CAR T cell therapy is one of the most promising new cancer treatments to emerge in recent years. It involves removing a patient's own immune T cells and engineering them to recognize specific targets on the surface of the cancer cell.
A major limitation of 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. This requires patients to wait until their cells are modified for infusion — precious time they may not have.
Now research done at Memorial Sloan Kettering Cancer Center (MSK) has demonstrated 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. 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," says physician-scientist Karlo Perica, MD, PhD, the study's first author.
The research, published in Nature , was conducted in the laboratory of Michel Sadelain, MD, PhD, who is a pioneer of CAR T cell therapy. (Dr. Sadelain left MSK in the fall of 2024.)
Using Viruses to Study How Cells Can Evade Immune Attack
The research builds upon important technical advances made in the Sadelain laboratory in recent years. The scientists knew that viruses had an array of tools to evade or withstand immune attack after entering the body and infecting cells. (When a virus invades a cell, it must keep the cell alive long enough for the virus to make copies of itself using the cell's machinery.)
"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," Dr. Perica says. "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 employed advanced tools developed in the Sadelain lab. By using a gene-editing tool called CRISPR, they could insert different viral proteins at a precise region in the genome of the CAR T cell called the TRAC locus.
CAR T cells made in this fashion have some remarkable properties. They maintain their cancer-fighting ability for a long time. In addition, inserting a protein at the TRAC locus replaces a receptor that can cause a donor T cell to attack the recipient's tissue — what is known as graft vs. host disease.
The researchers tested the different CAR T cells in a mouse model that contained human immune cells, making it possible to see which viral protein equipped the cells to best survive in this setting.
Nef Helps CAR T Cell Survival
The clear winner was a protein called Nef, which is used by the HIV virus to evade detection by the immune system. It worked in two ways: First, 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 a form of cell suicide called apoptosis in the CAR T cell.
"Those two mechanisms combined showed that Nef is uniquely suited to creating a powerful allogeneic CAR T cell," Dr. Perica says.
The hope is to begin testing these 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 Benefits of Donor CAR T Cells
Allogeneic CAR T cells could offer additional advantages for fighting cancer. Cancer patients tend to be older and have often received treatments such as chemotherapy that can weaken their immune cells. By contrast, allogeneic T cells could come from donors who are younger and healthier, making the modified cells more likely to survive after infusion.
"The multiple discoveries coming out of Dr. 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," Dr. Perica says. "Removing the need for manufacturing personalized CAR T cells would make the treatment much more widely available and more affordable."
