CAR-T therapy has been used most successfully to treat some of the more acute blood cancers, less so in treating CLL and with limited success in solid tumours. "Autologous" CAR-T therapies involve a time-consuming and expensive process: the extraction of T cells from the patient, genetically engineering the best cells into a CAR to target the cancer, then expanding the CAR numbers by the million before reinjecting them into the patient.
"Allogeneic" CAR-T therapies use off-the-shelf CARs, derived from healthy donors of T cells, their big advantage being that they can be produced more economically in large quantity and stored ready for use. Their big disadvantage is the likelihood that the patient's immune system will recognise the donated cells as foreign and reject them. Immune-suppressing drugs, like those given to organ transplant recipients, may counter allogeneic CAR T rejection, but in doing so may put the patient's life at risk from infections. Researchers have now turned to HIV, isolating the protein Nef, one of the so-called evasins responsible for shielding the virus from the host's immune system.
From genengnews.com/topics/cance...
The researchers tested the different CAR T cells in a mouse model that contained human immune cells, and observed Nef, which is used by the HIV virus to evade detection by the immune system, was the best viral protein to best survive in this setting. It reduced a protein called HLA-I on the surface of the CAR T cells. HLA-I normally serves as a red flag to the immune system, signaling that something is wrong and inviting attack—reducing HLA-I helped the cell stay undetected. In addition, Nef helped prevent apoptosis in the CAR T cell. “Those two mechanisms combined showed that Nef is uniquely suited to creating a powerful allogeneic CAR T cell,” Perica said.
The researchers hope they can begin testing the CAR T cells in clinical trials at some point. Off-the-shelf CAR T cells are already being tested at MSK to treat multiple myeloma, although that treatment requires immune-suppressing drugs as part of the therapy. This new advance could potentially create off-the-shelf CAR T cells that do not need deep immune suppression, which comes with an increased risk of side effects such as infection.
“The multiple discoveries coming out of Sadelain’s lab have helped bring us closer to the day when we have CAR T cells right at hand to give to patients without delay,” Perica said. “Removing the need for manufacturing personalized CAR T cells would make the treatment much more widely available and more affordable.”
Nef-powered allogeneic CAR T products are some way from the clinic, and may never get there, but I find it heartening to see such innovation, and a lot of research effort, going into the development of this therapy. As CAR T treatments become viable for solid tumours, they surely will for CLL.
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