In the Cartitude 1 trial, the strongest predictor of long-term remission with Siltacel was a lower burden of disease (measured by bone marrow percentage and soluble BCMA levels), rather than the number of prior treatments. This implies using CAR-T therapy earlier in the disease course is more effective.

Create's strategy is not limited to a single cell type. They view success in solid tumors as requiring the programming of all immune cells. Their platform can specifically engineer myeloid cells, T-cells, and NK cells in vivo, orchestrating a coordinated, multi-pronged attack on cancer.

Despite exciting early efficacy data for in vivo CAR-T therapies, the modality's future hinges on the critical unanswered question of durability. How long the therapeutic effects last, for which there is little data, will ultimately determine its clinical viability and applications in cancer versus autoimmune diseases.

The efficacy of Siltacel stems from a powerful initial expansion that eliminates cancer upfront. The CAR-T cells are often undetectable beyond six months, indicating their curative potential comes from an overwhelming initial response rather than persistent, long-term immune policing of the disease.

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 success of CAR-T therapy hinges on the quality of the patient's own lymphocytes. Procuring T-cells earlier in the disease course, before they become exhausted from numerous prior therapies, results in a higher proportion of naive T-cells, leading to better CAR-T cell manufacturing and clinical outcomes.