Viva in vivo: The next generation of cell therapy is fast approaching

Cell therapy is a field rife with innovation, but most of the novel therapies being developed fall into one of two basic categories: autologous cell therapies, which involve removing a patient’s cells, modifying them, and returning them to the body, and allogeneic cell therapies, which can be derived from donor cells and sold “off the shelf” to any patient.

Auto approaches have had the most success of any cell therapies to date, but they’re complicated to administer and come with huge price tags. Allo approaches promise more scalability and easier infrastructure, but they’ve yet to produce strong results and they have their own supply chain problems when it comes to cultivating a donor base.

The majority of the work happening in cell therapy falls into these two buckets. But not all of it. A handful of biotechs are asking a next-generation question: What if we could modify a patient’s own cells without removing them from the body first? This broad approach, called in vivo cell therapy, has the potential to offer the best of both worlds, with scalability and lower cost, not to mention a better safety profile, while maintaining the efficacy shown by autologous cell therapies.

Of course, like most things in science, it’s easier said than done. But in vivo CAR-Ts are not a far-off pipe dream. A handful of companies are pursuing them and have promising early results. Leaders of three of these companies – Philadelphia’s Interius BioTherapeutics, Seattle’s Umoja BioPharma, and Boston’s Kelonia Therapeutics – spoke with pharmaphorum offering a peek into what they were working on, and shared their view of how this space will evolve if and when in vivo cell therapy hits the big leagues.

Faster, better, cheaper, and safer

The different companies working on in vivo each have their own approaches, but in broad strokes the idea is the same. The companies all use modified versions of the same lentiviral vectors used in ex vivo CAR-T therapy.

“We're using the same basic vector backbone that's used to manufacture the cells ex vivo, but what we have done is engineered it specifically for use in vivo,” Phil Johnson, CEO of Interius BioTherapeutics, said. “That took us a while. That was a couple of years’ long process to re-engineer the vector so that it could be used directly inside the body. And what we've done is some fancy engineering to allow it to target very specifically certain cells inside the body.”

This precision targeting, dubbed ‘tissue specificity’, is the biggest challenge of working in vivo and the angle that all three companies play up. Kelonia calls their vector iGPS, to emphasise its ability to find its way around to a specified target.

This precision allows the vector to modify T-cells (or NK cells in some companies’ case) directly inside the body to start fighting cancer.

“The whole idea behind this is really to make CAR-Ts available for everybody,” David Fontana, CEO of Umoja, said. “The thinking behind this is, with VivoVec [Umoja’s proprietary viral vector], it'll be manufactured in our facility in Colorado and shipped and stored globally in a very economical way.”

Johnson says the motto at Interius is “faster, better, cheaper”.

“We know that these products, the approved products, cost hundreds of thousands of dollars to make and administer,” he said. “There're lots of technical fees associated with hospitalisations and so on. We now have calculated that we can actually make a dose for a patient for under $10,000. And it's probably going to be less than that, depending on of course, how the clinical trials go. So the faster and cheaper part, I think, is really self -evident, but the better part is what we're doing the clinical trials to prove [and the] chance that those cells are going to actually be better cancer fighters, of course, remains to be seen, but it's a theoretical possibility.”

In addition to being potentially much cheaper and more scalable, in vivo cell therapy eliminates the need for chemotherapy before the procedure, saving on costs and vastly improving the patient experience.

“The primary goal of chemotherapy for autologous cell therapies is to eliminate the circulating T-cells inside the body [to make] literal homeostatic space for the incoming CAR-T cells,” Kevin Friedman, CEO of Kelonia Therapeutics, told pharmaphorum. “We, on the other hand, need those same T-cells that you would otherwise eliminate through chemotherapy. We need those T-cells to be present because those are the cells that we're modifying to turn into CAR-T cells.”

There’s also early evidence that in vivo CARs are less likely to cause cytokine release syndrome, a common and dangerous side effect of cell therapy.

Developing a platform play

In vivo cell therapy is a new way of delivering cell therapy, but the actual therapies don’t need to be new. In theory, exactly the same CAR-T payloads that are currently being developed and deployed for ex vivo cell therapy could eventually be delivered by these proprietary, engineered viral vectors.

That means that these companies on the bleeding edge of in vivo are potentially positioned for a big future as a platform play – something that all kinds of biotechs and big pharmas will license to deliver their own already-developed therapies.

