Brown: T-cell fitness, persistence, and expansion are key to the success of CAR T-cell therapy. We wanted to explore the possibility of using this platform not only to extend antigen recognition or address tumor heterogeneity, but also to control persistence and expansion.
As a first test, we tested a meditope peptide–IL-15 construct in this paper. We showed that this biologic, this adapter, could regulate the expansion of CAR T cells both in vitro and, importantly, in vivo.
We showed that there was a dose-dependent response to the IL-15 fused to the meditope peptide.
We believe this could be a strategy to fine-tune the expansion of these cells after adoptive transfer. I think that could have important implications when T-cell persistence is limited and you want to expand and reexpand the function of those cells.
Again, these are mouse models, but we think the proof of concept is there. Now we are building this out further and looking not only to regulate persistence by itself, but maybe to combine that with extending antigen recognition.
Williams: Just to go one step further, this is really exciting. As Christine knows, and I think the field knows, there are a lot of other cytokines and other stimulatory molecules we may want to deliver.
The meditope–IL-15 construct gives really nice proof of concept and showed some really nice results. But you can imagine a plethora of different kinds of cytokines or other things that you would like to take to the T cell that could change its fitness or its particular state.
There is a lot to do here. These are exciting times.
Pharmacy Times: What control could clinicians have over the activity of these cells through the dosing or withdrawal of meditope-linked agents, and what safety questions must be resolved when targeting antigens also found on healthy tissue?
Brown: I will let John start with the biologic because it is something we have thought a lot about. In his thinking and design of these biologics, he has thought a lot about this.
Williams: One of the problems with hardwired CAR T cells is that you put them into the patient and they go, right? You have only so much control once they get going.
Generally, because of exhaustion and tumor heterogeneity, they start petering out. Christine is much better at answering this, but keeping them going for a long time is one of the enduring questions about persistence.
With redirection, on the other hand, if we can use a meditope to redirect them to another target, that is something we can inject into a patient. It is also going to have pharmacological properties: how long it will stay, how tightly it will bind to the particular target, and how long it will persist.
In general, the biologic could come in and bind for a very long time, or it may bind temporarily and then be excreted because of its size.
Those are properties we are going to have to play around with, but they are also really nice properties because, in some cases, if we start seeing something going awry, we can just stop dosing. We can stop adding that biologic.
The flip side is that we could also use that meditope site potentially to put in a kill switch or to do other things to those CAR T cells.
Finally, we can also use the site to potentially image those cells. This gives the clinician some new tools, including the ability to redirect them and change some properties.
Maybe you want a hard assault on one of these tumor types. Maybe it is going to be too toxic to continuously dose, but you want to hit it hard for a day or two. A meditope-linked antibody can be given. It will have a limited duration, and the response goes away.
Or maybe we want to see how long the CAR T cells stay there. Are they still where we think they are? The ability to see that in a patient in real time is a new feature and something I think would be very powerful.
Again, we have a lot of work to do.
Brown: Just to reiterate what John said, we see dosing this adapter molecule as an inherent safety mechanism. We can control dosing to control this redirected function.
There are contexts where we might want that to be a very limited window, and there are other contexts where we would want to extend it.
You could use this for expanding the cells with a meditope peptide–cytokine construct, as we showed in the manuscript, or extending antigen recognition, which we also showed in the manuscript.
We are also working on other iterations of the therapy to potentially image these cells after adoptive transfer. That would be a very distinct time point over the course of therapy when the clinician might want to understand where these cells are.
It could also be used as a safety switch. Again, that could be a very defined time point when you would administer that biologic.
Pharmacy Times: As you advance toward clinical trials in solid tumors and AML, what is the current development status, and what early findings would demonstrate that the platform is ready for broader investigation?
Brown: This is the exciting area. When John and I first discussed and thought about moving this toward cell therapy, this is where we wanted to be: bringing it to patients.
This year, we are actively working on our IND-enabling studies to move this platform to patients in 2 different settings, which is hugely exciting: both solid tumors and AML.
We are thrilled about the initial clinical data we will get for this platform.
What we are going to start with is understanding the meditope-enabled CAR by itself and understanding the feasibility, safety, and maximum tolerated dose of the CAR-engineered product.
As we build out adapters, we would then use later-stage trials to redirect the cells.
Williams: We are really lucky here at City of Hope, in large part because of Christine and her team pioneering and pushing CAR T-cell therapies. I think City of Hope is, if not at the top, very, very high up in our ability to do this.
The fact that we have all this infrastructure, largely built through Christine and her team, will allow us to get these into patients really quickly. It will give us signals.
One of the beautiful things that Christine and I both benefit from here at City of Hope is this close relationship with clinicians. We are going to start getting clues and ideas from clinicians about where this is working, where we could do something, and where there is a unique opportunity for us to tackle a problem.
Maybe it is persistence, or maybe it is the imaging part. Our ability to work with clinicians will allow us to move into those areas really quickly.
Pharmacy Times: From an oncology pharmacy perspective, how could a treatment combining engineered T cells with separately administered targeting agents change dosing coordination and toxicity monitoring, and where would pharmacist involvement be most valuable?
Brown: Thinking from a clinical perspective and a pharmacy perspective, we work with cellular therapy pharmacists for the delivery of these CAR T-cell products. Now we will also be working with pharmacists to deliver the appropriate doses of these biologics based on monitoring the patient.
We are at the earlier stages, but pharmacists are going to have to be intimately involved in developing and helping deliver these therapies and helping us dose them correctly.
I think it is the collaboration and interaction that make these therapies happen: working with our clinicians, our pharmacists, and the other clinical staff.
Williams: Again, I think this is a uniquely good place to be doing this at City of Hope. The pharmacology is going to be really important. We have very good pharmacologists here.
Monitoring the PK, monitoring other responses, and even developing all the ELISAs and other assays will help us determine the dosing regimen. Are we hitting the target hard enough? Then we have this broad patient population to be able to get those numbers.
For us, it is great as a protein engineer to be able to develop something. It is great as a protein engineer to be able to work with somebody like Christine Brown, who has the cellular therapies. It is great to have people like Guido Marcucci or Steve Forman, who are the clinicians here.
But we also have that whole pharmacology component. This is one of the advantages of being at a place like City of Hope, a comprehensive cancer center. This is what it is for, right? We have that expertise across pharmacology.
The pharmacists will be absolutely essential in that next phase as the treatment moves forward.
Pharmacy Times: Is there any additional information you would like to share?
Williams: I do not really. Christine?
Brown: Just that we are excited to bring this to the next stage and understand how these cells and their ability to be reprogrammed with these adapters work in patients. I think we are close to that, so it is an exciting time.
Williams: I think it is fair to say, Christine, that we will probably have 2 different products in patients early next year or mid-next year.
Brown: That is our goal. It is a near-term goal.
