A broad new strategy could hold hope for treating virtually all blood cancers with CAR T cell therapy, which is currently approved for five subtypes of blood cancer. Scientists in the Perelman School of Medicine have demonstrated the potential efficacy of this approach in preclinical tests.
In the study, published in Science Translational Medicine, the researchers used engineered CAR T cells to target CD45—a surface marker found on nearly all blood cells, including nearly all blood cancer cells. Because CD45 is found on healthy blood cells too, the research team used CRISPR base-editing to develop a method called “epitope editing” to overcome the challenges of an anti-CD45 strategy, which would otherwise result in low blood counts, with potentially life-threatening side effects. The early results represent a proof-of-concept for epitope editing, which involves changing a small piece of the target CD45 molecule just enough so that the CAR T cells don’t recognize it, but it can still function normally within the blood immune system.
“Up to this point, we haven’t had the tools to create a targeted cell therapy approach that could work across all different forms of blood and bone marrow cancers,” says senior corresponding author Saar Gill, an associate professor of hematology-oncology. “We’re excited to create a new solution that could solve a major issue in immunotherapy, which is the inability to target surface markers that are found on both cancer cells and healthy cells.”
Because CD45 is found on nearly all blood cells—and is usually highly expressed on blood cancer cells—a treatment that wipes out all CD45-bearing cells would leave patients without any blood cells, including red blood cells, platelets, plasma, and even the marrow-based stem cells that generate new blood cells.
Furthermore, since T cells are blood cells and normally express CD45, CAR T cells targeting CD45 effectively would kill each other before they could be infused into patients.
The team built on previous work to overcome this challenge, using CRISPR base-editing to develop a new strategy called epitope editing. This involves the genetic modification of both the CAR T cells and blood stem cells to alter a small piece of the CD45 structure or “epitope” where the CAR T cells bind to the CD45 molecule. The altered version of CD45 still works but differs enough from normal CD45 that the anti-CD45 CAR T cells do not recognize and attack it.
“It’s essentially a blood stem cell transplant paired with CAR T cell therapy,” says lead author Nils Wellhausen, a graduate student in pharmacology and a member of Gill and June’s labs. “The idea is that when the engineered cells are infused, the CAR T cells kill the cancer cells that bear normal CD45, but don’t kill each other or the newly engineered blood stem cells. This allows the engineered blood stem cells to begin making new blood cells.”
Read more at Penn Medicine News.
