Professor Saar Gill and Professor Carl June from the Perelman School of Medicine at the University of Pennsylvania published a research paper titled: Epitope base editing CD45 in hematopoietic cells enables universal blood cancer immune therapy in Science Translational Medicine, a sub-journal of Science.
CD45 exists on the surface of almost all blood cells (including, of course, blood cancer cells), and this study developed an “epitope editing” strategy using adenine base editors (ABEs). After base editing, CD45 can work normally in the blood system without being recognized by CAR-T cells.
Using this “epitope editing” strategy to modify hematopoietic stem cells and CAR-T cells. After infusion, these CD45-targeted CAR-T cells did not kill each other or the infused epitope-edited hematopoietic stem cells, but were able to kill blood cancer cells expressing normal CD45.
Professor Carl June, co-corresponding author of the paper and director of the Center for Cellular Immunotherapy at the University of Pennsylvania, said that one shortcoming of current CAR-T cell therapies is that each therapy must be developed individually according to the target of different cancer types. The study lays the groundwork for a more general approach that could potentially expand CAR-T cell therapy to all blood cancers.
CD45 is present on the surface of nearly all blood cells and is often highly expressed on hematologic tumor cells. If a CAR-T cell therapy targeting CD45 is developed, it can indeed eliminate blood tumor cells, but this will eliminate the patient’s other healthy blood cells, including red blood cells, platelets, and even bone marrow stem cells that produce new blood cells. In addition, T cells are also blood cells and usually express CD45. Therefore, CAR-T cell therapy targeting CD45 can kill each other before it is infused into the patient.
To overcome this challenge, the research team developed a new epitope editing strategy using base editing technology, which involves gene editing of CAR-T cells and hematopoietic stem cells (HSCs) to change the relationship between CAR-T cells and the “epitope” to which the CD45 protein binds. The base-edited CD45 is still effective, but it is very different from normal CD45, so CAR-T cells targeting CD45 cannot recognize and attack them.
So, this is essentially a combination of hematopoietic stem cell transplantation and CAR-T cell therapy. When these edited CD45-targeting CAR-T cells were infused, they were able to kill blood cancer cells carrying normal CD45, including patient-derived acute myeloid leukemia, B-cell lymphoma, and acute T-cell leukemia. But they did not kill each other, nor did they kill the transplanted epitope-edited hematopoietic stem cells. Unlike HSCs with direct gene knockout of CD45, epitope-edited HSCs were able to engraft, persist and differentiate to generate new blood cells.
The research team conducted extensive experiments in cell and mouse models to test the feasibility of this epitope editing strategy. The results of the trial showed that the new approach could not only prevent CD45-targeted CAR-T cells from cannibalizing or attacking epitope-edited hematopoietic stem cells, but also rapidly destroy blood cancer cells. In mouse experiments, CD45-targeted CAR-T cells eliminated leukemia cells within 3 weeks of infusion, and remained and were able to continue to kill leukemia cells more than two months later.
It is reported that the research team is conducting further toxicology experiments and verifying it in other models in preparation for entering human clinical trials.