“I am thrilled about the idea of, once we have that proof of signal, proof of clinical response, that then it opens up doors of people bringing us their therapeutic cargo to be delivered using our in vivo gene delivery technology, such that they can work on what's really valuable to them […] and we can make sure that it's safely delivered to the cells inside the body,” Friedman said.

The possibilities, however, are endless and go well beyond the current CAR-T use cases.

“The really cool thing about our vector is that we can target almost any cell in the human body,” Johnson said. “So, we can begin to think about other applications for our platform beyond just either haematologic malignancies or autoimmune diseases. We have the capability really of transforming in vivo gene therapy in general as we move forward and get proof of concept.”

Early efforts and pharma partnerships

So, how close are we to this proof of concept? Well, so far most of the data that exists on these in vivo CARs, that’s fuelling a lot of this optimism, comes from monkey studies.

But that’s all set to change very soon. Interius recently received approval to begin its first phase 1 trial for its therapeutic for B-cell malignancies. Kelonia, which has been operating in stealth mode for the most part, plans to be in the clinic next year with its anti-BCMA to treat multiple myeloma, Friedman said. And Umoja expects to have its first patient enrolled by the end of the year in its Invicta trial in large B-cell lymphoma.

As these companies get closer to market with their initial efforts, pharma companies are taking notice and looking to get in on the ground floor themselves – such as AbbVie, who are working with Interius on developing an in vivo version of their CD-19 CAR.

“We had a lot of pharma partners interested in in vivo, and Abbvie became an early adopter of our technology,” Johnson shared. “Our first product, this VV111, is the CD19 CAR, so very little target risk. We know CD19 CARs are some of the most highly functioning CARs across the board, with probably a dozen approvals now in different indications. We've chosen that molecule to team up with AbbVie in that relationship.”

Kelonia Therapeutics, meanwhile, has partnered with Astellas in a similar fashion.

“What I really, really liked about Astellas, in addition to just being an awesome group of people, drug developers, and providing real relief to patients that need it, is they brought a very synergistic technology to ours,” Friedman said. “They brought a therapeutic cargo in their universal CAR-T, their ACCEL platform that married very well with our in vivo gene delivery technology. It's really that technology marriage that I was particularly excited about as we think about the potential of such a technology combination and the ability to treat cancer patients moving forward.”

How cell therapy is poised to evolve

All this leaves one big question for the cell therapy space: As the rest of the industry works at a breakneck pace to build the infrastructure needed for autologous cell therapies, what will happen when those complex, expensive treatment centres get leapfrogged by off-the-shelf in vivo CAR-Ts? Is the industry headed for a “record scratch” moment and a sudden reversal of course?

Well, the easy answer is that it’s too early to say. To start a pivot before these technologies have really been proved out would be putting the CAR-T before the horse, as it were.

“There was a lot of excitement and enthusiasm about allogeneity, third-party-derived cell therapies, your NK cells, things like that, and those really didn't play out. I think, as a field, we need to learn to exercise scepticism around these novel approaches,” Friedman said. “Because the fact of the matter is autologous cell therapies are still the leaders for clinical benefit for patients that are suffering from these debilitating diseases. I hope and aspire to eventually supplant autologous cell therapies, but we’ve got to be true to ourselves and honest to ourselves that we're still very early as a field.”

But even if in vivo pans out to be as good as promised, there will still be a place for autologous therapies.

“I don't think there's going to be a record scratch,” Fontana said. “Those drugs are just too good to be dismissed immediately.”

Johnson agrees.

“I don't think there's a line in the sand where you cross and all of a sudden things change overnight,” he said. “I think you'll see a gradual implementation of newer forms of therapeutics, whether it's in vivo CAR -Ts or bispecifics or other modalities. The greatest news of all here is that patients will have therapeutic options available to them that previously weren't available.”

All that said, lined up behind the handful of frontrunners like Kelonia, Umoja, and Interius are a number of companies that see the incredible potential of in vivo. All three CEOs pharmaphorum spoke with expressed a “rising tide lifts all boats” attitude about competition at this stage, but, when and if the proof of concept comes, that rising tide could be more of a tsunami.

“As we start knocking over those first dominoes in this space and showing that this is indeed an attractable approach, I think we're going to see an onslaught of novel technologies and novel companies trying to make an impact in this space,” Friedman said.