Lessons Learned From the Past 25 Years of Cell and Gene Therapy Research

This is the sixth part of a transcript of a Special Report with Deborah Phippard, PhD, and Renier Brentjens, MD, PhD. For the fifth 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 sixth episode, Phippard and Brentjens shared advice for young scientists entering the field of cell and gene therapy. Phippard pointed out that certain elements of therapeutic design, such as specific delivery mechanisms, may become obsolete and others will only work for certain diseases. She also noted the importance of discussing ideas with regulatory bodies during the development process. Brentjens concurred, and emphasized the importance of not viewing certain assumptions about what works and what doesn't as hard rules. Instead, he stressed that investigators should remain open-minded and adaptable.

CGTLive: What lessons from the past 25 years should guide the next generation of developers and regulators?

Deborah Phippard, PhD: That's a really great open question. If I'm advising young scientists now, I mean, I just think about "stay the course, do good science, and don't get discouraged because there are going to be major setbacks." With this type of therapy, I would say that is almost inevitable, and not every approach is going to work. There's all these different engineering approaches, there's all these different delivery medicines. My colleague came up with an analogy, so I'll do one for the older crew: VHS versus Betamax. Now we don't even know what VHS is, but back in the day, it was "okay, which platform are we going to be watching videos on?" And then Betamax just vanished without trace.

I mean, there's a lot of that is going on, and if you're working in a company who has a very particular delivery mechanism and that ends up just not working, that company isn't going to survive. You can't put all your bets on one marker because I think different things will work for different diseases because there's different problems that we have to solve. So to me, you've got to drive the science and you've got to engage with the regulators. I hear that all the time, when we're thinking about a clinical protocol, what is the FDA going to ask for? I talk to various companies and I heard just yesterday, somebody is doing direct delivery to the brain, and the FDA had all these questions around the device that was going to put the delivery to the brain because that wasn't a medical device licensed for that use. You don't always think about those things when you're designing the therapy. These are so multifactorial. It really does take a village to bring these, companies like mine that bring different areas of expertise. I think there's so many brilliant ideas out there, [so it involves] sharing those ideas and thinking about how to solve the big problems. Historically, the FDA has been very open to talking and thinking about how we can test these things.

Brentjens, MD, PhD: I completely agree, and I'm happy you brought it up. When we ran our first trial, pedantically I think it was like the first time the FDA encountered engineered, or at least retrovirally engineered, T-cells. When we were writing up the trial, we had no idea what dose range [to use]. There was absolutely no guidance. I think there were some T-cell HIV studies that we kind of cited as saying, "well, that's a dose of T-cells that you can make, etc."

It's stunning to me that I literally started working on this a quarter century ago. Now, granted the first approval came, I think back in 2017, but that's still a very long time. That's still almost 2 decades. I think that if you're giving advice to young scientists, my advice to young scientists is don't get discouraged (obviously), but [also] revel in your victories. Revel and remember and retell the story of the first time that you injected this in a mouse model and you came back from vacation 2 weeks later, and it was 10-nothing and you didn't even have to do the statistics. Those types of victories in a wasteland of defeats are what keep you going and what make the time go by very quickly.

The other thing that I will say, at my age, with my experience, that I've learned is there are going to be rules that we think are in fact rules, when in fact they may not be. For example, I think that the field right now would say that the efficacy of cell therapies correlates to the persistence of the cell product, and also that if you're going to give cell therapy, you have to give lymphodepleting chemotherapy. I just highlight those two. If you live by those rules without knowing that a lot of them are just conjecture you may wind up missing stuff. So always challenge what the field's norms are, especially in a field like cell therapy that is so young. As we talked about earlier we have no rules as far as what a dose of cells means, or what the pharmacology is behind it. We have no idea how important the binder is. We have no idea of how important the signaling domain is. All those things we thought were critically important because we actually didn't have access to all these other things.

Along the same lines, when we started doing this work, we thought the biggest problem was going to be efficient gene transfer into T-cells. That now seems silly, when we routinely get 80% to 90% gene transfer—

Deborah Phippard, PhD: That's only because you solved that one!

Brentjens, MD, PhD: Yeah, we solved that one, and then we started learning much to our dismay about the tumor microenvironment, we learned about regulatory T-cells (which I guess the Nobel Prize was just awarded for)—I mean, we found out all about the biology and the immunobiology of tumors. So you have to remain adaptable. While you can use the rules of the road as guidelines, don't be blind to them, and always have the ability to challenge what the current norms are—not by going down too many rabbit holes—but always be objective to make sure that what we now perceive as critical may, in fact, be a red herring.

This transcript has been edited for clarity.