While in vivo CAR-T therapies eliminate complex ex vivo manufacturing, they introduce a new critical variable: the patient's own immune system. The therapy's efficacy relies on modifying T-cells within the body, but each patient's immune status is different, especially after prior treatments. This makes optimizing and standardizing the dose a significant challenge compared to engineered cell therapies.

An investigational in vivo CAR-T therapy uses viral particles infused directly into the patient to convert their T-cells into CAR-T cells. This approach eliminates the complex steps of apheresis, lymphodepletion, and ex vivo manufacturing, effectively creating an off-the-shelf product that becomes an autologous treatment inside the body.

While personalized cancer vaccines require extracting and processing a patient's tumor, Create Medicines' in vivo approach is entirely off-the-shelf. By delivering the programming directly into the body, they enable the patient's own immune system to do the complex, personalized work of attacking the cancer itself.

Early data from an in vivo CAR-T therapy suggests a paradigm shift is possible. By engineering T-cells directly inside the patient with a simple infusion, this approach could eliminate the need for leukapheresis and external manufacturing, completely disrupting the current cell therapy model.

While complex gene editing may be challenging in vivo, Colonia's platform presents a novel opportunity: targeting different immune cell types (e.g., T-cells and NK cells) with distinct payloads in a single treatment. This could create synergistic, multi-pronged attacks on tumors, a paradigm distinct from current ex vivo methods which focus on engineering a single cell type.

Create Medicines chose LNP-delivered RNA for its in vivo platform to give physicians control. Unlike permanent lentiviral approaches, repeatable dosing allows for adapting to tumor antigen escape and managing durability and safety over time. This flexibility is a core strategic advantage for complex diseases like solid tumors.

The T-cell delivery system is versatile. It can carry T-cell engagers for cancer, but also antibodies for Alzheimer's or oligonucleotides. By using different T-cell types (like regulatory T-cells), it can also be used to reduce inflammation, expanding its applicability beyond oncology.

Beyond transient RNA, Create has developed a unique retrotransposon based on the human Line-1 element. This technology allows for stable, scarless gene delivery using only RNA, providing an option for durable expression (e.g., for CD19 CAR-T) alongside their transient approaches, creating a highly versatile platform.

The platform doesn't just transport a drug. The T-cells themselves populate the tumor microenvironment, which is naturally 'cold' (lacking immune cells) in glioblastoma. This increases inflammatory activity, making the tumor more susceptible to the delivered therapeutic payload.