Julian Molina:
I’m Julian Molina, I’m an oncologist. I’m a thoracic oncologist from the Mayo Clinic, and we had our first morning discussion about the future of CAR-Ts for solid tumors. We’re very pleased to see that iwCAR-T now is dedicating a whole day for solid tumors. This is important because the number of clinical trials is growing, pretty much exponentially. I think there is a future for CAR T-cells in solid tumors, but this future is compromised by what we’re seeing from some of the early clinical trials, where safety is impacted, and we’re not seeing the best results as far as response rates or impact on overall survival for the clinical trials. So today, we have two presenters from this morning and they have very clever approaches to the design of these CAR T-cells, and I’m going to start first with Daniel and see if you can give us an introduction to your work.

Daniel Abate-Daga:
Thank you. I’m Daniel Abate Daga from Moffitt Cancer Center, and today I presented our efforts in the preclinical development of CAR T-cell approaches that use gamma 9 delta 2 T-cells as a platform for expression of those CARs.

Julian Molina:
Dr. Wang?

Daniel Wang:
I’m Daniel Wang from City of Hope, and today I present my study using 3D organoid co-culture system to generate iPSC-derived CAR-T, and potentially this platform will be used to do an off-the-shelf CAR T-cell product.

Julian Molina:
Yeah. And Daniel, I’m going to ask you a question that you were asked a few minutes ago and is why using biphosphonate, why using zoledronic acid to activate a CAR T-cell, what is the rationale? How do you expect this to increase the activity of your CAR T-cells or even to minimize toxicity?

Daniel Abate-Daga:
Yes, the rationale for the approach is that we may engage multiple mechanisms for tumor recognition by the T-cells, and that way we can maximize the cytotoxic effect and minimize the risk for tumor escape due to loss of the target antigen. Zoledronate, in particular, was selected because of the natural biology of this gamma delta T-cell subset, which can be activated through a series of events that are triggered by the accumulation of phospho-antigens induced by zoledronate in the tumor cell. We expect that by using this subset of T-cells that are very potent killers, but they produce lower amounts of cytokines compared to the alpha beta T-cells. We may minimize undesired toxicities and have a more targeted killing of the tumor cells. And hopefully, we might be able to increase the efficacy by supercharging the T-cells with this dual receptor targeting approach.

Julian Molina:
Very good. Thank you. Dr. Wang, same question for you. What in your approach do you see as a way to increase responses to the treatment with CAR T-cells and minimizing toxicities?

Daniel Wang:
So actually, there’s unmet need in the current CAR-T therapeutics to improve efficacy and also reduce side effects. People want to engineer the CAR T-cells, but however, primary T-cells are difficult to engineer and it is difficult to get homogeneous gene edited CAR T-cells, but for iPSCs as a source, it is easy to be engineered and gene edit to make a very consistent and homogeneous population of CAR-Ts that actually, I believe, will be used to improve the consistency, quality of CA T-cells and make it serve as off-the-shelf CAR-T products.

Julian Molina:
And they’re easier to engineer because they’re more abundant or because it’s easier to actually manipulate the cell?

Daniel Wang:
It’s because iPSC is a very unique cell type. It can be proliferated unlimitedly however, can keep the fully potential to differentiate into different cell type include T-cells.

Julian Molina:
Okay. Daniel, I have a question, and it’s, did you envision that you can do more than one treatment? We usually think of CAR T-cells that you get one treatment and then you’re done, and nowadays I’m rethinking about, for some patients actually doing tandem treatments and things like that. Do you think that this is a possibility for your approach?

Daniel Abate-Daga:
I think it’s feasible. We have not explored that in detail yet, but this certainly we may achieve an improved effect by multi-dosing the same combination of gamma-delta CAR T-cells and zoledronate, or we can think of other combinations. And I would think that we need to understand the biology underlying these processes in order to define what combination is going to be most likely to succeed.

Julian Molina:
Now, if these cells are going to stay, let’s say, in the bone or in the tissues for an extended period of time, we still don’t know for how long, do you also think that it’s possible to just give multiple doses of zoledronic acid to try to keep on stimulating them?

Daniel Abate-Daga:
That’s the expectation, yes. We think that if we can achieve long-term persistence of the T-cells, we might be able to pulse the administration of zoledronic acid in order to bring them back to the activated state, even if they may acquire a more dormant or less activated phenotype over time.

Julian Molina:
Very good. And Dr. Wang, pretty much the same question for you. Do you foresee your treatment as something that you can give multiple times, or do you think that this is a treatment that is given once and then there’s no weight or room for doing additional infusions of your iPSC CAR cells?

Daniel Wang:
So the purpose of the iPSC CAR-T strategy is trying to multiple dose and try to make a huge amount of CAR T-cells and to lower down the cost and make the CAR-T therapy cost efficient, and also to make the products more consistent. And because there are a lot of diseases, very aggressive and we don’t have enough time to produce CAR-T products and also the T-cell fitness is a variable in different patients. And iPSC CAR-Ts, because they derive from healthy donor and we can use fully characterized iPSC to produce a very consistent product, so that’s an attractive characteristic of iPSC CAR-Ts.

Julian Molina:
Now, in theory for this iPSC cells, you can target different antigens. So you can play with the antigens. Do you see this also as an option to have an off-the-shelf, something that you have on the shelf and then you have the particular antigen, I’m just going to pull it and give it to your patient or does it have to be something engineered from the patient’s own cells. Because I think the future of CAR T-cells is if I can pull a product from the shelf and I don’t have to wait four, six weeks until the product is manufactured for my patient while the disease is progressing. What do you see for your approach?

Daniel Wang:
For this project, definitely is aiming to achieve that off-the-shelf target. And in theory, they will get ready for every target iPSC CAR T-cells. And also, actually it’s also possible if you engineer some universal CAR in the iPSC CAR-T, and then you can combine with a different target antibody, then you can also achieve the universal targeting strategy.

Julian Molina:
Very good. Daniel, how about for your gamma-delta PSCA approach?

Daniel Abate-Daga:
So one of the benefits of gamma-delta T-cells is that since they do not recognize target via MHC restricted antigen presentation, in theory, we could think of a highly pure gamma-delta CAR-T population that could be used as an off-the-shelf type of reagent. So far, we have been working in the autologous setting, but that’s clearly an interesting application to explore down the road. And it’s pretty much the same line as what Dan was describing. If we have the ability to generate large numbers of gamma-delta CAR T-cells from a healthy donor, that will simplify the whole process.

Julian Molina:
Those are my questions. So you can have a healthy donor given these cells and then you engineer them and then you have them ready for the other patients. So you see this as a possibility for the patient?

Daniel Wang:
Absolutely. Yeah.

Julian Molina:
Okay.