Anne T. Bass Lecture Series in Hematology, Oncology and Stem Cell Transplantation
Advances in Immunotherapeutic Strategies in Pediatric Cancer
PRESENTER
Rupert Handgretinger, MD, PhD
Professor of Pediatrics,General Pediatrics and Hematology/Oncology, Children’s University Hospital, Tübingen, Germany
SESSION DESCRIPTION
Various forms of humoral and cellular strategies for the treatment of pediatric patients with leukemia and solid tumors will be discussed. In addition, haploidentical transplantation as a platform for post-transplant immunotherapy will be introduced. Current results will be presented and future outlooks will be discussed.
Good morning everyone I’m all Mar Colores I’m a pediatric nephologist here I thought we can get started thank you for everybody being uh here in the camp building with us today and everybody joining on Zoom um uh we are going to get started with today’s uh Grand runs
With a very special speaker who is uh joining us from children’s University Hospital in tubigan Germany Dr H gringer who will be speaking on advances in immunotherapeutic strategies in pediatric cancer is actually here for our uh best lecture series Hematology Oncology and stem cell transplantation I
Will like Dr ban introduce him in more detail later um first um just to draw your attention on the left to the text code where you can uh confirm your attendance and then uh later on with valuations get credit and Moc part two credit if if you fill out Impressions
From the meeting um to draw your attention for to the Future Grant rounds coming up on February 6 is Elena shei from University of Colorado and we’ll be speaking on mechanisms of uh inborn errors of immunity in IBD and then on February 13th um Dr Grace Le will uh
Present in our quality improvement series as always we want to acknowledge Stanford University um land acknowledgement where we recognize that Stanford sits on the ancestral land of the MMA Allon tribe uh moving forward another reminder uh is the California maternal uh and a perinatal uh quality uh care
Collaborative uh meeting that will be on February 5th this will be combined in person and online and will be addressing parental Health Equity so um uh it’ll be either uh here in the camp building or Zoom so please join on February 5th um another program that we uh want
Everybody to participate if possible is the Pediatric inter program at Stanford we are now um calling for mentors so the uh fifth is a six week summer research intership for under represented in Madison Bay Area High School students and our goal is to show students the exciting world of science research
Medicine so um on the bottom left is the ways to contact us if you would like to volunteer to Mentor in this program um and now uh back to um our lecture today in advance Z your therapeutic strategies in pediatric cancer it is my pleasure to um introduce
Dr Alice berana um who is the co-director of the bath Center for Pediatric cancer but also the chief of our stem cell program program here at lpch and I just recently to learn that some years ago she joined us from bambin jzu in Rome and um impressive to have
Transitioned your knowledge in from Italy to us thank you thank you very much thank you so much good morning everyone it is really my absolute pleasure to uh introduce today for our pedatric ground rounds uh Rupert and Grainger rert uh wouldn’t really need a presentation because his name um
Is quite uh a star into the into the field I have been lucky enough to meet him uh back in 2010 when I was in Rome and when I first started to do alphabeta T depletion I always admired his um his figure um his ability of really combining deep knowledge for this field
And passion for our patients that he never uh he never put aside um his career has been um incredible uh he trained uh at the hospital of chingan in in Germany in hematology and oncology uh and uh between 2000 and 2005 he served as a director of the division of sensor
Transplantation at St Jude here in the in the US uh then he went back uh to Germany uh where he was chairman of the Department of Pediatrics and Hematology Oncology at the Children’s uh Hospital in uh in chingan currently he’s a president Meritus at the University of
Chingan and he serves as a consultant uh for the Abu Dhabi stem cell center um he has written uh hundreds of peer-reviewed manuscript that really made part of the history of stemell transplantation and Hematology Oncology he’s a member of the German National Academy of Sciences uh leopoldina uh and he recently AED
Achieved the Lifetime Achievement Award from the American society uh of transplant and cell therapy really as a recognition of his contribution uh to the field it is a great honor to have you here rert thank you thank you so much uh Alicia for this kind words and uh it’s a pleasure to be
Here and to discuss with you a little bit about the advances in pediatric immunotherapy this is my disclosure and a little bit back what Alicia already mentioned I started my career at the old hospital in tubing and the former Professor head was Professor B maybe some of you know Professor B at
Least by name the B how the C our bit test of course very important but not only that was done in uh in tubing in there were some other achievements and some of you don’t know whereing is maybe you know the cars they are produced near
To tuing inart but tuing is a little city near the Black Forest it’s a University City there are 8,000 inhabitants by 30,000 students so every third or fourth person you meet in the city is a student which makes it very nice and academic it’s a big campus so
