New Trend of mRNA LNPs Platform: In-Vivo CAR-T(M) Therapy

The researchers from the Perelman School of Medicine of the University of Pennsylvania published a paper entitled “CAR T cells produced in vivo to treat cardiac injury” on the “Science” on Jan 6th, 2022. The study demonstrated that the injection of mRNA LNP is capable of creating CAR-T cells in vivo directly, which can attack specific targets through a single injection of mRNA to successfully attack cardiac fibroblasts in rats with heart failure and restore their heart function.

(CAR)T cell therapy, a type of cellular immunotherapy, is used to fight against harmful cells with the immune cells of the patients acting as target sites. In order to target specific cells, the researchers will use the technique to collect the patient’s T cells and then gene-edit them to express specific chimeric receptors before reinjecting them into the patient’s body. In this process, the patient will acquire immune ability against the specific antigen.

At present, the CAR-T therapy is mainly used for cancer treatment. However, as the reprogrammed CAR-T cells can survive in vivo for months or even years, it will attack the fibroblasts continuously which result in a weakened wound healing ability when it is applied to heart failure or other fibrotic diseases. The research team encapsulated mRNA in bubble-shipped miniature lipid nanoparticles (LNPs) and injected them into rats in a way similar to mRNA vaccines. After the encapsulated mRNA molecules were captured by T cells, T cells gained the ability to specifically targeted attack cardiac fibroblasts. As the mRNA was not integrated into the T cell’s DNA, aggressive T cells only existed for a few days. Subsequently, the T cells returned to normal and was no longer aggressive against fibroblasts.

Afterwards, the research teams reported to develop an in vivo engineered CAR-M monocyte therapy for cancer treatment. The mRNA LNP which is used to target the target cells was designed, and the target cells were reprogrammed using the gene editing function of mRNA to become specific targeted CAR-M cells capable of killing tumor cells.

This research expanded the applications of the mRNA platform. Modifying and reprogramming the in vivo cells using mRNA LNP is more cheaper and accessible as it can avoid a series of complex in vitro processes of traditional in vitro CAR cell therapy and greatly reduce the difficulty and cost of preparation. In addition, as the mRNA does not enter the nucleus and edit the DNA of the T cells, the modified CAR cells with potentially controllable safety and tolerance are only aggressive for a few days.

As a new technique, there are still a lot of possible problems in the practical application for therapy use. For instance, the quantity and quality of in-vivo immune cells of most of the clinically enrolled cancer patients are very poor as they have already received multi-line therapy before. As a result, whether they can respond to mRNA LNP to produce enough CAR immune cells for tumor killing use is still unknown. In addition, the problems including targeting, delivery efficiency and toxicity etc. must be solved before the technique is actually used for treatment.

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