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.

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.

CELMoDs are being actively trialed as a maintenance therapy after CAR T-cell treatment. The strategy is to leverage the CELMoDs' ability to enhance T-cell function and upregulate effector T-cells to boost the activity and persistence of the CAR-T product, potentially leading to more durable responses and preventing relapse.

Colonia Therapeutics' CEO argues that lentiviral delivery is ideal for oncology's required long-term persistence, while LNP delivery is better suited for autoimmune indications needing transient, multi-dose responses. This frames them as complementary technologies for different therapeutic "swim lanes" rather than as direct rivals in a zero-sum game.

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.

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.

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.

Five-year follow-up from the CARTITUDE-1 trial suggests a potential cure for multiple myeloma is achievable. With roughly one-third of heavily pretreated patients remaining in remission at five years—and some confirmed as MRD-negative—the concept of a cure is now part of the operational discussion among specialists, a monumental shift for a disease long considered incurable.