Preventing Toxicity in CAR T Cell Therapy
Kaitlyn Waters:
Hello everyone. Welcome to this podcast from Cambridge Health Tech Institute for the Protein Engineering Summit which will run from May 1st to the 5th 2017 in Boston, Massachusets. I'm Kaitlyn Waters, associate conference producer. We have with us today one of our speakers from the Preventing Toxicity in Immunotherapy Conference, Peter Emtage, PhD, senior vice president of research at Cell Design Labs. Dr. Emtage, thank you for joining us today.
Peter Emtage:
Thanks Kaitlyn and thanks to the organizers of PEG for having me onboard for this podcast. I would just like to take a minute to introduce Cell Design Labs. For those of you who may not be familiar, Cell Design Labs, we're a cell therapy company initially focused on oncology. Using our proprietary tools that, we transformed T cells by reprogramming their native cell behavior and targeting those T cells to specific indications from an oncology perspective. Essentially, we create living multi-functional therapeutic thinking machines, which we call cell bots.
Kaitlyn Waters:
At the Protein Engineering Summit this year, your talk will focus on controlling specificity and activity of adoptive cell therapies with switches. Could you give us some insight into why you're pursuing this line of research, and what problems you hope to solve?
Peter Emtage:
It's a really exciting area of therapeutic research. The ability to sculpt new classes of cellular behavior, initially for T cells to treat cancer, and then ultimately for many different diseases. Cell Design Labs has two real main technologies. One we call synNotch, which is a logic based decision making paradigm that we imbibe T cells with to maximize efficacy while minimizing safety, and our throttle switch technology, which is a small molecule controlled mechanism which allows the attending physician to dial the activity of the T cells up and down.
The company really sees the ability of having a command and control suite in this exciting are of adoptive T cell therapy as being the next gen or CARs 2.0. This allows us to really address and bring an indiscriminate technology down to a discriminating technology using either small molecule control switches or logic based decision making paradigms, which then uses combinatorial antigen sensing to bring safety, providing that T cell, for some thought, a GPS mechanism by which to hone to the microenvironment of the tumor and have a very well defined programmed response.
The opportunity to use as a standalone therapy or in combination with CAR-T, the company is taking a partnering strategy by leveraging our throttle switch with our partner Kite in hematological malignancies and having some ability internally within 2018 to bring our throttle and synNotch technologies to the forefront in clinical application and clinical programs. It provides us and potential partners with an opportunity to enhance safety while really optimizing efficacy with a rapid reversible and guided precision control suite of technologies and modules.
Kaitlyn Waters:
With more news of toxicity issues emerging in clinical trials, what is the field doing to ensure that these setbacks do not halt the progress of potentially curative medicine?
Peter Emtage:
The field is looking into alternative mechanisms, again, to really bring that indiscriminate approach down to discrimination. What you will see is when we look at indications like ALL pediatric or adult and other CD-19 positive malignancies, what accompanies that targeting [moiety 00:03:32] of the CAR is B cell aplasia. There is an on target but off tumor affect of eliminating normal tumor cells, normal B cells in the body. When we look at where the field needs to go so that we don't hold the progress of this potentially curative medicine we really need to start thinking about how we command and control these T cells to do exactly what we do from a precision based synthetic biology point of view.
Our ability for our technology for this reason really is set to increase safety through providing very highly controllable custom behaviors to the T cells. This is a paradigm that's not yet realized in the space. As I mentioned for instance, our switch technology allows for a very titratable and reversible control of T cell function, therefore controlling that immediate response from T cells to really minimize safety impacts of things like CRF or neurotoxicity while maximizing efficacy. When you think about that applicability and having that utility in a T cell from an adoptive T cell point of view, you can now start to think about extending these therapies beyond the well defined centers that they're currently practiced at into a more community based approach.
I think in addition to the throttle, if you look at technologies like synNotch, the ability to have logic based gates that are based on ands or nots or not gates, really then allows you to get that T cell to hone to a very specific location, substantially reducing the on target/off tumor toxicity seen with CD-19 and some other approaches. In addition, we can also give the T cell the ability to produce any local biologic at the site of the tumor indication.
In situations where folks have been trying to look at toxic molecules which are immunologically important such as IL-12, we can get that into a very localized environment allowing for the first time the ability of the T cell to harness that cytokine's potential in a localized environment rather than inducing systemic toxicity. Which, really then calls upon that central tenant which is needed going forward of command and control. How do I get a very indiscriminate system to a discriminate system using synthetic biology and molecular biology techniques? That's where the company is headed, and from a CAR 2.0 structure, to be able to bring that into this space going forward.
Kaitlyn Waters:
What would you say is the role of the physician in monitoring and reporting toxicities, and where is the field on developing standards for this?
