Latest / EHA Unplugged / Off-the-shelf CAR T-cells from iPSCs (with Prof Maria Themeli)

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Off-the-shelf CAR T-cells from iPSCs (with Prof Maria Themeli) · EHA Unplugged

• 0:04
  Greetings and welcome to EHA Unplugged, the official podcast
• 0:08
  channel of the European Hematology Association EHA.
• 0:12
  Hello, I am Isabella Rivera, a medical writer at the European
• 0:17
  Hematology Association EHA. Welcome to this podcast on the
• 0:21
  successes and challenges of generating allogeneic CAR T
• 0:25
  cells from IPC cells. Today I have the pleasure to be
• 0:31
  joined by Professor Maria Tameli.
• 0:34
  Welcome. Thank you.
• 0:36
  Thank you for inviting me. Could you please start by
• 0:39
  introducing yourself to the audience?
• 0:42
  Yes. My name is Maria Tameli and I am
• 0:45
  Assistant Professor in the Department of Hematology in
• 0:49
  Amsterdam University Medical Centers.
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  I'm group leader there and my focus of research is the the
• 0:57
  design of new chimeric antine receptors and new methods for,
• 1:03
  yeah, improving the safety and efficacy of cartes cells and
• 1:07
  accessibility. So a very big part of my work is
• 1:10
  based on generating cartesos from alternative sources such as
• 1:16
  induced repos and stem cells. So you do more research than
• 1:20
  seeing patients? Or do you do?
• 1:21
  Yes, I do more research although my background is medical so I
• 1:25
  have studied medicine originally but I never practice.
• 1:29
  I switched immediately to science and and research.
• 1:33
  Yes. So in this episode, we'll
• 1:36
  explore the latest progress in making off the shelf Carti cells
• 1:41
  a clinical reality. To start things off, could you
• 1:45
  please explain what are off the shelf Carty cells and how could
• 1:50
  they solve the challenges of existing autologous therapies?
• 1:55
  To begin with, when we say the off the shelf and this is this
• 2:02
  expression, we mean that we would like to make Carty cells,
• 2:07
  this living drug the same as other drugs that they're based
• 2:15
  on like antibiotics or biologicals that you can just
• 2:22
  prescribe and take from the pharmacy.
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  So that that's what we mean that they are available immediately
• 2:30
  upon prescription from the doctor.
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  This is not the case right now for cartesos.
• 2:36
  The cartesos need to be manufactured from the cells that
• 2:41
  are isolated from the patients. This means that there is a whole
• 2:44
  process that needs to be initiated.
• 2:48
  After taking the cells from the patient, the cells go to a
• 2:51
  manufacturing facility. There they go through a specific
• 2:55
  process and they are released to return and be infused to the
• 3:00
  patient. So this this is a process that
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  takes time. We strive to make this as short
• 3:08
  as possible, but in there still patients that cannot receive the
• 3:13
  product that has been made for them because the disease has
• 3:16
  progressed so fast that there was no time.
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  So they took long for the manufacturing.
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  Other reasons are that the sales that are coming from patient, of
• 3:29
  course they're not not the same for every patient.
• 3:34
  So every product is different because it is affected by the
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  previous therapies that the patient has received, the type
• 3:40
  of disease that the patient has and or the the tumor load at the
• 3:45
  time of leukophoresis. All these can affect the quality
• 3:50
  of the the cartesal product and subsequently the clinical
• 3:54
  response. So we would like to have a
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  uniform product like like with biologicals that you would to
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  predict more or less what would be its function and it would
• 4:07
  more uniform across the patients.
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  So which types of cells are being explored as potential
• 4:20
  cells for allogeneic Carty therapy?
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  There are several clinical trials that have been initiated
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  using allogeneic healthy donors. The idea behind this is that
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  when you have a younger and healthy T cell, it would have
• 4:37
  much more functional fitness and indeed this is what we see also
• 4:44
  in the lab in vitro. The problem starts when you have
• 4:51
  to apply this allogenic T cell therapy.
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  Because these cells need to be changed, we have to edit them
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  otherwise they will be rejected from the recipient or you.
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  You have to have estocompatibility otherwise
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  these cells will be rejected. So we are trying to generate
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  modifications in the cells so that they are not going to be
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  rejected. Another thing that we need to
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  take care of is that the cells are not going to attack the
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  recipient, what we called graph versus host reaction.
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  So they need to be edited so that they will not recognise the
• 5:33
  host, the recipient as a foreign.
