Without a doubt, tens of thousands of people afflicted with blood cancers—leukemia, lymphoma, multiple myeloma—have had incredibly positive outcomes with CAR T cell therapy. When Emily Whitehead was treated in April 2012 at the age of six, the hope was that she would live another day; if she survived until the holidays, it would be a miracle. Emily is a sophomore at the University of Pennsylvania today.
But it is also glaring that the number of people to benefit from CAR T cell therapy for blood cancers could be much higher if the supply of autologous cell therapy could be increased to meet demand. Looking solely at multiple myeloma, one study surveying 17 centers discovered that the median wait time for a slot was seven months. During that time, the cancer could progress to the point where CAR T-cell therapy would no longer be beneficial, and it was estimated that 25% of patients died while waiting for a slot.
Even with the surge in CDMOs offering autologous cell therapy manufacturing services, biopharma companies, many of which are joining the race to bring CAR T cell therapy to autoimmune diseases that affect an order of magnitude or two more of people, fair better while dealing with the challenges of industrializing ex vivo autologous cell therapies?
This manufacturing issue key to autologous cell therapy industrialization has not gone unnoticed at the heart of the CAR T cell therapy world in and around Carl June’s lab in Philadelphia. The in vivo method of CAR T cell therapy has long piqued the interest of Saar Gill, MD, PhD, associate professor of medicine in the University of Pennsylvania’s hematology-oncology division and founder of the cell therapy startup Carisma Therapeutics. In 2019, approximately ten years after establishing Carisma in 2008, Gill established Interius BioTherapeutics to build a platform for creating a therapeutic modality that is readily available to a wide range of patients.
Today, Interius BioTherapeutics announced a major milestone—the first use of durable in vivo CAR therapy in the clinic. This patient was dosed with INT2104, a lentivirus-based gene therapy that delivers a CAR transgene to generate effector CAR-T and CAR-NK cells in vivo to target CD20-positive B cells for the treatment of B-cell malignancies. Information about the patient has not been disclosed, and the company has stated that it expects to release early clinical data in the first half of 2025.
Phil Johnson, MD, CEO of Interius BioTherapeutics, told Inside Precision Medicine, “The simplicity of this is that you simply call the pharmacy, they send a vial down, and the virus gets infused directly into the patient. The patient can go home. The other part of this is cost. Currently, all of these ex vivo therapies are hundreds of thousands of dollars. [Interius] will be able to provide a drug for at least the cost of goods for less than $10,000. It’s faster, cheaper, and better.”
Interius has shown INT2104’s effectiveness in several preclinical cancer models, both in small and large animals. While Johnson is “optimistic that this will translate into a very beneficial new way to treat these types of cancers in humans,” they’ve got to get through the safety parts of the clinical trials first, which he agrees is the company’s primary focus.
“We’re in the early days of a phase one trial, which focuses primarily on the safety of the approach, especially with a first-in-human very novel modality like this,” said Johnson. “Our entire focus in the earliest days is going to be on safety.”
Johnson said that following this trial, Interius will start a typical dose-escalation trial designed to go from low to medium to high dose, which is scheduled to take place over the next year.
Ex vivo vs. in vivo CAR T
It is easy to understand how Johnson argues that, if successful, the in vivo CAR T therapy approach is faster and less expensive than the ex vivo approach. As for what is “better,” that is still in the air.
The way that ex vivo CAR Ts are made often uses a lentiviral vector to transduce the cells and put them in a bag back at the manufacturing facility, which essentially eliminates the concern for targeting unwanted cells. For the in vivo scenario, a lentiviral vector is injected directly into the patient. Ex vivo cell therapy needs to be prepared individually. In contrast, the same batch of what is being put into the patient can be used across a population with an in vivo approach, a major boon for not only cost and speed but also patient reach.
“We can scale up our approach,” said Johnson. “We can put together lots of 2,000-liter bioreactors and basically supply all the drugs that are needed as opposed to having any individualized therapies for each of these patients, which becomes prohibitive.”
The significant trade-off is in cell targeting specificity, which is essentially a non-issue for ex vivo CAR T approaches because the target cells are purified. To account for specificity in cell targets of INT2104, Interius engineered a lentiviral vector to attach to and transduce CD7-positive cells, which are present on the surface of T cells and NK cells. “We’re creating not only CAR T cells but also CAR NK cells with a single vector,” said Johnson. “This makes us unique among folks doing this too and provides a much broader population to attack the tumors—in this case, the lymphoma cells right next to where the [T and NK cells] live.”