Peter Emtage:
I think as we move towards a potential BLA from the players like Novartis, Kite, or Juno in the space, we will start to see an alignment on some of these paradigms as we start to understand better what some of the underlying mechanisms are. For instance, cytokine release syndrome, which is being fairly well understood now, as compared to something like neurotoxicity, which is less well described. It's going to be important that we start to apply standards to be able to understand patient triage and what we do in the space.
The reason I say it like that is because, as move beyond hematological malignancies and the lineage commitment markers like CD-19 or CD-20 or CD-22 into antigens that are more broadly distributed, understanding what the physician is seeing form an experimental point of view to a commonplace triage, a standard of therapy in late stage, is going to be instrumental in helping us to be able to streamline those guidelines on how to really use this exciting technology in the triage of patients with various hematological and solid tumor indications. We believe that the physicians play in integral role in monitoring and reporting these toxicities. As seen through the clinical studies that have been done today, have really started to set the standard by which the FDA can approve and their colleagues can actually start to now apply these technologies and be able to standardize against that toxicity and how we use these new technologies.
Our technology at CDL really plays well into that triage or into those standards because for the first time, rather than taking an unguided missile that will target everything that expresses its target of interest, we can now bring that back into the hands of the attending physician and give them the ability to control from a cell bot point of view using synthetic biology approaches to be able to really control and give you that finite specificity which is lacking in the space at this point.
Kaitlyn Waters:
What do you think are some of the biggest challenges moving forward?
Peter Emtage:
When you look at the space and you look at some of the issues that we're seeing with the first therapies, so the bulk of the therapies used mirroring SBSVs to detect CD-19, which has elicited an immunogenicity type point of view a limitation on persistence of CAR-T cells. I think, you know, moving that forward into humanized approaches where we have less specter of having the host immune response eliminate CAR-T cells thereby providing persistence and providing better tumor responses and durability are going to be important.
I think the ability to actually now engage in going beyond the lineage commitment markers like CD-19 or CD-22, into what really has been shown to be a paucity of targets which really specifically define that tumor for which you are targeting. From a hurdles point of view, from an impediment point of view, it's actually really starting to do heavy duty bio-informatics and immunohistochemistry work to start to understand what antigens allow you to target a specific indication and reduce bystander affect.
Going forward, it's all going to be centered around how we detect, how we understand antigen expression so we can build the best CAR for that indication to allow and reduce on target but off tumor affect. I think another real impediment, which is coming back now as being demonstrated clearly in the checkpoint space, is the impact of the tumor microenvironment on that CAR-positive T cell. I think if you look at where we are from a therapeutic space, there's now efforts ongoing to look at other mechanisms by which to modulate the T cell against tumor microenvironmental changes like the expression of PDL-1 engaging PD-1 on a T cell and having a negative impact.
From an impediment point of view it's going to be looking at where the system sees or where the space sees an affect of the microenvironment and how we then provide the T cell with the best armamentarium to allow it to get into a very hostile environment and function. There's ways that you can see doing that. For instance, our synNotch technology really allows you from a very localized [vocal 00:10:26] tumor microenvironment perspective, allow you to secrete a number of potential biologic modifiers from an immunological point of view that allows you to then start thinking of pairing technologies with modules to not only control T cell activity and safety, but also then address that tumor microenvironment and how best to modulate it to give that T cell a specific benefit in that microenvironment in that hostile environment. I think that's some of the biggest impediments, but that's where the technology has actually taken us in this space.
Just to wrap up here a little bit, one of the things that we are very excited about is that the space is evolving. We see programs that will end up at the FDA and a BLA for approval in a space using a technology which has really changed patient perspective in relapse refractory CD-19, especially pediatric and adult ALL. It's really a good time for those individuals and their families. I think going forward we still need to look towards creating customized molecular sensing systems for our immune cells.
CDL's technology is well positioned to improve safety by minimizing things like cytokine release syndrome and other neurotoxicities, to be leveraging the ability to mount a highly controlled by rapid and powerful anti-tumor response by endowing the T cell with that safety control mechanism, but also modules that allows it to persist and have a biological impact in a very hostile environment. We can do that by delivering customized payloads to local therapeutic affect, and at the end of the day, creating a long-lived anti-tumor response. I'd like to thank you and PEG for your time and interest, and I'm looking forward to having a number of very engaging discussions at the conference.
Kaitlyn Waters:
Thank you, Dr. Emtage. We're looking forward to your talk as well.
Peter Emtage:
Thank you.
Kaitlyn Waters:
That was Peter Emtage, PhD, senior vice president of research at Cell Design Lab. He'll be speaking at the Preventing Toxicity in Immunotherapy Conference at the upcoming Protein Engineering Summit, which runs from May 1st to the 5th 2017 in Boston, Massachusetts. If you'd like to hear him in person, go to www.pegsummit.com for registration information and enter the key code podcast. I'm Kaitlyn Waters, thank you for listening.