What has been achieved in tubing and it was founded very early in 477 4 in 1477 had the first University hospital that was very unusual and you see some of the famous people who were their students you see the pope was there on the faculty the Catholic faculty I know
Whether somebody recognizes this gentleman this Al Alzheimer he was also there for a while and the castle Kitchen in tubing is the most important Castle I think or was the most important castle of the world not because they cook there uh this is shown here this this was the
Castle it was made a laboratory as you can see here the laboratory of Professor Felix Hy uh in about 1870 who has certain name H not that many this was Felix H and what he found he found a hemoglobin the first he published in 1864 that he could
Crystallize the blood and named it hemoglobin and he found out that this car is oxygen so this is all uh actually done there but in the same lab there was another guy working this is this guy his name is Fred Misha he was a guest doctor from
From Switzerland and he work in the same lab and no have ever heard of Dr Misha fortunately not he was the one who purified the DNA first in 1869 he was the first and he named it he called it nucleic acid because he had the acid substance purified from wound
And this is still there this white Pulver you see there they recently analyzed it again there a little Museum now it contains DNA and RNA and then it was forgotten for almost 100 Years of course like a lot of things in medicine so there are a lot of things going on
There and then of course immunotherapy and we always think this was the beginning of immunotherapy of cancer and you know koola is toxine here in the US uh where the injected bacteria into locally into tumors and they saw some responses of course then at that time
That was at the what is now called the memorial Zone cerine Cancer Center I think in New York hospital they did this and then when James Ying came he was head of the department he was a radiologist or radiation oncologist uh Dr COI was not allowed to
Do this anymore so very similar politics there like sometimes today still going on but he was not the first also there was this professor brunes he published in German this is of course at that time all in German he imp published the efficacy of Aras on two mes and he
Injected thisto Coco so induced ER p in tumors and they saw quite responses by this inflammatory reaction which they cause fever reactions local reaction and Professor brunes was also head of surgery in tubing and at you can see at that time a little bit in another outfit of
Course so a lot uh was was being done there and then came the discovery also that RNA also carries genetic information in 1956 that was not so clear at that moment what RNA is doing of course we knew from the Wilson quick or DNA maybe uh that is the genetic information DNA
Was not known and now comes that’s at the moment a big discussion of course who discovered first that uh from d and from you can make mRNA vaccines there is still an ongoing struggle the first publication came from from in Mahar who was a a student after of Professor
Rammen in the Immunology department and they published first that injected RMA is transcribed into protein which they injected it into mice and then they started this CC which were not so successful in the race for the for the covid-19 this is imma and biotank was found later so now
They cor a little bit who was the first and the usual but and issues I don’t know where this stands but the science is is good and then we know that from DNA to RNA to protein and this is what we use also for tumor treatment and I
Show you why you know that every protein every whatever comes into a cell is it a protein a virus is uh is uh is produced to small peptides everything what a cell incorporates is produced to to small peptides and these peptides are then presented uh to uh in the from the
Presenting antigens to the via the HLA class one for CD cells or VI the HLA Class 2 to cd4t cells uh and this happens with any other substances which goes into a cell it’s it’s presented to see for the body is it foreign or is it
My is it or is it my own and this is how it looks like then uh this is presented to the teer and it must be a complete fit there cannot be one amino acid difference otherwise the diesa receptor would not recognize that peptide and this is something what also was was has
Been found out in the 90s by Professor Ramy who was the head of Immunology is now just also retired last year and they found exactly out how these HLA peptides are presented in in the uh in the HLA Grove or in the HLA context they identified this anchor positions how how
They interact with the HLA because this is very important if you want to use pepti for vaccination they have to fit exactly in this uh in this groove there can be no error otherwise it will not work especially anchor positions the amino acid sequence of these peptides
Are very important and this is what they use or what we use now to start tumor vaccination and for example if we take a tumor this is healthy healthy tumor and a tumor in the kidney for example from a patient after surgery then this tumor is sequenced the
Normal cells are sequenced the tumor cells are sequence and then we look for self peptides and we look for tumor specific peptides either for class one this is peptides based on nine or 10 amino acids size or for class two it can be 12 up to 15 peptides and each individual patient has
