CTA: I actually saw an op-ed by Siddhartha Mukherjee in the New Yorker recently,4 and then on Twitter, he questioned, ‘Well, what are these therapies anyway?’ It kind of reflects what you said, ‘Are they drugs, or are they our own cells, and who owns them, and at what point do we say that it’s a drug, or that it’s a person’s own immune system at play?’
Dr Marasco: Right. Now, it’s really both. There’s different types of cellular therapies, obviously. Some people just take an antitumor cell and expand it in culture and give it back to the patient, in great numbers. That’s done by Steven Rosenberg at the NCI [the National Cancer Institute] and other groups, and those are really the patient cells that really do not require engineering, rather just expansion.
In what we’re doing, there’s really a set amount of engineering. I don’t want to get into the bioethical arena here, whether it’s a drug or a patient’s cells, but my point is that — and, this is one of the reasons I believe in using autologous, and not allogeneic cells — is because it’s not just about the initial hit to the tumor. It’s not about the short-term killing of 99% of the cells, it’s about killing 100% of the cells. Killing the solid tumor is not an easy task, and to expect it to all be done by a hit-and-run approach, where you go in there, you just kill a bunch of the cells, and expect it to be cured — I think it’s wishful thinking, actually.
I think we can get that; we can certainly get a massive killing once the CAR-T cells are infused, but I really think it takes surveillance afterwards to be able to mop up anything that’s left over to keep the tumor microenvironment from re-establishing itself, to really keep the balance toward host defense, and against the commandeering of the tumor cells against the immune system.
Another part of it is really an engineered cell that’s still floating around in your body. So, whether you call it a drug, or a cell; I’m not sure. It’s certainly a cell, but it’s been made “druggable,” if you will, to be able to have that property. So, it’s an interesting ethical consideration, but [a] bioethical consideration; it’s really a cell at the end of the day.
CTA: So is CAR-T a cell therapy, a gene therapy, or is it both? When the first CAR-T was approved, the FDA press release announcing the approval referred to it as being both a cell therapy and a gene therapy.
Dr Marasco: It’s an interesting question. I think it’s a cell therapy. But, you can’t just isolate it like that because it’s more than that. So, not everybody does CAR-T cells the same way. Some people do it by electroporation of RNA into the cell, in which case they’re not integrated — the DNA is there transiently, so those cells, at the end of the day, may survive, but the gene part of it is no longer intact —But, there’s no question it’s a gene therapy. You’re genetically altering the cells in those cases.
In some of the newer forms of therapy, or some of the experimental forms of therapy, I’m sure you’re aware of this, there’s also gene editing involved, where one’s using CRISPR-Cas9 or related CRISPR technology to be able to, specifically, integrate into a site, like knocking out the endogenous T-cell receptor, and putting in CAR-T cells, directing that locus.
So, it’s not one thing. At the end of the day, it’s cellular therapy. But, it certainly involves a gene therapy approach. So, I don’t think you can ignore one, and rely on the other. You have to just come to the realization that this is a combination therapy that is both gene therapy and cellular therapy, cellular therapy being a product, really. You’re not, so much, delivering genes as you are delivering cells that have been genetically modified. So, I still think it’s a cellular therapy, but it got there by gene manipulation.
- OncoSec Medical Incorporated. OncoSec receives exclusive licensing rights from Dana-Farber Cancer Institute to CAR T-cell therapies for the treatment of solid tumor cancers [press release]. Published June 27, 2019. Accessed September 16, 2019.
- Ma L, Dichwalkar T, Chang JYH, et al. Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science. 2019;365:162-168.
- Lawrence L. Nonrelapse mortality after CAR-T therapy remains high. CancerTherapyAdvisor.com. Published June 13, 2019. Accessed September 17, 2019.
- Mukherjee S. The promise and price of cellular therapies. New Yorker. Published online July 15, 2019. Accessed September 16, 2019.