(Guest Lecture): Novel Imaging in Myeloma: Development of Targeted Immuno-PET | MCRT Webcast: Myeloma Imaging

[Music] it's also a great honor for me to work together with jens so we have been friends for more than 15 years and uh jens spent time with me in my group when i used to work at the nih outside washington dc and i spent time with jen's in heidelberg and we continue to work right now we are both located in the state of new york uh i should say as a disclosure that i'm not a radiologist but i have a lot of interest in imaging and my interest from the standpoint of imaging really comes from trying to track residual disease so i have a long-standing interest in minimal residual disease detection and that's really uh what i would like to accomplish from trying to develop new strategies with imaging so for those reasons uh i was asked to give a talk focusing on novel imaging and multiple myeloma the development of targeted immuno pets which has never been done in patients with myeloma until this work i share with you now was done and this was just published i think two months ago or so so this is really new information there are similar approaches taken in other diseases not so many i do think this is probably where there will be a lot of development going forward so i labeled this as spatial characterization uh so as you heard from dr healing x-ray has a lot of mutation it requires a lot of destruction of the bone in order for x-ray to even read out as a normal you also heard from dr hill and gas that pet cts are negative for the reed for the pet component in about 30 percent of patients that are known to have bone destructions we also know for patients who undergo bone marrow biopsy that there is so-called sampling error so if there is no disease where the needle goes in and the result is negative that's obviously accurate but if there is disease elsewhere the needle would not capture that and we know that in some patients my long growing manner in the bone so these are background reasons for why we have thought about the targeted imaging another reason is also the fact that we heard from dr hilling as that the tumor burden can be asked a little bit in technologies but no one can really tell if this really is myeloma or what you see is the immune system trying to eat up my lawn muscle so when we with the current technologies with pet pet ct mri see that there are alterations it looks abnormal we can say abnormal versus normal but abnormal could actually be a healing phenomena where the immune system is trying to chew up myeloma cells so that would be very important to know what we are looking at with current technologies is that really disease or is it healing so that set the stage for this so-called targeted immunopath so targeted immunopath in a way is very similar to the idea of targeted treatment so if you have a particular target you're after you could go after that and try to kill those cells but you could also go after that target with something that you can detect and now you actually have a targeted imaging of potential residual disease so we're looking at here is preclinical work that was published in 2019 and there are a couple of groups around the world that have taken miles and put them in mice and then they have injected antibodies that they have tagged with certain tracers and then they inject these antibodies to see if they could see these antibodies in mice and that's what we're looking at here so we form the hypothesis by synthesizing a targeted myeloma-specific pet tracer which is an antibody in our case we will be able to perform a comprehensive spatial characterization of myeloma in human patients with myeloma which has not been done until this work was conducted so there are obviously very many many ways to to go after different things so one would be to develop a completely new antibody and label that the problem with that would be that it would take a long time to go through all the different filings through the fda to get permission to use these things so we need to save a lot of time what we did was we took a antibodies already fk approved and then we tagged on something called dfo key later and then we label that with something called zirconium 89 so it's basically a way to make the antibody visible in a camera then we took mice and on the top left we had mice where we had injected my low muscles that sending out the particular type of light called luciferase the same as the fireflies at night and on the left lower left you see my do not have myeloma inject so on the top left so my injected mass and on the lower left these are my mice without myeloma cells in the mice bodies and then if you move to the right if you look to the very right on the top right we can see where the antibodies light up and on the lower right we see there are no antibodies lighting up and this is because we took these mic after we injected antibodies pains and then we wait a certain number of hours we took pictures with mice cat scan machines so we have pet scan machines for animals so we could see if the antibodies actually were able to light up in those areas where we know that we had injected myeloma we also had proof from this luciferase and that was very good correlation here you zoom in on that right mouse and all these arrows indicate that here we see antibody uptake and these are actually where we knew that the myeloma was present mouse we also looked all the different tissues throughout these to see whether there was uptake of antibody and in a nutshell the reason we did this is because we want to make sure that these antibodies bind to the myeloma cells and not to normal tissues because then the technology would be useless and on the very right you see that the bone marrow lights up and the blue means that this is myeloma cells and because there are normal plasma cells which are variants of myelomas as myelomas also very helps the normal plasma cells you also see the right red that the healthy also lights up but not as much as the myeloma cells you also see in the spleen it lights up so the reason for that is because when you inject antibodies it travels through the