Enhancing CAR T cells for blood cancer treatment

Epitope editing for universal blood cancer immunotherapy.


Researchers at the University of Pennsylvania have devised a new approach to treat many types of blood cancers using CAR T cell therapy. CAR T cell therapy is currently approved for only a few types of blood cancer. However, this new strategy could work for almost all of them. They used engineered CAR T cells to target a surface marker called CD45, found on most blood cells, including cancerous ones. 

However, because CD45 is also on healthy blood cells, they used an “epitope editing” technique to modify a small part of CD45. This modification makes it so CAR T cells don’t recognize it. However, it can still work usually in the immune system. This research is still early but shows promise for treating a wide range of blood cancers.

Senior corresponding author Saar Gill, MD, PhD, an associate professor of Hematology-Oncology, said, “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.”

Cell-based immunotherapies for blood cancer are currently designed to target specific markers on cancer cells. For example, some therapies target the CD19 marker to treat certain lymphomas and leukemias. In contrast, others target the BCMA marker for multiple myeloma. These therapies have been successful, but they must be developed individually for each cancer type.

Scientists are now trying to create a more universal CAR T cell therapy approach. They want to use CAR T cells that can work against many types of blood cancers.

However, there’s a challenge. CD45, a marker found on most blood cells and often on blood cancer cells, is essential for the blood system. If we remove all CD45-bearing cells, patients will lose all blood cells, including the ones that help clot, carry oxygen, and generate new blood cells. Additionally, CAR T cells themselves are blood cells that usually have CD45. So, if CAR T cells target CD45, they would destroy each other before they can help patients.

The team used CRISPR-based editing to create a new strategy called epitope editing. This involves modifying a small part of the CD45 structure so CAR T cells don’t attack it. This approach combines a blood stem cell transplant with CAR T cell therapy. It allows CAR T cells to target cancer cells with normal CD45 while sparing each other and the modified blood stem cells, which can then produce new blood cells.

This strategy could also be used as a milder form of chemotherapy before a bone marrow transplant. Tests in cells and mice showed that this approach effectively eliminates blood cell cancers without harming stem cells.

In conclusion, the epitope editing strategy significantly advances CAR T cell therapy. If successful in clinical trials, it could expand CAR T cell therapy to treat a wide range of blood cancers and offer a safer alternative to traditional chemotherapy conditioning.

Journal Reference:

  1. NILS WELLHAUSEN, RYAN P. O’CONNELL., Epitope base editing CD45 in hematopoietic cells enables universal blood cancer immune therapy. Science Translational Medicine. DOI: 10.1126/scitranslmed.adi1145.
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