It individual peptides of course this is a very excuse me a very patient specific approach and uh this is one example in one a patient with a primary metastatic tumor as you can see here this is the wild type this is the white type and this is the mutated
Peptide and you can see there is only one amino acid difference and this is already enough for the immuno for the immune system to recognize this as as uh different as non belonging to the body and the tea cells would be activated and fight this tumor based on this single
Amino acid difference so the immune system is sensitive enough to recognize that this is not a cell which belongs to this body based on this one single amino acid difference and this is also of course with the other peptide you always look for peptides where you have these
Differences so it’s a and then you can synthesize these peptides is not that difficult to do chemically and then you can uh vaccinate a patient with this peptide you choose for the best peptides which their algorithm which would would fit fit best in the groove this must also of course
Be there and it’s HLA specific you have to know the HLA type because every immune response is based on the HLA type of your patient and then you find out the best peptides of those and then you try to immunize the patient and see whether he mounts a immune response and
This is of course for every patient different There is almost no off the shelf tumor vaccine that this works has been shown by us and also others this is a case report some years ago this was a patient who had a metastasized relapsed pancreatic dual cin which is normally a death sentence
As we I think we know a relapsed metastasized pancreatic cancer and he got a this peptide vaccines the details are shown here and this peptide lived many many years he had a very good immune response we could monitor his CD4 cd8 response and those patients who m a
Very good immune response they have a very good chance that they can control their tumor this is another example just recently published that was a patient with a with a febr lam hepatocellular carcinoma this was a young lady she was 16 when she came to us and the tumor was
Not uh surgically remov removable so she had a she had a liver transplant for this but then she had a metastasis outside the transplanted liver of the two more uh and which could not be really addressed by anything so she also went into this uh vaccination
Program and here we have this uh fusion protein and if you have a fusion protein your chance is very high that you find peptides from these Fusion proteins which are only for the tumor because it’s a tumor specific fusion protein so you only have to look in the fusion
Protein for peptides not in the whole tumor to see differences and to find the appropriate peptides and as you can see this was the patient she had a liver transplant and she had some chemo then she had up to four relapses you know and then we did this uh two
Vaccines with this uh peptides adjusted to this fusion prot fusion protein she has and as you can see here she mounted a very very good T response also also here uh this is the this is the T response and she responded very well to this and uh this is her pet
Uh before now she had this leion here which even could not be removed and this is the the B Imaging and it’s completely dissolved by this t- cell expansion of the of the tumors of the tumor specific t- cells and she’s still in remission as
We speak so it’s still done once you get these T cells ongoing or we can repeat the vaccination this is something of course we have to still figure out and based on this results we have now ongoing phase one two trial uh for patients for Pediatric patients and a patients with
Metastasized fion driven SAS if you have a fusion it’s much easier to find the peptides fly one ew1 or uing or some raptor have they have all this Fusion uh prot Fusion uh in coin so it’s easier to find specific peptides and this is now an ongoing study first patient have been
Uh um uh included already so we and it’s a safe therapy this has actually no side effects this vaccination this is uh and and it can be effective if you can expand somehow this the cells but then in in adults in adults you know monocon antibodies play a big
Role r took them up and all this but in children the question is does do they also play a big role in children monoclonal antibodies have a lot of actions one of them is of course this antibody dependent cellular cytotoxicity with natural killer cells some with mcroof fures and also the complement mediated
Liis and also overall they can be used to Target tumor cells even tumor micro environment or two more targets and the question is do they play a role in Pediatrics and I think the best example is and maybe you know and you know this example is neuroblastoma where we had
This murine 14 g2a antibody made by Prof professor rfel at at scrips clinic in La Hoya who originally also came from stutgart near turingan and U he made his monoclonal antibody against the Dio gang gd2 which is highly expressed on the pedatric neuroblastoma a very nasty tumor in young
Children uh with with a not so good prognosis and we treated this we did a phase one a phase study very early in the in with this morine antibody I have to say there were not yet all these regulations as we uh have today so at