blood into the spleen and the spleen is a control station in every uh biological creatures body that controls the immune system to some degree it sends out a lot of immune cells after so these antibodies undergo some form of checking in the spleen and then they're being released out through the bloodstream again so it's actually important to know when you do these studies because to time the inject with the picture so if the antibodies are temporarily caught up in the spleen that's not when you want to do the picture you have to wait till the antibodies have been released and they are where you want them to be so we did a lot of work and we were able to just data that gave us the confidence to write up a protocol that we then submitted to the fda and we obtained permission to do a study in human beings with multiple myeloma so this was a so-called first in human phase 1 study that was based on 10 patients we did not really know what was the optimal duration waiting from the injection of these antibodies still taking the pictures so that's what we wanted to determine of course we were very much focusing on safety so optimal imaging parameters safe and also uh we wanted to see if this could kind of give us confidence in thinking of developing additional studies could we use this technology in the future from bone marrow could be compared with m spikes and light chains could be compared with the current standard of care fdg pet cts it could even compare it to mod assays so these are questions if we wanted to see if there was any early lead from early study that gave us confidence to write a future protocol so here we have pictures from one of the patients that was participating in this study that we have just conducted there were 10 patients patients were imaged up to four different time points and as i indicated we didn't really know exactly how long out it would be optimal to take pictures we knew that the antibodies probably would take his human and tissues and we need sarcomere at five times we would be able to all the way out so what you're looking at here is the same person imaged one day after two day five and seven days after and you see also how the different comp blood pull the liver and the the leg on the right leg lights up differently from left to right and if you plot this out you actually see that there is a sweet spot where you can detect what's going on that lights up in the leg and there's less going on for example in the liver and the spleen and other organ systems so if you do it too early after one or two days you have a lot of problems and you see what's going on in the leg and right see that that's more optimal so this study gave us a lot of important information on how there is another patient and if you zoom in here uh at one of these lesions if you look on the lower side of this slide on the very right there is a round black dot that where i put an arrow uh that is the antibodies up and then if you move to the left in the middle there on the lower side that's the cat scan so this et shows that there is a hole in the bone from the right that's where the antibodies lights up on the lower part in the middle you have the hole in the bone and then on the you have both the ct and the antibody put together and instead of having the antibody being black we made it yellow and there are different ways of setting the computers when you do this analysis so this is this is typically how we do it so basically what we see is that the antiviral light area where there is also hole in the bone so we strongly believe this is my here's another patient on the study and we look at the leg and you maybe look at the bone carefully here and you see there are some areas that look maybe a little bit darker or these holes so what we do see here is that there's a lot of antibody uptake unfortunately we would not be able to really imagine with current cities here is a patient that was imaged with regular pet cd the standard ct pet ct that we normally would do in the hospital every day for every pain and this is in decline and we have worked together with dr hilingas and other doctors around the world to put your guidelines this patient was worked up with standard pet cd and seven days later this patient participated in this study just like the antibody so there are very many areas that light up so i'm not saying that this is proof every single area with these lights up but it's quite suspicious that that could be cause of disease what we are doing now is that we will go forward uh with these findings actually before i go into that i should share with you some more detail on this patient you see this area on the right in the black panel that's the antibody on on the left you have a hole in the bone so it is indirect evidence that you really have probably uh myeloma cells growing here because it's caused hole in the bone but what we are doing now is that we can be done in mice we conclude that it's safe in humans there was one patient in the beginning who had a little bit of a reaction with fever so we amended the protocol so we in the beginning gave no antihistamine no steroid no no tylenol as we normally would do when we treat patients with their atrium amount but because one patient the third patient had that type of reaction we said let's get something in steroid and tylenol before and after we did that none of the other patients had any reactions and there are no other toxicities noted so we conclude that it's safe it works we do it after five to six days in shock and um we think that is suggestive of being more powerful than current standard so therefore we have already opened or written a study that will open in november in phase two study where patients can come and be imaged so we will enroll up to 60 patients total for baseline for patients only diagnose could be it could be after therapy has been given the imaging could be repeated again before areas that light up if the patient agrees they could be picked up with a thin needle and we could take out those cells and try to characterize them and see how we could get them for patients who have had myeloma for many years if there is a