed which is a sepsis like syndrome as these cells are proliferating and and and causing cytokines that is fevers rigors hypotension and fortunately though we found the antidote and the antidote is an ant and it or it's driven by interleukin 6 and the test that you follow is ferritin and C reactive protein and those things go up as the people get all the this in in inflammation and then they go down usually within a couple of weeks but if the syndrome is getting serious then by squirting in tosylizumab and anti- isle 6 a receptor monoclonal antibody it can turn off the syndrome within like four hours so it's really is the secret to all things this is ALL published in the New England Journal of Medicine and somewhere in the neighborhood of 60 percent of the patient the kids with ALL who've received this thing are long-term doing well when they were dying of ALL so what about myeloma there are many targets so the first question is what's the best target in myeloma right and and there are many of these have been occurred the problem the thing is we had CD9 an anti CD19 car ready for for use but CD19 is not particularly on the surface of myeloma cells it's on on all of these other cells our hypothesis was that the that even though the plasma cells tend to be CD19 negative their lymphocytes so there must be some precursor some screwed up precursor that CD19 positive that evolved you know that is is the mother cell of these plasma cells additionally we thought that maybe a CD19 small subset of the patient of the cells were the malignant with the resistant clone and that if you could somehow target those things you might result with a better result but we wanted to design a study that in a few patients might show us some proof of principle so the study we designed was to take people who had already had a had had initial therapy an autologous stem cell transplant and they were of poor prognosis because the duration of their response was less than a year after their autologous transplant then they can get all these different other therapies and then as a and then when they finally did nothing else is working they need a salvage auto transplant to try to get them better we would then do a second stem cell transplant and our expectation would be that the duration of that remission would be shorter than the first one and then we'd squirt in these cells to see if we could have a remission inversion and try to have a longer duration of remission. So here's the famous patient that we published in the New England Journal and was on the cover of Parade Magazine I'm so sorry. It was too hyped it's not cure but anyway so and what Dave David showed earlier today is the patient had had a initial therapy a stem cell transplant did not go into complete remission progressed within three months actually within six months had IMWG criteria but actually started progressing in three months got ten lines of therapy after that was treated at the Dana-Farber so got Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib, Avarinostat, Latuzumab when it was still an experimental medicine etc and and then we did a stem cell transplant in a few cells and if I had known that I'd be showing this slide I would have liposuction myself a little bit more. This is our this is the patient this is her husband who looks a lot like Peter Sonofeld I think so I think that's it and then the whole team this is Al Garfall who's really all the brains behind the whole thing. Anyway so what we did was we tried to keep her alive by giving her a little bit of cytoxin infusions then did a second stem cell transplant because she was sort of sickly we actually gave her a lower dose of Melflin than we gave gave the first time 140 milligrams per meter squared and then two weeks later infuse the CART-19 we wanted her to recover from the acute toxicities of the auto transplant before we squirt in the cells and boom she went into the deepest remission she's ever had and and this is and this is what we showed in the New England Journal that and and as I said at the meeting it was about for at least 15 months so so where she had a three month prior remission 50 months later complete remission and this was molecular you know we did every sort of molecular testing we could do it is now MRD negative no evidence of disease and oh and most interesting she was CD-19 negative plasma cells so and it's not 100% it was 99.5 percent negative she had a 0.5 percent positive set of CD-19 positive cells nevertheless the whole thing went down she actually recovered her B cells which is I think not a good thing and didn't really experience anything more than a serious and this is six months later against medical advice she was skiing in veil but so so what happened was about 15 months later we trying to think we did a routine scan and saw a a plant an extra medullary plasma cytoma evaluated her otherwise nothing else gave her and and sort of and it was CD-19 positive interesting but we didn't have the ability to squirt in any more so we decided let's give her some Daritumumab and melt it away and so she is now over two years from that treatment with that progression but no evidence of she was in another complete remission we treated 10 patients with this it's not 