Last week, Vironexis Biotherapeutic, a cancer immunology company launched with $26 million in seed funding and an Investigational New Drug (IND) application clearance from the U.S. Food and Drug Administration (FDA). But unlike other immuno-oncology companies, Vironexis’s approach comes with a twist: it uses adeno-associated viruses (AAV) vectors to deliver gene therapy against cancer. Its lead candidate, VNX-101 is set to enter the clinic for the first-ever AAV-delivered cancer immunotherapy.
This trial could be an important step in the broader application of AAV technology in cancer therapy, which has historically been used to treat rare genetic diseases. As the field of oncology explores new ways to harness the immune system’s potential, Vironexis’ approach could represent a shift toward more streamlined, off-the-shelf immunotherapies.
So how does it work and what does it imply for the broader field of immuno-oncology? Let’s find out!
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Understanding the TransJoin platform and Vironexis‘ VNX-101
At the core of Vironexis Biotherapeutics’ efforts is its TransJoin platform, a technology designed to enhance the body’s immune response against cancer. The underlying principle of this platform is relatively straightforward: use AAV vectors to instruct the liver to secrete a therapeutic protein that guides T cells to recognize and attack cancer cells. This approach not only simplifies the treatment process but also provides a long-term, consistent delivery of the therapy, avoiding the peaks and troughs often seen in other immunotherapies.
Dr. Timothy Cripe, co-founder of Vironexis describes the technology as transforming the body into a cancer treatment factory. “Normally, the liver secretes hundreds of proteins into the bloodstream. We use gene therapy to instruct the liver cells to secrete one more, a therapeutic protein, that enters the bloodstream and attaches to T cells, causing it to recognize and destroy cancer cells.”
This technology relies on the liver’s natural function of secreting proteins into the bloodstream. The secreted proteins, enabled by AAV delivery, bind to CD19+ cancer cells and activate T cells via the CD3 receptor, triggering a targeted immune response. In the case of VNX-101, the therapy specifically targets acute lymphoblastic leukemia (ALL).
“The concept was inspired by the successes of gene therapy in correcting genetic diseases such as spinal muscular atrophy (SMA). If we can safely and effectively deliver a gene that has long-term effects, why can’t we use it to treat cancer?” said Cripe.
And they are using it for cancer, and not only ALL with VNX-101, Vironexis’ most advanced candidate. “Our second product in the pipeline (VNX-202) is treating HER2+ breast cancer and gastric cancer. We are thrilled with the results of our preclinical studies and plan to file our second IND in mid-2025. The beauty of the Vironexis platform approach is that we can relatively easily swap out the gene payload inside of the AAV to target any cancer antigen. For this reason, we have completed initial proof of concept across an additional eight indications,” said Allen Reha, chief development officer (CDO) of Vironexis.
The evolution of AAV: From rare diseases to cancer
AAV vectors have been a reliable platform for gene therapies targeting rare genetic disorders like SMA and inherited retinal diseases. Their low immunogenicity and ability to deliver long-term therapeutic effects have made them an ideal tool for these conditions. However, the application of AAV to oncology is relatively new, and companies like Vironexis Biotherapeutics are now pushing the boundaries of this technology.
Cripe explained why AAV is relevant beyond rare diseases and specifically for cancer. “AAV naturally tracks mainly to the liver after it is given by continuous intravenous (IV). That has been a challenge for rare diseases because the therapy was replacing a missing or defective protein that was the cause of the disease – such a situation often requires doses to be very high. In addition, such high doses need to fill up the liver and then go elsewhere, such as to nerves or muscles. Because of our mechanism of action, and because we only need it to go to the liver, we can use low doses that have less chance of causing side effects.”
But what does this approach bring to the table in comparison to more established technologies in immuno-oncology such as CAR-T or bispecific antibodies?
“It overcomes the limitations of bispecifics because those either need to be given by IV infusions for weeks or months wherein patients are hooked up to an IV all that time, or they need to be given frequent shots. Also, it avoids the peaks and valleys of drug levels one gets after each shot, as it provides a steady-state level, thus reducing the chances that cancer cells can evade the treatment during the valleys,” explained Cripe.
One of the key advantages of the TransJoin platform is its ability to offer an off-the-shelf solution, which contrasts with the personalized manufacturing required for CAR-T cell therapies. “It doesn’t require individualized manufacturing and is ready to use when needed; it doesn’t require conditioning chemotherapy like CAR-T does; it has a more gentle onset of T cell engagement, thus minimizing chances of side effects seen with CAR-T; and it is more effective because it utilizes the native T cell receptor for T cell activation, not a weaker chimeric receptor. It also engages all T cells, not just a subset that were manufactured, including those freshly produced by the patient’s bone marrow daily,” added Cripe.
Vironexis’ approach stands out in a crowded immuno-oncology landscape, where CAR-T therapies and bispecific antibodies have dominated the conversation. While these therapies have shown success, they come with challenges that Cripe claims Vironexis’ technology could overcome. But Vironexis might not be standing alone in that crowd for long. Indeed, it might only be a matter of time until other companies working with AAV vectors increase their focus on oncology.
What’s next: VNX-101 trial and beyond
The VNX-101 trial will proceed in two phases. “We need to find the right dose for patients. In part one of our planned trial of VNX-101, we will only enroll those patients who have a low burden of disease to give us time to make sure the dose is right. Once we confirm our dose is correct, then we will open up the trial in part two to sicker patients and younger patients, including pediatric patients down to age 13,” said Cripe.
“We believe the most powerful drug in the world is the human immune system. Technologies that are able to effectively harness that power to fight cancer will be the future. We are already seeing this broadly in the field and strongly believe that safer and more effective therapies, like ours, will rule the day. Our vision is to make the Vironexis products an adjuvant therapy delivered as soon as possible after the diagnosis of disease,” said Reha.
Success in the clinic would likely attract more interest from both biotech companies and large pharmaceutical players, potentially speeding up innovation and making gene therapies more accessible to a broader range of cancer patients.