CAR T cell therapy is one of the most promising new cancer treatments to emerge in recent years. CAR T cells are engineered cancer immunotherapies that boost or hijack a person’s immune system to target their cancer. To date, all of the approved CAR T cell therapies are autologous approaches—dependent on extracting a patient’s T cells, engineering them to express a CAR that redirects them to tumor targets, expanding them ex vivo, and reintroducing them to the patient. A major limitation to this type of CAR T cell therapy, called autologous therapy, is that the cells are taken from the patient and must be custom-made into a treatment. Now, researchers at Memorial Sloan Kettering Cancer Center (MSK) report a new advance that could make it possible to use off-the-shelf CAR T cells provided by healthy donors and stored, so they are ready as soon as the patient needs them.
Their findings are published in Nature in an article titled, “HIV immune evasin Nef enhances allogeneic CAR T cell potency.”
“Autologous chimeric antigen receptor (CAR) T cells are a genetically engineered therapy that is highly effective against B cell malignancies and multiple myeloma,” the researchers wrote. “However, the length and cost of personalized manufacturing limits access and leaves patients vulnerable to disease progression. Allogeneic cell therapies have the potential to increase patient access and improve treatment outcomes but are limited by immune rejection. To devise a strategy to protect allogeneic CAR T cells from host immune cells, we turned to lymphotropic viruses that have evolved integrated mechanisms for immune escape of virus-infected lymphocytes.”
The research identifies a way to modify the donor CAR T cells, called allogeneic CAR T cells, so that they won’t be rejected by the patient receiving them and will persist in fighting the cancer.
The new approach involves equipping the CAR T cells with a protein called Nef. The researchers showed that inserting Nef into donor CAR T cells enabled the cells to survive and remain potent in a mouse model for cancer.
“This could be an important step toward creating safe and effective allogeneic CAR T cells, which would greatly increase the number of patients who could benefit from this immunotherapy,” said physician-scientist Karlo Perica, MD, PhD, the study’s first author.
The research was conducted in the laboratory of Michel Sadelain, MD, PhD, who is a pioneer of CAR T cell therapy.
The research builds upon recent technical advances made in the Sadelain laboratory. The scientists knew that viruses had an array of tools to evade or withstand immune attack after entering the body and infecting cells.
“We wanted to learn which components of the immune system might cause rejection of donor CAR T cells, and how different viral proteins could figure out a way around that,” Perica said. “We thought that these viruses, which have been invading cells for millennia, would have something to teach us about avoiding immune detection and keeping the cells that they invade alive.”
To identify the viral protein providing the most protection, the researchers used CRISPR to insert different viral proteins at a precise region in the genome of the CAR T cell called the TRAC locus.
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.”
