Countless nature shows on television have that seemingly miraculous scene where, year after year, generation after generation, many turtles return as if on cue to the same breeding grounds after living hundreds of miles away in the open sea using an internal global positioning system (GPS).

The GPS systems of honing turtles reminded the founder, president, and CSO of Kelonia, Kevin Friedman, PhD, of the lentiviruses he has been programming to navigate the body to find a specific target and integrate, where they then multiply and persist with each cell division.

Kelonia, which Friedman named after the former name for the animal order containing turtles (chelonia), now has data for their lentiviral system called the in vivo Gene Placement System (iGPS) for targeted gene therapy. At the American Society of Gene & Cell Therapy (ASGCT) annual meeting, being held in Los Angeles this week, Kelonia revealed the results of preclinical research demonstrating that its iGPS technology efficiently delivered CAR molecules specifically to T cells at therapeutic dose levels in both mice and nonhuman primates (NHPs).

Friedman told GEN Edge that the iGPS enables an off-the-shelf, potent CAR T-cell that lacks the toxicities and chemotherapy that are associated with standard CAR T and has potentially more persistent and durable clinical benefit, all without any of the time-consuming ex vivo manufacturing issues. “The tissue specificity, manufacturability, and most importantly, gene transfer efficiency [of iGPS] are such that, if you can give low doses, we believe it is going to be an absolutely transformative drug for cancer patients,” said Friedman.

Incubate and develop

Friedman has been working in the gene therapy delivery space, specifically immunotherapies, for two decades. During that period, Friedman put a couple of cell therapies into the clinic and one ultimately into commercial development: ABECMA (idecabtagene vicleucel), an autologous CAR T cell therapy for the treatment of multiple myeloma. But through that process, Friedman saw limitations and hurdles that needed addressing, such as improving specificity while avoiding certain tissues, such as reproductive organs, at very high efficiency. According to Friedman, many in vivo gene delivery approaches, such as adeno-associated viruses (AAVs) and lipid nanoparticles (LNPs), have relatively low efficiency and thus have to give really high doses, which lead to toxicities.

Michael Birnbaum, PhD, associate professor of biological engineering at MIT, developed the technology that Kelonia uses. This technology was originally used to screen for antigen-specific T-cell receptors (TCRs).

“It was purely used for an assay,” said Friedman. “There was an ‘aha’ moment in some conversations between him and others [academic co-founders at Kelonia] that said this could be therapeutic because of the advantage it had in the application of TCR screening: it’s incredibly fungible and malleable. And they could direct it at whatever cells we want with relative ease.”

After a long conversation about where to point the technology, this group eventually brought Friedman to the helm. “I had tons of experience in CAR T therapy and knew that this could be a solution based on those early data to solve for essentially the biggest hurdles in the space, which are cost, access, and toxicities that are limiting this incredibly potent drug from reaching patients,” said Friedman. “Essentially, we’ve wanted to get this drug into the clinic as fast as possible, and oncology and CAR T represented that path. We had tons of experience in CAR T and specifically in myeloma after developing ABECMA.”

Friedman believed that pointing this technology at CAR T could lead to an off-the-shelf drug that wouldn’t impact and could maybe even improve upon the clinical benefit of current autologous CAR T cell therapies. It could even help cancer patients who are just too sick to receive the chemotherapy necessary for cell integration and potency.

While under the radar, Friedman and the team put their heads down and focused to get the data they are presenting at ASGCT. It took Kelonia 18 months after being seeded in 2020 to transition the technology from MIT to proof-of-concept. In mice, Kelonia has shown that iGPS is specific, functionally persistent, and durable, which is essential for translation to the clinic.

The data that Friedman is most excited about is the data he said he didn’t know they were going to get when submitting their abstract to ASGCT: the NHP data.

“What we show is a very low dose, and I think we’re going to be able to go lower, at 108 IU/kg,” said Friedman. “AAV is given at 1013 or 1014 IU/kg. So we are five to six logs below what AAV is administered! We have to make the in vivo gene delivery efficiency high enough to satisfy clinical development. Our goal here is to get into commercial development, so it has to be manufactured with high titer and yield to achieve those.”

Friedman cannot stress the off-the-shelf potential of iGPS enough. “We literally take a vial out of the freezer and administer it to the animal; there is no chemotherapy, leukophoresis, or ex vivo CAR T manufacturing,” said Friedman. “It’s just a drug right out of the freezer pumped into the vein. And that’s exactly what we’re going to do clinically intravenously.”

It’s important to note, though, that Kelonia isn’t quite ready to wrap up all their preclinical research, primarily because the NHP model they are using is a surrogate. Instead of doing their experiments in a cancer model or with chemotherapies, they’ve used a model of B-cell aplasia.

From hatchling to open sea

Kelonia was founded to solve in vivo gene delivery, and that doesn’t end with CAR T cells and oncology. Rather, it’s just the beginning.

“We absolutely want to take advantage of this technology, leveraging the preclinical and clinical learnings that it will have in CAR T, to direct this technology to additional indications that are either in oncology or even ideally outside of oncology,” said Friedman. “If we can solve a hurdle that is limiting other in vivo gene delivery approaches, that’s where I would want to orient this technology. We have some work ongoing to look at other cell types. We know it can go to B cells, hematopoietic stem cells, and other solid organs.”

They’re also exploring the kinds of payloads that iGPS can deliver. Kelonia is looking at delivering other genetic tools like editing machinery or non-integrating cargo.

Friedman said that they need to tinker around a little bit more with the construct and get the data that will convince them that they have something truly amazing. Only then will they initiate engagements with the health authorities to begin their drive toward the clinic. At the same time, they’re working on the clinical manufacturing side of things with the hope of administering the drug to a patient in the next 18 to 24 months.

It’s too early to tell whether this will all pan out. Kelonia, like the sea turtle, has all its eggs still buried below the surface, waiting for the hatchlings to develop, crack out of their shells, poke through the warm, sandy surface, push through the waves and currents of clinical testing, and swim on through into the open ocean of drug approval.