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Advancements in cancer care have been numerous in recent years, with several chimeric antigen receptor (CAR) gene therapies approved by U.S. and European regulators in the past decade. Now, a U.S. trial of an in vivo off-the-shelf therapy has expanded to Europe, marking the first trial of its kind in the region.
The phase 1 trial of INT2104, developed by the U.S.-based Interius BioTherapeutics, was signed off by German regulators to test the therapy on patients with B-cell cancers this week. Interius’ chief executive officer (CEO) Phil Johnson was “thrilled” to widen the study in the European Union (EU). The study in Germany follows the dosing of the first patient in Australia back in October.
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Global phase 1 trial for Interius BioTherapeutics’ in vivo CAR gene therapy INT2104
The investigational therapy INT2104 is a single dose that is delivered intravenously to patients. It is designed to target CD7, a protein that is highly expressed in blood cancers. Unlike other CAR gene therapies that have been greenlit, like Kymriah, Yescarta, and Carvykti, which are all ex vivo treatments, INT2104 works by creating CAR-T cells and CAR-natural killer (NK) cells in the patient’s body, which set out to kill cancerous B cells. Preclinical studies have shown that a single dose of the drug was able to destroy B cells and get rid of tumors in mouse models. A toxicology study demonstrated INT2104’s safety profile.
“In the phase 1 study, we will be looking for translation of these findings into human study participants, and our main focus will be on safety, safety and safety, as we are introducing a new treatment modality into clinical studies for the first time via intravenous administration. We plan to share interim safety and proof-of-concept data from the study in the second half of 2025,” Johnson told Labiotech.
The in vivo CAR gene therapy candidate is born from Interius’ lentivector platform. Lentiviral vectors are frequently used for stable gene delivery and expression in gene therapy. What’s unique about Interius’ platform technology is that in vivo therapies like INT2104 – where changes to patients’ cells occur inside the body – can be given to people without them having to undergo chemotherapy beforehand, which tends to be the case for many immunotherapies.
Ex vivo vs. in vivo: overcoming limitations
Despite the benefits of ex vivo CAR-T therapies, which have been effective in generating durable cancer remissions, Johnson expressed that “current ex vivo CAR-T cell therapies require the complex and time-consuming process of extracting cells from a patient, modifying them in a lab, and shipping them back to the patient for re-infusion many weeks later.”
“The personalized nature of ex vivo CAR-T cell therapies, where each therapy must be made specific to each patient, leads to extremely high treatment costs and logistical challenges. Patients must also undergo chemotherapy to prepare their bodies for CAR-T cell infusion, which can lead to severe side effects and, in some instances, patients are not able to withstand such treatment,” Johnson added.
In theory, an in vivo gene therapy approach would be able to overcome the limitations that ex vivo treatments pose. This includes eliminating the need for cell extraction, prolonged wait times, and chemotherapy.
“The Interius products are designed to be delivered by intravenous infusion, which is immediately available to the patients. The Interius manufacturing process is scalable and projected to deliver in vivo CAR-T treatments at a cost comparable to biologics, which is significantly lower than existing ex vivo CAR-T options,” said Johnson. “By simplifying the process, lowering the cost, and expanding access, in vivo CAR therapies hold the potential to transform cancer treatment and improve outcomes for a broad range of patients globally.”
While there aren’t any in vivo gene therapies for cancer that have been approved yet, drugs like Zolgensma for the muscle condition spinal muscular atrophy and Luxturna for Leber congenital amaurosis, a degenerative eye condition, are on the market. For conditions that affect the eye, brain, and liver, in vivo gene therapies are preferred since cells in these organs cannot be easily extracted.
In vivo CAR-T: Umoja, Allogene, and Vyriad discover and develop cancer treatments
Moreover, there are other in vivo CAR-T therapies in the clinic. American biotech Umoja Biopharma has been making moves in the space. Its in vivo CAR-T therapies are based on its VivoVec platform, which is also a lentiviral vector technology. Like INT2104, VivoVec-derived therapies enable the body to create its own CAR-T cells that target cancer. UB-VV111 is the first drug from the VivoVec pipeline that was cleared by the FDA to begin clinical trials last year.
Meanwhile, Allogene Therapeutics has also been working to take on the challenges of autologous CAR T therapies. Its AlloCAR T products use T cells from healthy donors. Its candidate ALLO-316, targeting CD70, is being evaluated in patients with advanced renal cell carcinoma. A phase 1 trial revealed that the drug had a 50% overall response rate and a confirmed response rate of 33% in patients with CD70 tumor proportion score (TPS) of greater than 50% – a measure of the level of CD70 in a tumor.
The company was awarded the Regenerative Medicine Advanced Therapy (RMAT) designation by the FDA in October.
Recently, Swiss pharma giant Novartis and Vyriad banded together to discover and develop in vivo CAR-T therapies. They aim to do so by leveraging Vyriad’s lentiviral vector platform.
As CAR gene therapies are being trialed to ensure safety and efficacy in people with cancer, the first in vivo CAR gene therapy INT2104’s debut in European clinics marks a significant milestone.
“Unlike current therapies for B-cell malignancies, which often involve lengthy wait times, significant toxicity, and high costs, Interius’ off-the-shelf CAR gene therapies aim to offer a “faster, better, cheaper” way to address patient needs, aspiring to “democratize” genetic medicine,” said Johnson, as high hopes for INT2104’s safety in the clinic lingers.
