Every year at the BIO International Convention, FierceBiotech hosts a panel discussion about what we see as the biggest R&D talking point of the year.

But we are not content with just speaking about the latest innovations but rather looking further at what’s on the horizon, the truly cutting edge. This year, that is CAR-T 2.0.

CAR-T itself is, in market terms, not even a year old, with Novartis and Gilead/Kite getting FDA approvals for their CAR-T drugs for several blood cancers late last year. We’re still waiting to see how well patients respond in real-world terms, how much pricing will be an issue, and how many further indications they and others can stack up across a host of blood cancers. These approvals were real milestones, but the life science world doesn’t stand still and already, biopharma is thinking next-gen: how to make CAR-T more efficient, safer, and whether it can work with older drugs, or the latest immuno-oncology therapies.

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FierceBiotech editor Amirah Al Idrus sat down with key executives from Johnson & Johnson (which recently penned a $350 million CAR-T deal with ASCO 2017 star Nanjing Legend Biotech), Mustang Bio, ImmunoVaccine and Nkarta to discuss their work on the next generation of cell therapies.

Michael Kalos, Ph.D., VP of Janssen immuno-oncology and oncology cell therapy, told our audience that combinations are one opportunity to help push CAR-T forward. "Rational combinations are the name of the game. The immune system and the tumor interactions are complex. So, the challenge is figuring out these rational combinations based upon what we know.

"But the truth is that, as with most of science, what we don’t know is more than what we think we know, so being able to go into clinical studies and really interrogate what is happening, and what is not happening, is critical in how we’re going to move forward in this space. So, develop your best rational combos, learn from those, and then make them more rational."

Sadik Kassim, Ph.D., chief scientific officer at Mustang Bio, a small outfit with big hopes to compete with the likes of Gilead and Novartis, said: "In order to develop, and building on what Michael was saying, we need to design a space where we have many phase 1 trials, because not all your rational combos will work, so you need to have a mechanism that can rapidly test these things out, in a systematic way.

"That’s the opportunity you have with cell therapies; the time it took from the initial findings at Penn to registration is unprecedented, and you can build on that speed to test out different combinations."

He said that can involve checkpoint inhibitors, as well as oncolytic vectors and cytokines. "The field is really wide open," he explained.

Kassim added that the respective approvals for Novartis and Gilead in 2017 have helped a small company like his "tremendously," notably with the investor community, by proving that the science is approvable and worth putting money into.

"When I got into the field 10 years ago, it was very difficult to make these CAR-T therapies," he explains. "You were limited by the number of suppliers, but on that front, there has been a tremendous boom in competition, we have better providers, and folks that are providing the raw materials to scale up these therapies.

"And we’re seeing a general innovation boom in this space; innovation we haven’t typically seen. Ten years ago, there were maybe four to five centers that were full-blown CAR-T centers, and now you’re finding places in Albany, Nebraska and even MIT, which 10 years ago wasn’t even involved in this space. That’s what happens as a result of these approvals."

Fred Ors, CEO of ImmunoVaccine Inc., said that the first wave of CAR-T will inevitably lead to "people thinking of ways to program T cells and to make them manmade; built by design rather than relying on the natural ability of the immune system—that’s one very promising avenue."

Angela Shen, M.D., CMO at Nkarta, which is working on natural killer cells, said as well that "It’s important to remember that the CAR-Ts that are approved and are in those bags—it’s not just 100% T cells; that’s a mix of all sorts of stuff, and that this is contributing to the activity. So, moving forward, I think there will be a more purposeful allocation of the various cell components, as well as combinations with other products."

Shen, and who has also worked with Kassim and Kalos, adds that "all the bells and whistles, all the switches for the next generation and improvements upon current therapies, for me are all ways at attempts to control better the actual cell therapy. So, it’s not just this technique or that technique, it’s all these wonderful technologies that are being studied that will allow us to better control the cells, because they are living drugs.

"The ones that are approved now work wonderfully but fall short of just unleashing the cell into the system in vivo, and it’s going to do what it’s going to do. Now that we know more about it, and we have a little more experience with it, the field will come up with better ways to control that."

Kassim adds that greater safety is also needed, and that doctors, as well as tech, can help here: "People have put in these safety switches to help, but I don’t know if these safety switches have been used effectively in the clinic. A lot of the toxicities to date have been managed by clinical insight. Sometimes a well-trained physician can be just as effective [in managing toxicity] than having these products with bells and whistles, and I think it’s going to be a balance between effective clinical management and more effective and well-defined products."

And finally, one of the big caveats with CAR-T is that while it can produce some stellar results in blood cancer, in solid tumors, the evidence is far weaker, and getting it right here is part of the second or third generation of CAR-Ts.

Kalos, however, said that there is "ample evidence that T cells work in solid tumors; all the evidence from the checkpoints tell us that T cells work in solid tumors, that effect is mediated through T cells."

But he admits that "We haven’t yet cracked the nut on why CAR-T, or engineered cell therapies, don’t appear to work in solid tumors; part of it might simply be that we’re not targeting the right antigens, and part of it might be that we haven’t really added, or fully dealt with, all the other mechanisms that natural T cells don’t have to deal with, so checkpoint inhibitors and microenvironment might be different to T cells because they haven’t adapted.

"It’s complex, but I have all the confidence in the world that we’ll figure it out because, as we said, these cells can work in solid tumors."

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