That time this was in the early 90s this would not have been possible probably to do this but Professor Ricefield was very open to give us this antibody so we treated this patient in Germany this was a patient a three-year-old patient relapsed metastatic neuroblastoma then he had mibg therapy
Didn’t respond then he even had a m siing trans that was end of the 80s to do a med sibling transpl in neuroblastoma was already a little bit something but he relapsed again so I asked Professor Rell for the antibody and he was willing to give it to us so
We gave this antibody to this patient and we reported in that paper that this patient is longer in remission now since 104 weeks but they changed a little bit this patient is still with us and it’s a pedatric oncologist now by the way so it can be effective
Uh and then based on this we and this is R reld I think we own him a lot in the Pediatric field and you see all his uh he he was a mentor of many of us including James Allison the Nobel Prize La was a was working at PhD in Ral s you
See a l ISU who L the also the the randomized study here so you see a lot of people and I think that was and he unfortunately passed away in 20 21 and all these antibodies based on this R reinfeld achievement 14 g28 the murine antibody then Steve Gilles also
Work with Ral made the c1418 antibody which is nowadays known as dinim map which is now approved after 30 years of work in Pediatrics for the treatment of refractory neuroblastoma and Steve also made this u1418 k 322a antibod which is a humanized version a little bit different from the other ones and uh
As you know probably all know the paper the uh pivotal paper from alisu done here in the US the randomized study with neuroblastoma where they randomized standard chemotherapy versus immunotherapy with this gd2 antibody a little bit different approach with the how they produce the antibody and that
Led to the earlier end of the study uh because the immunotherapy was so successful as you can see here the event fre survival and the over oil survival and that lead to the approval of the din toim up and now of course uh it has become very expensive therapy
Unfortunately so we have also to work on this how we can make this antibod available to other patients outside the let’s say the high income countries U and this is something we has we have so to think about so this antibody was then very successful and the s s uh they do
They do a similar study or have done a similar study with this antibody with the U14 K 3228 is a little bit different antibody this antibody has a reduced complement binding activity so it does not cause this much pain by complement activation like the ch1 1418 so you can give higher doses
And Sanu is using now this antibod successfully in combination with chemotherapy like arop now they do in Adil they use antibody plus chemo in lymphomas so now we do it very similar in neuroblastoma that we use together with the chemo we use the antibody which makes maybe the the cells more
Susceptible to chemo or the immune system the inflammation we don’t know yet but uh and then this patient go to a transplant and then they get all all post transplant if they still have minimal residual disease this antibody as a like a maintenance therapy I think this is also something very interesting
In the future to combine immunotherapy with chemotherapy uh and this is their published results recently published uh that uh in the this is Frontline therapy so they see a very good uh response also of the tumor size if they combine their if they combine their uh chemotherapy with this uh antibody
Treatment and uh we have just recently published our results we have done a large study in tuing in and in in Germany with tiing in as the as the study center where we did a similar approach but this were patient who all relapsed after oous transplantation so they had a relapse refractory
Neuroblastoma they under already the standard approach chemotherapy transplantation and then they relapse and we know still about 50% of our patients relapse after our standard therapy and then the prognosis is not very good of this patient so we thought we need to do also a different approach so what we
Did we gave them a h and liquid transplantation of course T Cell depleted that’s why uh in order to change the immune system of the patient just to give them a new immune system and then activate this immune system with this antibody up to up to nine
Cycles of the gd2 antibody theim MAA which I have shown you and we have done this study from 20110 to 2017 uh so we have a long follow up in 68 patients which just published our results and if the patients this is shown here if the
Patients are in a CR when they come to the hubo or to the antibody treatment or in a good PR they still have now a survival longterm seven year sh follow up of about 50% and this is for refractory relapse neuroblastoma I think this very good data and uh I think this
Will also uh maybe has to be expanded more uh into into immune approaches you can see that the immune system is important and here of course we try to give the patient a new immune system because uh we have seen that when these patients had six eight Cycles chemotherapy had ous transplant their
Immune system is just not working anymore you cannot expect a lot you see this also when we when want to produce C cells from some patients who had endless chemotherapy it’s just not working very well so can we do the same in acute lob blastic glucemia there’s a nice overview on