One of the major differences between the two approaches lies in the safety concerns. With the in vivo gene therapy approach, there’s a greater need to monitor for off-target effects. According to Johnson, Interius has yet to “find off-target transduction” in their preclinical in vitro and in vivo testing. When throwing in an integrating virus, a whole new set of safety concerns can arise, such as the potential for insertional oncogenesis or mutagenesis. Johnson doesn’t believe their approach is going to cause problems because the vector uses an HIV integrase, which he backs up with a thought experiment based on HIV infections.
“100 million plus people have been infected with HIV over 100 years, yet how many cases of insertional oncogenesis have there been in HIV-infected people?” posed Johnson. “The answer is zero. So, I think what you can rest on is that the mechanism of HIV integration is not designed to cause insertion of oncogenesis or mutagenesis.”
What’s compelling about this thought experiment is that the target for HIV is T cells. As Johnson put it, the number of integration events outnumbers the number of stars in our galaxy, and there have been no reported cases of insertional oncogenesis, which would most likely flourish in immune-compromised patients. But just because such an event hasn’t been reported doesn’t mean it hasn’t happened. At the end of the day, Interius can’t gamble on just the thought experiment if they ever want to get INT2104 in front of the FDA, so they are monitoring insertion sites preclinical work and will do so in their human patients.
Applying the lentiviral platform
A topic that intersects with the ex vivo and in vivo CAR T debate is delivery methods for genetic material. There are essentially two camps: viral and non-viral (though a hybrid of the two is being investigated with lentivirus-derived nanoparticles).
The reasoning for Interius to go with a lentiviral approach over non-viral methods like lipid nanoparticles (LNPs) in great part due to the cargo type and size. LNPs are great for delivering RNA, which yields a transient mode of action—it only lasts as long as the RNA avoids degradation—which is great for a vaccine. On the other hand, the lentivirus integrates into the genome, providing a more permanent solution, which is needed if the goal is to achieve a long-term effect. The only way you get rid of an integration event is for the cell to die or go away. In fact, if the antigen stimulation goes away, the T cells will eventually go away as well.
That’s been the case with Emily Whitehead, now a sophomore at the University of Pennsylvania, walking around with no B cells because her CAR cells hang around, probably getting stimulated by the occasional B cell trying to work its way back out of the marrow. It’s a circular thing. Johnson added that “If I’m her, this is fantastic because I’ve got a sentinel there waiting to see if I’m a malignant cell where it to show its head again. People go, ‘How can she walk around with no B cells?’ The answer is she’s easily treatable with immunoglobulin that’s given subcutaneously at home.”
Genomic integration will be particularly useful in treating autoimmune diseases. Interius has a second program focused on CD19, also a B cell marker, which, according to Johnson, is more appropriate for autoimmune diseases such as lupus and myasthenia gravis. He expects to hit clinical trials in 2025.
“‘You’ve seen all the ex vivo companies slide into [the autoimmune disease] space, which makes sense because there’s a huge need for patients,” said Johnson. “So the faster, better, cheaper mantra I mentioned for B cells and lymphomas applies directly to all the autoimmune space. The challenge is very simple: there’s not enough [CAR cell therapy] capacity to treat all these patients. There’s a ton of these patients with various diseases with a very common final pathway mechanism—autoantibodies.”
There’s no reason that Interius BioTherapeutics’ platform has to be limited to targeting immune cells. Theoretically, swapping out the binder on the vector can enable the targeting of different kinds of cells. Johnson said, “We’re a platform company that has a pipeline right now that is aimed in the hematologic malignancy space and the autoimmune space, but we’re constantly thinking about other ways to use this to treat other kinds of diseases, and we have, again, on the whiteboard, we have lots of those possibilities.”
The march to the front of the line
At the end of the day, while Johnson’s mantra of “faster, cheaper, better” has a nice ring to it, the idea of in vivo CAR T cell therapy being “better” than ex vivo cannot even really begin to be debated, as there is no data from Interius in humans. Importantly, these approaches are not mutually exclusive, providing benefits and risks better suited to particular situations.
Johnson agrees and says, “I think there will be a place for ex vivo because some people may not qualify for in vivo, or there may be other reasons they can’t get it. We view [the two approaches] as providing optionality for patients. That’s really what’s important to us because most of the people that are coming to these types of therapies have already relapsed off of standard of care, which, you know, often is curative, but many times it’s not. So, our goal is to provide patients and their families with options they have not had before. If they relapsed off ex vivo or aren’t eligible for insurance, we want to provide the optionality with in vivo CAR T gene therapy.”
If in vivo CAR T gene therapy proves safe and effective and the treatment options expand, the main thing keeping these therapies from patients will be when they can be brought into the patient’s journey. Currently, CAR T is only entertained as an option once everything else has failed. For CAR T to get on the map required a leap of faith in people like Emily Whitehead and her family. If and when CAR T can be reliably offered at scale and reasonable costs, then one day, it may be provided as a first-line treatment.