relapse patient could be enrolled on this study asian could start relapse therapy and after relapse therapy has been completed per plan combination therapy that would be a new round of imaging again so we want to see technology can better er burden or disease both adding diagnosis and relapse response to treatment if there are areas of focal residual disease if we can really achieve minimal disease negativity and also could this be in the future way to detect early uh evidence of recurrence before i end i share with you a couple of slides this is a team uh i work with jason lewis uh in the mouse lab and i worked laner to do it in humans so the three of us on the bottom are the principal investigators for this work and then we have our colleagues on the top that include our pharmacist our physicist and and our colleagues overall in the team i also want to share with you some work we have done on genomic profiling because it ties really into this business of imaging so when patients unfortunately with myeloma have the disease coming back we know that in each and every site where there is evidence of disease if you were to do multiple biopsies dr hilling has mentioned imaging and then biopsies of various sites throughout the body that there is evidence of diversity and it's so they're a little bit different genomically but this the middle bullet here on this slide the key questions i think for the field we have really been wrestled with for a very long time we don't really understand but we didn't understand until this study was done i'm going to share with you whether there is evidence that each site that relapse is mentioned of pre-existing previously undetected disease meaning that could there be some cells that are so few that are sleeping that are hiding throughout the body and at some point they wake up and then they cause the relapse is that what it is or is it rather a matter of a seeding so is that one cell that could hide somewhere and that cell cells everywhere proliferate so is it multiple sites of sleeping hidden cells or is it one cell that sends away seeding so that's a key question that we have not known the answer to before but i will share with you in a few seconds what we have found it's also unclear how this goes over time it can go slowly or fast if there is one cell sending out cells if that's a slow process or if it's sleeping if it wakes up at different time points over time these are unknown until this study was done so we set the hypothesis genomic profile myeloma with special samples so these those samples were done throughout the body engagement with relapse myeloma to study these what's called temporal patterns so we had patients who under who have chosen to sign consent in the very unfortunate event that they could they would pass away from myeloma that they would agree to undergo an autopsy uh allowing us to do very advanced sequencing and the protocol that's long catering has for patients with any type of disease when they come to our center so there were a couple of patients with myeloma that said that in the unfortunate event of me passing away i would agree to be part of a warm autopsy so these individuals here are example of people where we did biopsies at very many sites and this has given us insights that go beyond anything we have ever done so what we show here is that unbelievably the median number the average number of mutations we can see with whole genome sequencing is more than ten thousand we also are able to do what's called phylogenetic tree solutions so it's a way to if you think about like a tree with a trunk and branches how the disease evolves over time and when we did these different biopsies in all these different sites we looked into how the disease have evolved it's like if you cut a tree in the forest and you look at the rings uh for every year for every season uh you can see how the rings are there and if the seasons are longer or shorter you could see the distance being a wider or more narrow between the different rings so that's basically how we approach the data and put together these phylogenetic trees with trunks and branches to define the evol the evolutionary trajectories and then we also define what's called key evolutionary trajectories and drivers for these sites so in a nutshell what this study shows is that in the beginning when a person is diagnosed with myeloma there are cells that go out and seed over many many years this is how myeloma initially seems to establish itself a few months ago a study in the journal called nature communications where we show that the first cells of myeloma in the body of someone who eventually develops myeloma those cells probably start around age 20 to 30. this distribution of these cells throughout the body we have evidence from this study that we're looking at here that it's a process of many years but what this study shows in particular for the purpose of relapse disease is that once the late relapse happens that is a matter of an accelerated dissemination so there's really one cell that spreads everywhere and this is very very similar to what has been found in solid cancers like in breast cancer or lung cancer or so so there is no evidence that there are cells hiding throughout the body instead it's there is evidence that is one cell that is the source for seeding throughout the body and that causes the revelation so when i think about these things together i think if we could identify with the imaging that residual site that'd be a way to prevent this from happening and that's really what we want to do so here's the core team this is my lab on the upper left for my research lab for genomics and then we have a lot of collaborators both at sloan kettering and outside the institute as well i would like to thank all uh our colleagues athletic and outside and thank the funding support uh i would like to thank you so much of your attention thank you jenny so much for inviting me and greg for inviting me and lastly also say welcome to miami so i'm moving to miami november 1st and i will lead the myeloma program and clinic and my telemedicine clinic from there as well thank you so much you