Immunotherapy and of course one of the most important antigen is cb9 you noce all from the C cells but it’s not all about only C cells it’s just about all maybe only a simple monoclonal antibody and we have generated our immunologists have generated an anti- cd2 anti- cd9
Antibody and this antibody has two amino acid changes here and uh this makes this antibody very active to enhance this antibody dependent cellular cytotoxicity so if you incubate this antibody with natural killer cells like on this side uh and then uh uh against leukemic blast you can see the the enas Cs get
Very much activated through the FC receptor which activates en Cas cells by the FC binding part and when they have this uh this this mutation and the ch2 domain uh this red one the ADCC is much more effective and uh we have used this antibody that was a a first uh result in
In in one patient also one of these patients as a compassionate use this patient also had a had a very had a relapse after matched unrelated transplant and then he never went into remission you can see here this was his mrd by flow and by PCR so we did both
And then we did a hlo transplant on this patient here alphabeta depleted difficult with the mouse here we did a h transplant and then of course these patients have a high risk of relapse and you do a transplant when they are not in the mission we know that and then we
Gave him for two years we gave him the cd9 antibody every two weeks we gave him a dose of antibody outpatient after one year we wanted to stop but then was very interesting the parents refused to stop huh because they know this is the last
Chance so we did in the second year we did every four weeks but without big scientific Foundation but you can see the of course what’s going on in this in these families of course and uh fortunately this patient is still in remission now as we speak so based on
This is still now more than eight years and almost no side effects with this infusions no this is outpatient infusion and then we did a more more clinical study uh so we treated 15 patients and uh 11 patient relapsed after a first transplant and got a h identic transplant or the second trans
Is only H identity because it’s experimental we don’t do a experimental transplant with a M transplant again that only goes to Hao Alaba depleted of course and then you have to because if you want to have do Post transplant strategy you cannot use immunos supression afterwards that’s the and
Then uh two four patients even had a relapse after two matched unrelated transplant and got a third transplant is it possible and then we treated these patients also with uh uh with the monoclonal antibody for two years and of course can see the probability of relapse this is without is a historical
Control not a randomize this was the relapse when we only only did hlo transplant this was the risk of relapse when we uh when we gave the antibody for two years and the event free survival was also much better for those patients who get the antibody of course course this is still
Something something we have to improve the nice thing is the this is the overall this is this is the data I was looking so this is the overall survival of our patients who receiv received the who received the I shouldn’t touch this this is the overall survival of the
Patients who receive the antibody those without antibody but not random this was a historical control and the event fre survival but you see we have a number of long-term survivors this is the relapse and what’s also interesting these patients when we stop the antibody treatment they recover their B cells as
You see on the right side so all of them get their B cells back and uh and uh most of them they stayed in remission based on this we work now with this humanized anti- cd9 antibody taas map the adult colleagues might know it is has been approved now for the treatment
Of diffus large B cell lymphoma and adults in combination with this is also a optimized antibody has also these two amino acids now the mouse is completely gone yeah it’s also these two amino acids so to make it more effective and works with natural killer cells this antibody dependent Silo cytotoxicity has some
Direct action or also can work with macro FES and now we also initiated a study uh with this antibody in tubing in as the sponsor so IID study where we now evaluate the role of this antibody in the setting of uh refractory leukemia so all patients now who get a second
Transplant will get this antibody for one year maintenance post transplant or if they are mrd positive before transplant they get the antibody they get the transplant but then one year the anti body afterwards or if they are mrd post transplant positive they will also get the antibody of course if they do
Not respond by mrd they will change to cars or whatever is then available so we have now finished the dose escalation we know the dose it’s well tolerated uh so so far it looks promising but of course we have to wait for the results then most of you have heard of
The BL tumor map of course the the hematologist this is Professor Reed Miller who Al fortunately also passed away uh last last year he developed the anti CD3 uh uh cd19 bfic antibody where we where he fused the cd19 anti antigen binding site with the CD3 antigen
Binding site to this uh to this bite this uh and this upon binding to the to the cd19 Target the TS get activated and that can be very effective and uh we started the first patient in 2008 that was also a patient with us in tubing in that was a patient uh seven
