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Chimeric antigen receptors are artificial structures added to immune cells such as T cells in order to direct the cells to aggressively attack a cancer. Such CAR-T therapies have proven effective against leukemia, and researchers are working on making them effective for solid tumors as well. At present delivering such a therapy is a slow and onerous process, requiring cells to be harvested from a patient, engineered, expanded in culture, and then injected. This is very expensive. A potentially cheaper approach is to use gene therapy tools to engineer some fraction of circulating T cells in situ in the patient. Researchers have been working on this for a while now, and here find a proof of principle demonstration carried out in mice.

CAR-T cells are made in the laboratory by tinkering with the genetic instructions in immune cells called T cells that are removed from a patient. In particular, the T cells are tweaked to recognize and bind to a protein called CD19 that is abundant on other immune cells called B cells. Many blood cell cancers, including some types of lymphomas and leukemias, develop due to uncontrolled B cell growth.

In this study, researchers used tiny, fat-soluble bubbles called lipid nanoparticles to package messenger RNA (mRNA) molecules encoding a receptor protein that binds to CD19 as well as a modified version of another protein that is highly expressed in prostate cancer cells but is rare in other tissue. This second protein allows the researchers to trace the generation and movement of the recipient cells noninvasively using a common medical imaging technique called positron emission tomography. Finally, they designed the surface of the nanoparticles to include an antibody that binds to a protein called CD5 that is primarily found on T cells. Once the nanoparticle latches onto the T cell, it is engulfed, the lipid bubble disintegrates and the mRNA molecules are released into the interior of the cell to be made into proteins.

When researchers injected the nanoparticles into mice with a type of B cell lymphoma, they were able to track the generation of the CAR-T cells in the animals - or "in situ" - and see that they traveled to the location of the animals' tumors. The in situ method generated about 3 million CAR-T cells per animal, which is similar to the cell numbers infused into patients undergoing conventional CAR-T therapy. Importantly, the newly generated CAR-T cells were efficient cancer killers; six out of eight mice with lymphoma were tumor-free 60 days after treatment began, and tumor growth in the remaining two was controlled.

Link: https://med.stanford.edu/news/all-news/2025/07/in-situ-t-cell.html