In a previous blog (CAT-T + mRNA for Cancer Therapy), we discussed a special cancer therapy in which engineered CAR (chimeric antigen receptor) -T cells and mRNA encoding neoantigens were combined for enhanced treatment of blood cancers and solid tumors.
There is another approach that links these two terms together, wherein T cells are equipped with CAR through an in vivo process rather than an ex vivo process. The mRNA molecules are encoded with the CAR protein and administered, targeted for delivery to immune cells. These immune cells, such as T cells, take up the mRNA, translate it within the cells into CAR protein, and thus assist the immune cells in targeting tumor cells. Several biotech companies, including Moderna, Carisma, Capstan, and Orna, are currently exploring this possibility, and some have seen promising results from studies conducted in mice. However, this approach has not yet been tested on humans. Orna plans to initiate clinical trials in 2024.
When comparing this approach with ex vivo CAR-T cell therapy, it has its advantages and challenges:
- Overall, in vivo immune cell modifications are much more complex and less controllable compared to ex vivo methods. One challenge lies in the targeted delivery of mRNA molecules to immune cells and their uptake by these cells. The delivery platform needs to be carefully designed to specifically target immune cells. Conventional lipid nanoparticle (LNP) formulations wouldn’t suffice and must be replaced with other delivery systems or modified with different functional groups. Another challenge is the difficulty in controlling the quantity of immune cells taking up the mRNA and expressing the CAR protein. If this is not controlled, there may not be enough cells to effectively target and attack tumor cells. In ex vivo CAR-T cell therapy, the incubation step ensures the generation of enough cells, making this less of a concern.
- However, there are potential advantages to this approach as well. The main challenge with conventional CAR-T cell therapy is that, after the cells are extracted from the patient and undergo several steps of engineering to incorporate the CAR, they become vulnerable and unstable. Consequently, after they are reintroduced into the patient’s body, it becomes challenging for them to persist long enough and continuously proliferate to eliminate tumor cells. In contrast, in vivo modification of immune cells does not face this problem. Additionally, it offers the advantage of targeting different immune cells apart from T cells, such as macrophages or other myeloid cells. This could be a significant benefit since solid tumors often employ defense mechanisms to deter T cells1.
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