Greetings and welcome to EHA Unplugged, the official podcast channel of the European Hematology Association, EHA. Welcome to EHA Unplugged, the official podcast channel of the European Hematology Association. My name is Sarah DeFdcher and I'm the head of education at EHA. I'm here today with Sarah Tete Manti. Sarah, could you please introduce
yourself. Yes, hello everybody, I'm Sarah Tete Manti and I work in Montser at Fundats and Tete Manti Research Center in Italy and we are interested in immunotherapy strategies for ectubule chemi. Your research focuses on how to use the immune system to fight AML. We're here at the CAR T meeting in Valencia. Are we any further in that regard getting CAR T cells to work in AML? Yes, it is a really challenging field because
CAR T cells have achieved a really good success for bee ectubule chemi. While for AML we are still in an infant phase, I would say because we are trying to move from the experimental clinical phases to the approved commercial products but we still need to be good in balancing the
efficacy profile and the safety profile of this product. AML is another a really different disease as compared to BALL and so we are like learning a lot from the clinic to go back to the lab and try to improve our CAR T cells because we know that we need to improve them in order to make them more persistent and more efficient but at the same time to be safe
because of course we have some challenges and limitations in AML. We know from the biology of the cells of the tumor microenvironment that we have to deal with these immune-suppressive tumor microenvironment we have to deal with the blasts, the AML blasts are so really able to try to make T cells dysfunctional and also we do need to care about the selection of the antigen because for AML we do not have a proper specific leukemia specific antigen.
So in my career I had to deal with the balance between being efficient by the same time being safe because we are sharing these antigen also with the normal counterpart and the side effects could be really detrimental in our case. For the BALL you have B cell applaia, you can cope with the immunoglobulin infusions but with AML of course you could have myelotoxicity and this would be detrimental for patients. So this is the balance that we needed to think
about and to envisage more smarter cartisels. So actually we the cartisels filled as developed a lot so we started from first generation cartisels, then second, third and now fourth generation cartisels. I would say that this is the future. So try to combine the targeting of the
leukemic cells but also try to target also the tumor microenvironment. So to be able to make cartisels to eliminate the cells and to be able to make their activity inside the body and another issue is trying to make these cells working and also probably we need also to combine the cartisels with other immunotherapeutic strategies such as checkpoint inhibitors in AML. They are not so successful because they are studies with antipid 1, anticetyl-4 but they are not so successful at the moment.
Antitien 3 is kind of emerging. Etien 3 is an immune checkpoint. We are also interested in because it is also overspressed by leukemic stem cells. So you can use both for the targeting of leukemia stem cells and also to immune modulate the tumor microenvironment. So this is a really interesting target. And yeah so checkpoint inhibitors we are a little bit moving fast also in this field and the combination of all these strategies could be something interesting.
And also I would say cartisels are living drugs and they act at the surface. So they target a surface antigen but we know a lot about the molecular therapy. So probably also we can play with the surface target with cartisels and also molecular targeting with you know these small drugs that we now know that they are really specific for some altered pathways that are in the inside of the cell. So I would say that this can be something that we
can think about in the future. Which of these strategies do you have the most hope for? Around this combination because in my opinion if we are I would like to avoid the high chemotherapy to patients. So I would like to really pursue the targeted therapies meaning
cartisels, monoclonal antibodies, bi-specifix and molecular targeting drugs. So in the future my dream is to have like a protocol in which you can really make low regimen chemotherapy and to make patients you know being healthier in the path during the disease treatment. And also the cartisels of course if they have good balance with safety and efficacy can
be something interesting. And also nowadays we know that for example cartisels are used as a bridge maybe to other therapies but at least you know that in that treatment if you are safer than compared to chemotherapy the patient is healthier. So it can continue his disease treatment in another way. So the quality of your path
I think it matters and immunotherapy can also help in this way. Of course we all hope to cure the disease and to treat all the diseases but at least also offering a good quality of life during the treatment of patients is it matters. How far do you think we are off this sort of ideal in the clinic?
