Key Unknowns Remain in Cell and Gene Therapy

This is the fifth part of a transcript of a Special Report with Deborah Phippard, PhD, and Renier Brentjens, MD, PhD. For the fourth part, click here.

The past 25 years, from 2000 to 2025, have been an unprecedented and rapid period of development of the field of cell and gene therapy. To get a perspective on how far we've come, and how far we have yet to go, CGTLive® reached out to Deborah Phippard, PhD, the chief scientific officer of Precision for Medicine, and Renier Brentjens, MD, PhD, the chair of the department of medicine and the deputy director at Roswell Park Comprehensive Cancer Center, to hold a Special Report discussion on the topic entitled: "Quarter Century Update: What’s Holding up Progress in Development? Where Have We Seen the Most?"

In this transcript of the fifth episode, Phippard and Brentjens spoke about the many unknowns that remain with the ways in which cell and gene therapy products function in the body. Brentjens emphasized that T-cell therapy is a "living drug" and therefore sometimes acts in ways that are, at least currently, unpredictable to us. Phippard agreed, pointing out some of the difficulties with figuring out how to properly administer and dose gene therapy products.

CGTLive: What are some of the key unknowns remaining with regard to cell and gene therapy products?

Renier Brentjens, MD, PhD: The pharmacology of cell therapy is still quite undefined. The treatment dose, from a pharmacologic standpoint, is hard to determine. It's dependent on the amount of target cells that are in the patient and the phenotype of the T-cells that you infuse into the patient. There are a lot of "what-ifs" and a lot of questions. I remember way back when, when we would treat our acute lymphocytic leukemia patients, we would paradoxically give the patients that had more disease in the bone marrow 1/3 the number of cells than we would have given to someone who had minimal residual disease. That's just the pharmacology because the patients that had more disease on board would develop rip-roaring cytokine release syndrome, which by the way was really unheard of until us and the Penn group started treating patients at regular intervals. We call it a drug, but it's a living drug and that living drug is, as of now, quite unpredictable once it goes into the bloodstream.

Deborah Phippard, PhD: I'd add to that, I don't know that gene therapy is much better. You're looking at the dose, it depends on the route of administration, depends on the capsid type, depends on the age and the size of the human and then you've got to think about durability and what cells are getting transduced. You think about cystic fibrosis, if you get it into the surface epithelial cells, they're going to be shed. You're not going to get a durable response. So how are you going to get that virus into stem cells? There's all these things that have to be worked out. I mean, these are very nontrivial questions, which is why 25 years is not that long when you think about progressing these treatments.

Renier Brentjens, MD, PhD: There is an element of "we'll figure that out later," right? With my microbiology background, I often tell my students that everybody knows who discovered penicillin and we used penicillin for years before we understood how it worked because nobody cared. And nobody remembers who figured out how penicillin works.

We are kind of in that area now, where we kind of play it by ear a little bit. But the great thing is something looked so good in cartoon form when you wrote your first grant that it actually worked. It's kind of hard to sober up from an experience like that.

This transcript has been edited for clarity.