CTA: Something in the press release1 referred to this electrotransfection, and, it said that it would make CAR-T more affordable and accessible, to patients. How [might] this very scientific technique make CAR-T more affordable and accessible?
Dr Marasco: Well, I think this still needs to be worked out. So, Carl June’s team published a couple years ago, a paper on local injection.3 I think it was in TNBC.
That did have some local antitumor effects. So, if you got a situation like that — you significantly cut down on costs, because you don’t need to expand the cells in culture at the level what one needs to be able to get a therapeutic effect, if you’re giving them systemically. The systemic delivery is really based on a number of cells per kilogram of body weight. So, the more you weigh, the more cells you need — the hope is that there is a minimum fixed number that one needs to be able to get [to get] a therapeutic effect.
Anyway, to achieve that number, whatever that number may be, it really takes, on average, let’s just say 2 weeks to be able to get those cells expanded, and that’s really where a significant amount of the cost comes, because of the laboring, and testing, and reagents, and so on, that’s required to get these T cells stimulated and expanded to the level to be able to hit some target dose of cells per kilogram of body weight. So, if you deliver it locally, you’re cutting down on that dramatically. I don’t know what the number would be, but it’s really a fraction of what the numbers would be, systemically.
So, the question really is, if you were going to do it locally, how would it be done? So, right now, electroporation of cells, of CAR-T cells — the idea here is that you could, somehow, through a direct delivery of the CAR-T cells to the tumor, with the assistance of the electroporation device, be able to deliver them exactly to where a cutaneous lesion would be, and I know they’re working on other electroporation equipment that would allow visceral delivery. And, in doing so, you’re really allowing, potentially, a high concentration of CAR-T cells to get to the tumor site, without having to do it through systemic administration.
So, it’s a nice idea. It requires some additional development. And, they’re working on it. I share the vision that anything that we can do to decrease the cost would be beneficial, ultimately.
CTA: So, do you think that, maybe, that type of advancement could spur that site of [manufacture of] that creation of this cell therapy? In other words, there seems to be a centralized model for a lot of companies, or a lot of [companies] envision a centralized model. Do you see, because it’s a smaller amount that you need to really make and deliver, that maybe that could move processing from a centralized model, [to a localized cell-processing model] right in the hospital?
Dr Marasco: To an extent … because you still have to deliver a cGMP [current good manufacturing practice]-quality qualified dose of whatever it is. But, the cost and infrastructure that one would need to be able to set that up could be scaled down significantly. And, with the scale-down there would be a significant cost savings. The therapies require stimulatory agents, culture media, monitoring of the cells, and then everything that goes with the vial and preparation of the cell. So, there’s a significant cost in all that.
If one could cut it down to the point where you could achieve a target number under much more downscale manufacturing, I think that you’re now opening the door to potentially doing it at site of care. Now, that can’t be a little, rural hospital (unless they were set up to do it), but I think that you can achieve smaller-scale manufacturing facilities in a lot more locations than you could to do at large build-outs.
Keeping that in mind, look at local injection, at least in the case of cutaneous tumors, such as triple negative breast cancer, and cutaneous T-cell lymphomas, melanoma, head and neck cancer, wherever a needle can get to. If you were able to direct the therapy locally, and importantly, get a systemic effect, to know what the unknown here is, then I think you could change the paradigm significantly.
The issue is, when you inject locally, and you see a antitumor response, then that’s all fine and dandy, and it’s important, and it can make a significant life extension in many cases — but it won’t necessarily lead to a cure, unless one’s really getting some kind of a systemic effect.
We didn’t make it to adulthood without having a potent antitumor immunity going on every day of our lives. Cancer cells crop up all the time, except you’ve got an immunosurveillance system that keeps them in check, and ultimately, it’s when that balance shifts towards the tumor having commandeered the immune system to be able to grow that the battle has shifted toward the tumor growth.
White blood cells that accumulate at the tumors are educated; they know there’s a tumor there, they just can’t do anything about it. So, if we reverse that by local injection, and can get some systemic effects because those educated T cells now leave the tumor — not only do they take care of what they need to do at the tumor site, but they become systemic — then we may be able to see some durable responses that would really be achieved at a fraction of the cost.
But, those are directions that the work could go on, and I applaud the company for trying to get there, but, I mean, there’s a number of scientific hurdles, I think, that we have to get through to be able to declare that victory, if you will.