I do see that we really did a lot in the last decade because if I think about me 10 years ago I was during my PhD and cartisels were only something that you know really high good biologists were like studying and then in 2012 of course we had this breakthrough of these cartisels in the clinic and we started to really think about this option that could be a really valid option. So in a decade of course everything happened and cartisels were
also useful, started to be useful also for AML or for solid tumors. So I think that we are really making the difference in the treatment. Immunotherapy is one another arm of the advanced medicine and we still need to understand a lot especially in the solid tumor context and in this kind of immune suppressivity disease also in the context of hematology or hematology
like AML or CLL for example is another tough disease to treat with carti. I mean we don't have the same rates of CRS compared to the BALL even with the classical CID in the 19 cartisels. So I think that we are in a moment in which we are really learning a lot from the trials and we also have the technologies to understand what happens inside our body and also inside our experimental setup. I mean we started doing basic cytotoxicity essays.
I remember you my PhD I was using from you essays to see the cytotoxic activity and now we have real-time devices that can measure how the cells are making the anti tumor activity. You can follow them for weeks and months and you can image them. We can go inside the cells. We can study the single cell RNA and what happens and also from the patient. So
immunomonetoring and taking the cells out and understand them in a better way. So I think we have the right tool to make another step and to put a step forward in the treatment of tumor. We've primarily been talking about cartisels. Is there any role for any of the other cartisels, natural killer cells, for example, with an AML? Yes, right. I mean as maybe you heard by my talk, from my talk I do, we do use these
effectors that are called cytokine induced killer cells. They are of T lymphocytes but we know that they have some functional properties related also to the NK part and K cells are really good especially for AML in clinical trials. Only using NK cells, there was a really
good success result. I think that NK cells are really useful. Of course, they are safe and you can redirect them with a car and in the AML I'm really curious to know about the upcoming trial that will start in this sense in the next future.
Yes, so also playing with the effectors is another important aspect. So we know about gamma delta T cells, classical T cells, our CAK and natural killer cells of course because if you think about the car, okay it is an artificial receptor that helps you to be more specific and to what at the end you are using a T cell so you know that you need also a fit T cell. So the effectors are a good point but also their fitness. So autologous source versus
anogenic source, this is another important point especially in AML. The first wave of clinical trials in AML were all made from autologous source and now we know from the biology of the disease that these cells have already seen the AML cells and so they are already dysfunctional. So that's why we had this low persistence of the first clinical trials
with AML. I mean this is my opinion I think that also using autologous source it's okay, it's safe, it's something that of course we had to try but now we probably need to move to more of each cells as well. Okay, so I mean there's a lot of discussion about moving car therapy towards an off-the-shelf product. Do you think that that could ever be a reality? So okay we are working on that. We are trying to derive carcicase from the core blood source and I think this
is a useful way to derive aloe carcicase cells. In our case we are not thinking about removing the PCR because we have already data that CAK cells are kind of safe in terms of GVHD. We have to know if they will persist in a aloe setting or upload setting. This is something that we are going to investigate in the next future but still I think that the off-the-shelf is a really good option
because of course we are dealing with highly proliferative disease. So I mean sometimes you don't have the time to treat the patients so you need something that is ready, ready to use and I think it is a useful source also the core blood or other sources to make a low of the shelf. I think about elderly patients for example in AML they maybe they are not fit for the
transplant and so the core blood can be a third-party source to make the off-the-shelf. So these are all the thoughts that we have in mind thinking about off-the-shelf in a AML particularly in AML and also this is an really aggressive disease so we need a source to be used immediately and also you know you can also organize the production by making some banking and then you have the time to do the matching and then you have the cells ready to go into the patients so yes.
Sounds like there's a lot of exciting things happening in AML. Yes. Is there anything else that we haven't discussed today that you'd like to mention or? I probably we can discuss about the clinical trial design. I think that we need really to think about how to design the clinical studies and also another topic that we didn't discuss about is the affordability of these therapies.
So in our place we are using non-viral system it's one log less the price of using non-viral versus spiral and also in our case we can treat HIV positive patients in potentially because we don't have the problem. I mean we are using non-viral cathedrals and so for example in the upcoming trial for non-achieving former patients we will enroll also HIV patients and for the low-income countries and we know that there are lots of HIV patients and so this can be something
that in the future can make can help in making cathedrals more affordable more accessible. So this is another important point that we have to think about maybe not only the viral but only maybe streamlining the process the manufacturing process. If you do the cells in two days is different the price if you do the cells in two weeks okay. So shortening the culture will be it seems to be good also for the T cells but also from the cost point of view probably.
So this is something that we have to take in mind also from the clinical point of view. Fantastic thank you so much for the insightful conversation. Thank you and thank you for being here and thank you to our listeners to tuning into this episode of the HA Unplugged.