Year old boy with refractory relapse after M transplant and this is oil therapy he got one chemo after another and you see by flow citometry PCR here he did not respond to anything so then the parents were asking they were both colleagues that came to T what what can
We do and I heard of Professor r m I knew him because he was former on the faculty in tubing enologist before he went to Munich so I called him with a I heard about his by specific and he gave it to us that was no engine involved yet
That came all later that was called Mt 103 so we gave this patient this antibody really didn’t believe that it will work after two weeks it’s a four we infusion after two weeks the patient was negative it was for us it was a miracle and then of course we did a second h
Blue transplant and this patient is now a lawyer also so he might sue me because we did a unapproved therapy so he’s yeah yeah he’s now also interesting so his his he made it through and then we did some more patients and out of this compassionate use then still under Mt
103 and we see a lot of uh complete responses and and two patients we also learned something we had two patients here who started with a this a two I maybe this were two patients who started with very high blast load and it didn’t work normally you say oh this is
Not working but the the parents backed us try it again try it again please so we gave this patient a chemotherapy again just to stop their progression and fight it again and then they have lower blast load and both went mrd negative so we learned the blast uh is important how
You start and that came later out of course in the studies that was then the study which led to the approval of the BL tumor map the first eligibility was more than 25 blast but the follow up study then we had much a lower blast eligibility we could even uh use mrd for
Indication of BL tumor map and that also gives us very good responses as you can see mrd response those patients who are treated in the mrd situation they almost all respond uh to negativity but the thing is of course uh L Tuma map does not induce any memory
What we want like vaccination we want a long memory but Lum isn’t do it will not do that it says a short half life if you stop the infusion the activity is gone the next day that’s why you have to give it as a 24hour infusion for for weeks so
It’s not something to to maintain and you cannot give it forever because we have also normally it was five Cycles in the initial study we have seen relapses after the third or fourth cycle during tumor M so nowadays I wouldn’t give more than two cycles and then go to the next
Step either transplant or car or whatever you have so it’s not worthwhile in my view to give too many cycles because you might relapse still also cd9 positive very rarely cd9 negative but also cd9 positive in nowadays of course BL Tumo m is started also in Frontline
Therapy P this is the this was the inal stud study where one chemotherapy in the relapse protocol was replaced by one BL tumor map this this this intensive chemo was replaced by B tumor M the patients were randomized and then went to uh to a transplant and this was just recently
Published by by Franco uh of course and you can see the significant results those patients who got a B tumor instead of the Intensive chemo they did better than patients in event free survival and overall survival and also uh in the risk of relapse also
As you can see here so this is also something that we try now in Pediatrics also maybe to go away a little bit from more chemotherapy and make a little bit more smarter using immunotherapy or combinations to treat patients because we know this all this long-term side
Effect I don’t think we have to talk about those what we induce in these patients with with intensive chemotherapy especially in younger children they have done the same in the US uh uh pet Brown uh but their results were not so clear there were maybe there was a tendency that they have also
Replaced in the relapse protocol two chemo Cycles spinner tum up but I think this is the future a little bit now that we go more from front line with this kind of immunotherapy and in Germany in Europe we try this the with the Italian bfm protocol 2017 that we introduce here randomized
Two cycles of Lina tumor map instead of two cycles high do chemo Ander patients who have a high risk feature this is not relapse this is Frontline now or in the intermediate risk we give uh before the maintenance we give one cycle of uh L
Tumor M so we have to wait the result my gut feeling is that in the future we will even go a little bit more earlier also here that we maybe replace some of this uh some of this uh chemotherapy for example maybe if we can get rid of of doxorubicine would be good
For the hearts of our children or some of the asparagines which is my view a horrible truck with all the side effects if you can replace some of these trucks with immunotherapy and of course you have seen probably this data on infant lymphoplasma where BL tumor map was added to the
Chemotherapy and uh was recently published in the New England Journal and the results are just daggering you see the current study two years survival 80% versus 50% and for the for the disease free survival and also the overall survival for for infants so this is now in the
Inant study also a fixed protocol to use BL tumor map for infant AI That’s I think that’s a huge progress for for lymphoplasma in infants so then of course we have the cheric antigen receptor I think I don’t have to talk too much about it you have