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  So all this editing process is an extra step in the
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  manufacturing and and it's not perfect.
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  The allogeneic cartesal products after manufacturing they, they
• 5:53
  still don't have the same functionality as, as autologous
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  just because we cannot really perfectionise with all this
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  editing the immunotherapeutic properties that we need to have.
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  So there's still have limited persistence within the the
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  patient's circulation because even though we do some editing,
• 6:26
  they, they will still be rejected.
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  So this is the the areas of improvement and this is where
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  the IPC derived cells as an alternative source comes to
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  potentially resolve some of this because so there are.
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  Allogenic cells that could come from a donor.
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  Yes. That is compatible, but that's
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  very hard to find somebody that is compatible.
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  So you're trying to make cells that would be some kind of
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  universal, so compatible with many people, if not everybody,
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  by removing the reaction to. HLA exactly.
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  So we have to remove the T cell receptor from the cells so that
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  the T cells will not recognize the the recipient and we will
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  not have graft versus host reactions.
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  And we have to remove the expression of HLA molecules from
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  the cell so, so that they are not going to be rejected from
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  the immune system of the recipient.
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  So these things have to both happen Until now clinical trials
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  with allergenic cartesos, they added the TCL receptor because
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  this is this is the most important, but still the editing
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  that aims into prevent a rejection is not optimal.
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  So these patients we try to lympho deplete, so reduce their
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  immune system so that we can expand the lifespan of these
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  allergenic cells within the system of the patient.
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  And but that's, that's not the optimal way.
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  They will still be rejected so that their persistence is
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  shorter than the autologous and we know cardesils and we know
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  that persistence is very important for the clinical
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  efficacy, so. So you have been working for a
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  very long time using induced puripotin stem cells, so IPSC
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  cells. Why use IPS cells?
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  So first of all, induced puripotin stem cells, they can
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  be cultured unlimitedly. So it's an unlimited source.
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  So this is one of the benefits. So we will not need to have
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  donors or search for donors all the time.
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  A second is that Ibcs can be because they can be cultured
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  unlimitedly. You can generate and, and
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  introduce any genetic modification and, and with every
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  modification, you, you generate clonal populations that have a
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  specific, the specific change and you can test them for any
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  gene toxicity or, and, and this can happen once.
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  So it's not like you generate, you do the editing and the, and
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  the engineering in a bulk population of patient cells.
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  And then you have to test this bulk population and every time
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  that we are doing this new production, every time it needs
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  to be tested. So theoretically in Ipcs you can
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  you do it and you do it once and and you can do multiple edit,
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  multiple engineering rounds, which is not possible in a
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  primary T cell setting. So this is the second benefit of
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  IPS CS and when we're moving towards improving CAR T cell
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  products and talking about multiple changes, multi
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  engineering, multiple receptors, mutations, new transcription
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  factors or cytokines that can be secreted and going into
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  modification of the tumour microenvironment that will be
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  needed in solid tumours so that cartesos can be effective.
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  This multi engineering is very, yeah, it's limited in the
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  primary cartesos setting, primary cartesos setting patient
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  derived or healthy donor derived.
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  So this is 1/3 yeah. Benefits.
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  Advantage of having IPCS as a source.
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  But so to make IPCS you need to 1st also have a donor cell, you
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  have to turn it into an IPC cell and then you have to
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  differentiate it again as AT cell and you have to put a CAR
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  at some point to also How? Do you?
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  Work through all these steps to get a final cell that really
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  could go into a patient. It's a long process.
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  It is a long process. The first step is to find a
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  donor, and that would be theoretically it's one donor and
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  we have to find. We're still investigating what
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  is the best donor, but not only the best donor, but the best
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  donor cell. Is it better to have a
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  haematopoietic cell as a as a initial parental cell or any
• 12:03
  other type of cell could could do the same job as efficiently?
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  We tend to think and our experimental data show that if
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  we want to go to T cells it's probably better to have as a
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  initial cell a haematopoietic cell or better at diesel.
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  So that's the first then selection of a donor.
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  You know the informed consent of the donor has to comply and the
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  donor has to be to agree that his or her cells will you know
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  will be used for therapeutic purposes etcetera.
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  So that is also an ethical point of view important.
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  And then you have to make this IPC line from the cells using,
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  you know, GMP grade materials under GMP conditions and
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  generate AGMP grade line. That's also, you know, it costs
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  a lot of course. And but when you have this GMP
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  grade line then this line will be modified.
