Engineering strategies to overcome current roadblocks in CAR T cell therapy in mice with pancreatic cancer by making IL-2 only when encountering a cancer cell
The University of California, San Francisco led synthetic biologists who were able to reprogram CAR T Cells to make IL-2 only when they encounter a cancer cell. The team found that this IL-2 production was most efficient at fighting tumours in mice with pancreatic cancer when it was activated through a pathway that was separate from the one used to recognize the cancer cell — a detail that could help in shaping future therapies, says Andrea Schietinger, a tumour immunologist at Memorial Sloan Kettering Cancer Center in New York City.
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T cells typically patrol the body, looking for foreign proteins displayed on the surface of cells. Such cells could be infected with a virus, for example, or they could be tumour cells that are producing abnormal, cancer-associated proteins. T cells called killer T cells can destroy abnormal cells.
The Challenge of Making the Next Generation of T Cells a Living, Stable, Active Candidate Anticancer Cytokine
The approach was approved to treat certain types of leukaemias and lymphomas. But researchers have been pursuing ways to make the treatments safer and more effective, and to expand their use to other diseases.
Other synthetic circuits have been designed to allow precise regulation of CAR expression, by placing it under the control of genetic elements that activate the necessary genes in response to a drug8. Most of the complicated designs have yet to go through the safety studies required for use in people.
The ability to turn the T cells on and off could also help to reduce a phenomenon called T-cell exhaustion, in which T cells become inactive after a prolonged period of stimulation, says Evan Weber, a cancer immunologist at the Children’s Hospital of Philadelphia in Pennsylvania. Some studies have found that giving T cells a ‘rest period’ can reduce T cell exhaustion and boost their overall effectiveness against tumours3.
Even so, the challenge of making such a ‘living drug’ from a person’s cells extends beyond complicated designs. Many of the newest candidates still face safety and manufacturing problems. “There’s an explosion of very fancy things, and I think that’s great,” says immunologist Michel Sadelain at the Memorial Sloan Kettering Cancer Center in New York City. “But the complexity cannot always be brought as described into a clinical setting.”
CRISPR, T cells, and Mol. Ther. How to Engineer and Design Chimeric Antigen Receptors (Dev. 12), by Alexander Marson and Robert A. Macaulay
As yet, there are no simple solutions to any of these problems. Mackall says that they have a long way to go. “But we’re seeing promising signals now.”
CRISPR has been used to modify T cells in many other ways. Alexander Marson and his colleagues used the genome editing tool to modify the expression of thousands of genes in T cells, and then looked at the effect the changes had on the production of an immune-regulating molecule called cytokines5. In another screen using CRISPR, the team found that reducing the activity of a protein called RASA2 enhanced the ability of CAR-T cells to kill their targets6. Marson says that learning from the genes we can turn up and turn down will help them behave as they want.
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