Heard a lot of this probably here in in this campus by by by your colleagues uh just to show you the pict who had the idea of it this this is the same with the with the DNA from tubing and he he published this in 1990 then it was
Forgotten for about yeah 20 25 years no this is artifact or something like like all these things nobody has work with with this Cel or whatever know long time ago when he published it I think people didn’t believe him so really and you all know the data then of
Course now it came uh the data which led to the approval of the of the kraa the Elana study with uh the event free survival of about 50% in the overall survival but to be honest for as Patrician to be H 50% is not good only
100% is good so we have to work more we cannot say oh we have a good therapy if you have 100% I would agree but even 90 is not good enough for us right so we we should not stop but and this is also this was a study
And this is the real world data on uh on kimra this again lloid sale and you still see a lot of cd90 negative relapses so there is a problem also with this this the cd9 this target Escape in C cells and if you have this relapses
The prognosis is not so good these are not not done under studies now of course under study everything is controlled this is the real world data which is probably the real data which you have to look at so what can we do again against the cd90 negative relapses if the blasts are
Smart enough to just get rid of their target they cannot be seen by the C CS anymore and there are different methods or different approaches how the tumor cells can do this they either just lose they have a receptor genetic mutation or whatever whatsoever they just get rid of this
Antigen and there are several approaches we have looked into this approach as a tandem approach where we used it in 1922 car at the same time with one transaction and of course manufacturing with the companies is very expensive to takes very long so we make them
Ourselves as you do this here I think on the campus also you make the C sales in in 6 to 12 Days you have your sales ready we don’t freeze anymore this is fresh in fresh out we don’t freeze any of these cells uh that’s all gone so
These are all fresh cells and we tweeted uh initially some years ago already nine patients with the in 1922 even adult patients uh some patients had already a relapse after a transplant what we call true pseudo allogenic they received the C after the transplant but the cars the T cells were
Actually from the donor not donor car T cells but from the patient but donut arrived uh and uh the transaction efficiency is very good and this is uh the patients again all patients received this 3 million per kg of the C 1922 and this is the
Response uh so six of them had a complete remission as you can see here uh and then so it worked quite nicely and there was one patient I want to show you this is was allogeneic patient she had a completely refractory leukemia this is her disease she came from outside from
From Saudi Arabia to us and she was very sick when she came because she had severe toxicity after conventional FY she couldn’t move she was like in a Kuma and then we took it took about half a year just to make her a little bit mobile with some lowd dose femo so that
She’s not basting off and then we tried autologus it in 1922 cars didn’t work short response but then she had a again progession and then we did another boost of the cars no result multiple chemos partial response she never went into remission for a whole year never and
Then we did a m transplant on her with a matched unrelated donor but which we normally don’t do because you wouldn’t do a a transplant in a patient who is not in the mission especially like her but we had the idea with the Dona cells
Coming uh we make cars out of this so what what we did so we transplanted this patient and she had H this residual microscopic disease we gave her the allgenic donor car and she cleared all the leukemia she had a very nice expansion of her cd9 in City 22 cars uh
And this is the result as you can see here this was four weeks after transplant and she had it not only there she had it the whole body bone marrow lymphomas it was all full then she had even a progression after after transplant and then she got the donor C
And since then four weeks after donor car she’s she’s cleared completely in remission I just visited her few weeks ago in Saudi Arabia so the colleagues there measuring her C she still has 25% C sales after three years that keeps her remission so this is something we need
To achieve but we don’t know why is in this patient 25% in some patient they disappear after a few weeks so there is still I think a lot uh we have to learn so we need also new car models so what are new car models and
This also what we published and we work together with mil company on it that we make not a car against a tumor Target we make a car against an adapter and then this adapter is labeled to the antibody so we make a car this is the normal car
Goes Direct to the Target cell this is the this is the car goes against an adapter and this adapter is labeled to the antibody so if you remove the antibody the car is not active because this car is in our case it’s biotine it’s a biotine car uh doesn’t recognize