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  Can be modified for different with different cars.
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  You can put any other modifications that are needed.
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  It's. Like removing the HLA or?
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  Exactly, exactly. And then you the, the purpose is
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  to make this what we call the master sell banks.
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  So master sell banks of this Ipcs, the modified Ipcs and when
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  when there are differentiation protocols, we and others are
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  working on making these protocols for differentiation
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  more efficient, scalable, expandable that that it's not
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  only a protocol that you can use in a specific centre, but it can
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  be used easily transferable. So this is what we're working on
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  in in bioreactors. This process can lead to, you
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  know, the production of multiple doses of CAR T cells at the
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  moment, for example, at least at research level, we are able from
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  one IBC to generate thousands of T cells.
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  So imagine if we go higher in scale right then from from a few
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  Ipcs that we can make a lot of Cartisol doses.
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  So that's the idea of in the end reducing, reducing the cost, so
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  depreciating actually the cost of generating all these cell
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  lines by the fact that they will be available for more patients,
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  yes, because. You produce them once.
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  Exactly. For many patients.
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  So which steps are more challenging at the moment?
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  Yeah. There are many things that still
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  are not optimal because first attempt, first clinical trial
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  with CARTES cells from IBSCS has been done.
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  And it's very important that it has been done because it has
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  shown that this type of cells are safe.
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  They have function, they are functional, they had antitumor
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  responses. But there are many steps that we
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  need to do in order to improve the IPS derived T cells.
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  And that's because our in vitro differentiation and
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  manufacturing processes are, are still not optimal to get us to
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  the same developmental maturity that is needed in order to, to
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  have the full memory and proliferative function of of T
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  cells. There are still now there are
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  efforts to generate both lineages, sub lineages of T of T
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  cells CD4 and CD8, but also T regs for let's say if we go to
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  autoimmune diseases. So until now the generation of
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  CD4 cells was not possible with the protocols that we were
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  applying. Nowadays there are new studies
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  showing that it is it is possible to generate CD4 cells.
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  We still need to find out what is the functionality of of these
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  cells, but it is, it is critical that we make mature cells with
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  memory properties and that we have both CD4 and CD eights.
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  We know from from carteso studies that those two
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  subpopulations they need each other, right.
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  So having ACD force to help the CD eights is, is important.
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  So these are yeah specific aims that we have in order to improve
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  IPC derived cartesos. And then is the manufacturing,
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  as I said, we have to generate protocols that are scalable.
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  We have to have feeder free, Xeno free methods that can be,
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  you know, applied at the GMP grade, Yeah.
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  Yeah, so that there can these products can be applied to
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  human. Yeah, exactly.
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  Yeah, Yeah, there are, there is a clinical trial and at the
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  moment it's using feeder cells still this is possible, but you
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  have to this feeder cells need to be GMP approved.
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  So they have to become GMP. Great.
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  That's a step that is, yeah, it takes time and it is and it's
• 18:22
  not transferable, right. So it's not that in every place.
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  AGMP yeah, feeder line which is from nurine origin, right.
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  So, so it's not easy to be done if there are protocols that are
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  free from the use of feeders and can be, you know, dependent on
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  just combinant proteins that we can use or media and chemicals
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  that that would make it much easier to apply.
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  So also there could be a risk of contaminated undifferentiated
• 19:08
  IPS cells. Now, how do you minimise this
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  risk? So in in the T cell
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  differentiation process, that risk is very, very low because
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  the steps that this process takes, there are very, there are
• 19:29
  many intermediate steps. So in order to go from IPC to AT
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  cell first you need to make hematopoietic progenitors, CD34
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  positive hematopoietic progenitors.
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  And at this stage we can select those cells and purify them.
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  So there's a first purification step, and after that step those
• 19:56
  cells are being put into the. T cell differentiation part of
• 20:02
  the of the protocol and most of the times the during this
• 20:07
  process, the cells either become the T cells that we want or they
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  die. We have never seen any other
• 20:15
  type of cell in this product. But yeah, these things if you go
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  of course, if you go into at GMP clinical grade manufacturing,
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  the product needs to be of course characterized and
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  eliminate any trace of previous non differentiated cell.
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  So you mentioned there was, there has been one clinical
• 20:44
  trial with IPS cells, only one. With T cells, Faith Therapeutics
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  has done also clinical trials with IPC drive NK cells and
• 20:55
  there's one study that was with IPC derived T cells.
