On December 16, 2025 Vyriad, Inc., a clinical-stage biotechnology company developing targeted genetic therapies for cancer and other serious diseases, reported detailed data on its lentiviral vector retargeting technologies and its lead therapeutic in vivo chimeric antigen receptor (CAR) T program, VV169, at the recently concluded 67th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.
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The first poster detailed the company’s three in vivo T-cell-targeted delivery systems, the first of which will soon be tested clinically through the VV169 program in a U.S.-based clinical trial in patients with multiple myeloma. The second poster presented strong preclinical data for VV169 that supports its progression into clinical development. The therapy achieved a durable complete resolution of disease in mice with disseminated myeloma at all doses, including the lowest level.
"While we have recently seen remarkable proof-of-concept for in vivo CAR T in heavily pretreated multiple myeloma, the next hurdle is eliminating infusional toxicities, so that we can truly unlock the promise of this modality," said Stephen Russell, M.D., Ph.D., CEO of Vyriad. "Our singular focus is solving this technology challenge, and the data presented at ASH (Free ASH Whitepaper) demonstrate Vyriad’s strong and rapid progress. We are advancing our vectors’ targeting, transduction and safety capabilities to ensure this new generation of in vivo CAR T therapies carries the field’s momentum forward."
While recent breakthroughs have validated in vivo CAR T as a scalable alternative to complex ex vivo therapies, Vyriad sees an opportunity to optimize the modality for broad clinical use. Leveraging its deep expertise in virology and oncolytic viruses, the company has developed a proprietary platform anchored in advanced G protein engineering, yielding lentiviral vectors with high serum stability and enhanced transduction efficiency — key requirements for safe, precise, and low-dose in vivo gene delivery.
Evaluation of three in vivo targeting approaches
Vyriad has developed three distinct retargeting strategies to selectively transduce resting T cells in the lymphoid niche. This effort is part of the company’s ongoing pursuit of improving lentiviral vector targeting not only for precise and safe delivery, but also to streamline manufacturing and development even further. The three methods are:
Direct Covalent Display: This approach uses a chimeric VSV-G protein that displays a CD3-targeting ligand but is modified to blind its natural interaction with the low-density lipoprotein (LDL) receptor. This method was then applied to retarget the LV169 vector used in the VV169 program, enabling precise T-cell targeting for in vivo CAR T delivery.
Trimeric Adapter Proteins: A protein adapter is used to "cap" the unmodified VSV-G trimer and redirect it to CD3 while masking its ability to bind to natural receptors. This was achieved by mixing a conventional lentiviral vector with trimeric adapter proteins. The association between the G protein trimer and the trimeric cap remained highly stable during freeze-thaw cycles and at room temperature, underscoring its viability as an in vivo targeting platform.
Modular Covalent Display: SPY-tagged VSV-G proteins are covalently modified by mixing them with a SPY-catcher/CD3 ligand fusion protein at room temperature, which spontaneously binds SPY-tag, thereby redirecting entry to the SPY-catcher targeting ligand.
The direct covalent display method is currently undergoing clinical translation through VV169. Manufacturing studies for all three targeting approaches are currently underway.
Lead in vivo CAR T candidate VV169
VV169 is designed as a single intravenous administration of a B-cell maturation antigen (BCMA)-targeted CAR transgene, delivered by the LV-169 lentiviral vector. The second poster presented at ASH (Free ASH Whitepaper) 2025 details the complete elimination of disseminated multiple myeloma in humanized mouse models.
Key highlights of the data include:
100% of mice treated with a single intravenous injection of therapy cleared OPM-2 tumors completely within 28 days. This response held true for all dose levels, including the lowest dose tested. The mice remained tumor-free 84 days post-treatment and successfully resisted tumor re-challenge.
The treatment was well tolerated. Analysis of cytokines confirmed the absence of a severe cytokine storm. While IFNγ was elevated during T-cell expansion, inflammatory markers, such as IL-6, TNFα and GM-CSF, were barely detectable.
The use of a T-cell-specific promoter prevented CAR protein from being expressed on the virus particle itself, minimizing off-target gene delivery to myeloma cells
Vyriad is continuing preclinical work for the development of VV169 and plans to begin a clinical trial in the U.S. in 2026.
(Press release, Vyriad, DEC 16, 2025, View Source [SID1234661474])