Anything it’s not a human biotin it’s the one you use for biotin relation in the lab or something uh so you can stop the cars anytime it doesn’t it doesn’t hurt you and this is quite effective as good as with the with the direct car
This is a model for cd20 you can see here that this is the car alone doesn’t do anything because he doesn’t recognize this is uh with the ruim up and this is the C20 car and this is our at car so we get very good results and why are we
Doing this because this is I think a little bit for the future because we can we are now very flexible to use maybe even two or three anti and targets at the same car at the same time only one car of course we are trying whether we
Get other other adapters there is still a lot of research but I think this is something we can combine you know also a little bit specific to the patient has the patient a lot of cd20 maybe you add it maybe not so much 22 maybe you use
Another panel so and the same is for AML of course the our goal is AML because we can stop we can we can treat a patient even if it’s myis goes down we just withhold the adapter the cars alone don’t do anything you can you can have
The hopis recovered and this is now what we are trying and the first clinical trials will hopefully start even in the next months uh so my conclusions are I think tumor vaccination will become I think a first pillar of cancer therapy especially for solid cancer especially those with this Fusion onco where we
Have very good time targets and effective targets I think monoclonal antibodies of course now car is all over but don’t forget the monoclonal antibodies they can be very effective I I would not uh put them uh off yet uh I think B specific antibodies are a bridge
To transplant I think uh I I would say they are induced long-term remissions because the memory is missing I think ktiss will become a standard Frontline therapy in our in in in the leukemia uh and I think it should and I think it might also replace transplant in some of
The patients if we find out I personally think if we do c cells uh in very high risk patient I would go to donor C cells because of the long persistance u and also the healthy immune system we are dealing with is the same with the neuroblastoma patients where we induce a
New immune system not not to give the patient more chemotherapy this not I idea of our H transplant patient had already just to give him a new immune system which might better control the tumor and I think of course the new car model should also be evaluated or to
Avoid Target negative relaps there’s still a lot to do and of course you are on the best track here in Stanford also to do these things and thank you for your attention you very much rert for this Beau full lecture uh I’m looking around to see if
They have there is any uh question from the from the audience uh I I I would hate to see V recovery to be honest even the post exactly in the post transplant setting that means my cars are still there and active I can deal
With a B cell deficiency this is I not I cannot deal with a progressive refractory leukemia but I think with a B cell deficiency this patient is on a four weekly immun globuline maintenance and she still needs it but I think uh so if you have to choose between you know
Huh so but but there are some patients of course who recover B cells that’s our biological Mark now but if they recover B cells you better look very closely on your mrd better NGS mrd what you see so I think this is something I I rather have the B deficiency
Robbie oh so question looking at this is what’s the relative thing very Matt’s question of the antibod vers spit question is how do you resolve in a post transplant setting which of those is the better way the antibodies versus the after after transplant yeah of course you can you can uh also is
Better we don’t know we the study is ongoing the antibody is easier because it’s a outpatient uh every two or three weeks infusion not at 24 Hour 4 week continuous infusion I think the antibody is very effective but we have to we have to wait the studies PL tumor map is also
Effective post transplant but if it’s very cumbersome to give it at the moment at least until they come up with another maybe device or subcutaneous or something and and if they are very T Cell lymphopenic early post transplant might not have enough uh t- cell to engage so that might be another antibody
Uses in Cas cells can do microage ADCC uh works partially via compliment you can also modify the antibodies to activate compliment and this is why I I’m still thinking but of course nowadays the murine antibody which we had originally from R was our best antibody we ever had because that was
The best complement mediator and we measured that in our paper which we published there we measured anail toxins c3a and c5a half an hour after the infusion these things went up and the compliment was activated and complement is very effective in killing or making holes into cancer cells but this is through
This engineering and humanizing this is all a little bit lost it also makes the pain is the compliment so there is uh but I think nowadays to go back to murine antibodies would almost be a Sak leg or something but I in my feeling they were they were still very
Effective thank you again we have a little um gift for you as a memory of this um endowed Lector ship so oh thank you that back with you and hope that will be a good memory for the future I’m sure it will thank you so much thanks everyone the proceeding program is
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