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  And right now there is another open study with the same product
• 21:05
  against autoimmune diseases. So this is the the second let's
• 21:13
  say trial with IPC derived cells, T cells.
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  And so the results are already available.
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  Of the first yes, yes, there there was some reports from the.
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  How close are these kind of sales them for being able for
• 21:36
  being used for clinical purposes is?
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  As I said, the the results in terms of efficacy is it was not
• 21:46
  so good as a autologous product. And we know that for the T
• 21:53
  cells, Ibis derived CAR T cells, we still need, they still need
• 21:59
  to be improved for their for reaching the same efficacy as
• 22:05
  primary CAR T cells, so. Do you think that at some point
• 22:14
  you will have this universal Carty cells that will replace
• 22:18
  the autologous or will they be a compliment?
• 22:21
  And this is also the same the same question from for also in
• 22:28
  vivo cartesos. So in vivo cartesos and off the
• 22:31
  cell cartesos are the 2 strategies to overcome the
• 22:39
  accessibility issues for cartesos and also the you know
• 22:44
  the fast need. So if they will take over for
• 22:53
  the moment, I don't think so. For the moment, I think that
• 22:56
  they there is space for the cases where you have really
• 23:03
  rapid progression. So this is the time where you
• 23:06
  you need a fast, fast to have access to a CARTISO product when
• 23:15
  and we find that we will have a superior efficacy by engineering
• 23:25
  because multi engineering probably will give us the
• 23:28
  opportunity to have a superior efficacy.
• 23:31
  We I hope in the future when we when we reach that place and for
• 23:38
  specific two more contexts maybe there we would think that they
• 23:45
  are preferable to have this, you know, IPC derived products, but
• 23:50
  that only the future will show like what would be the the
• 23:53
  advances in the field. You need comparable efficacy at
• 23:57
  least and lower cost. Exactly.
• 24:00
  Exactly. Yes, but you're that's what
• 24:03
  you're aiming for in in any case.
• 24:05
  Yes, yes, yes. So we are at the Carty meeting
• 24:14
  in Strasbourg in 2025. Have what new developments got
• 24:21
  your attention specifically? Yeah.
• 24:25
  We had today a very nice session which was dedicated to the very
• 24:36
  innovations in cartesal therapy involving genome editing, I
• 24:43
  think and in vivo diesel generation, cartesal generation.
• 24:50
  I, I think this is a rapidly developing field and which is
• 25:00
  sparkled by the need for, you know, access and reduce cost.
• 25:06
  I think this is the major driving force at this moment.
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  And we saw very nice presentations of how we can use
• 25:17
  genome editing to identify ways to improve CAR T cell function,
• 25:25
  but also to, you know, to, to generate in vivo CAR T cells.
• 25:33
  So I, I found at least today I was, I found this, this session
• 25:37
  very inspiring. But I also find very inspiring
• 25:44
  the fact that in, in our meeting we will have, I see a lot of new
• 25:50
  clinical trials initiated also in Europe.
• 25:56
  And I think this is very encouraging that we are you know
• 26:06
  starting to try and and invest in human trials, new next
• 26:16
  generation Cartisol products. And yeah, I think we have to
• 26:22
  find a way that we will increase that the opportunity to try and
• 26:27
  have more clinical trials because there are very there are
• 26:30
  many researchers that are reporting improved improvements
• 26:36
  in Cartisol engineering and this have difficulty to find their
• 26:43
  way towards a clinical translation.
• 26:46
  Yes, and also so cortisol therapy started in hematological
• 26:53
  melancholis, but now it has spread to other kinds of
• 26:57
  indications beyond oncology. So I guess this is also the
• 27:03
  reason why you have so many clinical trials going on.
• 27:06
  It's it's really exploding as a technique to treat different
• 27:11
  diseases. With the this expansion of of
• 27:16
  Cartesian therapy is increasing also the the need right for
• 27:20
  manufacturing. So there is a one more reason of
• 27:29
  the self sources can serve here because the demand sorry for
• 27:37
  carteso therapy will will be increasing the next years.
• 27:41
  So and I don't know if you know centralised manufacturing or you
• 27:45
  know this type of manufacturing processes of from autologous
• 27:51
  based products would be sufficient for the such a high
• 27:58
  demand. Thank you very much Professor
• 28:01
  Maria Temeli for this insightful conversation and for sharing
• 28:05
  your valuable insights with with us.
• 28:10
  Thank you to all of you for listening and stay tuned for our
• 28:13
  next episodes.