100% three of the 10 patients have had remission inversions seven did not but that is much we we look back I don't know have you looked we look back at our at our prior transplants salvage transplants we really have never had a remission inversion with a standard salvage transplant so we see this as a positive thing and incidentally what we're doing right now is a follow-on study doing doing the anti CD-19 infusion after the first auto transplant and high risk patients so if you have any patients we they have to have cytogenetically high-risk disease and we're just doing initial therapy which you can do stem cell transplant in the standard way and then squirting in the anti CD so we'll see the only and but as I've suggested this is not the the major setting this is not the logical target for CML I mean for for multiple myeloma the logical target is BCMA so BCMA the B cell maturation antigen is virtually 100% expressed on plasma cells though the the assess the assays for it are really screwed up what we so what we're doing so we're so we have a we have a BCMA trial at Penn we're not part of the bluebird and stuff like that at our study though we are not doing it we're doing assays but we're not using that to determine eligibility so we're we're not where if there are relapsed refractory patients we're assuming that everyone's going to be BCMA positive and in fact that has been the case when we use our assays they're all positive yeah I know it's torture right yeah I know I've heard this I've heard this this is the problem so so what we did but so so let's see so so our study is to take a person who has relapsed refractory disease and this is Adam Cohen who's in charge of this study at Penn and then they they know they get a T cell leukophoresis and our first cohort of patients after they cooked up the cells they we just gave them the cells no lympho depleting chemotherapy whatever and then but in our next cohort we we're giving cytokine and so here's the first patient who got the anti BCMA 66 year old guy 11 prior lines of therapy and was full of disease he was BCMA positive by flow cytometry and we squirt in the cells no lympho depleting therapy he did he developed grade 3 cytokine release syndrome in a similar fashion as as the ALL patients getting the disease and and had a tremendous improve and actually had persistence of his cells and then had a tremendous drop to complete remission of of his monoclonal protein he's in a strict complete remission no evidence of disease and and that has lasted for about nine months now incidentally update of our cart 19 experience as well as our BCMA experience is going to be oral presentations at the Ash meeting the the guys at the NIH have done this also they reported 12 patients using the BCMA and that's what the base is based on the bluebird stuff and you know that that a subset of those patients did respond there was some CRS I think CRS does predict for who's going to respond though not everyone would CRS responds so it's a really cool thing but it's not everybody it's not everyone with the BCMA it's not everyone with the cart 19 so we we're going through a whole bunch of different ways of trying to improve the likelihood of response to these cells you know give it earlier prior to the development of resistance clones give better lympho depleting therapy dose intensity of the cells serial infusions engineer the cells for greater potency I don't know if you heard but we were actually going to you we applied to the rack and got approval to do CRISPR editing of the of the T cells to try to make them a little bit more potent and to take away PD1 and things like that and perhaps cocktails perhaps giving anti BCMA and there's a whole bunch of other approaches of the the by specific antibodies using T cell receptor engineering etc so successful immunotherapy started with linolytum and pomylidomide the monoclonal antibodies have really become a part of myeloma therapy and as you heard may become the initial therapy checkpoint inhibitors when combined with this seems to activate things there's multiple promising targets for the cellular therapy and we've proven that functional CAR T cells can be removed and engineered for myeloma and the age of immunotherapy for myeloma is upon us so thank you very much if it takes a village of course and there's the whole crew this is the guy who's going to win the Nobel Prize is Carl June and David Porter's the guy who did the original studies with CLL and of course these are all the other doctors the nurses the research people and the people who really do all the work so thanks a lot any questions any questions any questions science fiction come to life so so literally two weeks though most but we prepare for up four weeks I think I think we you know in terms of planning we make it four weeks but but we can generate them that's only because of the you know there's a queue of patients we don't want to tax the processing lab etc so obviously this is all done in house our processing lab is making these cells and generating them yeah yeah but I'm sure that you know techno you know engineering will make these things a lot better as they become more and more proof of principle all right get home and enjoy my pleasure