NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)