CAR T Cell Therapy To Treat All Blood Cancers

With CAR T cell treatment, which is now licensed for five kinds of blood cancer, a broad new approach may offer promise for treating almost all blood cancers. Researchers from the Perelman School of Medicine at the University of Pennsylvania have shown in preclinical studies that this method may be effective.

Using modified CAR T cells, the researchers in the study—which was just published in Science Translational Medicine—targeted CD45, a surface marker present on almost all blood cells, including almost all blood cancer cells. The research team employed CRISPR base-editing to create a technique termed “epitope editing” to circumvent the problems of an anti-CD45 strategy, which would otherwise result in low blood counts with possibly life-threatening adverse effects. CD45 is located on healthy blood cells as well.

The preliminary findings show the viability of epitope editing, which modifies a small portion of the target CD45 molecule just enough to prevent it from being recognized by CAR T cells while preserving its ability to operate normally in 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,” said senior corresponding author Saar Gill, MD, Ph.D., 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.”

Based on their target antigens, each of the cell-based immunotherapies for blood cancer that are currently available is made to be effective against a specific subset of malignancies. For instance, Carl June, MD, the Richard W. Vague Professor of Immunotherapy, created the first CAR T cell treatment at Penn to treat B-cell lymphomas and leukemias by specifically targeting the CD19 protein marker on B cells.

CD19 is the target of four of the six CAR T cell treatments that have been given approval to treat blood malignancies. To treat multiple myeloma, the other two drugs target the BCMA protein marker. Despite the remarkable success of CAR T cell therapy, scientists at Penn and elsewhere are attempting to make it even more efficient for a wider range of patients.

“One drawback of the current approach to CAR T cell therapy is that each therapy must be developed individually based on the targets for that cancer type,” said June, co-senior author of the study, who also directs the Center for Cellular Immunotherapies at Penn. “This study lays the groundwork for a more universal approach that could potentially expand CAR T cell therapy to all blood cancers.”

A treatment that eliminates 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 produce new blood cells, as CD45 is present on nearly all blood cells and is typically highly expressed on blood cancer cells. Additionally, because T cells generally display CD45 and are blood cells, CAR T cells that specifically target CD45 would kill one another before they could be administered into patients.

To solve this difficulty, the scientists improved upon earlier work and created a novel method called epitope editing using CRISPR base-editing. In order to change the “epitope”—a small region of the CD45 structure where the CAR T cells connect to the CD45 molecule—both blood stem cells and CAR T cells must undergo genetic mutation. While the modified CD45 still functions, it is sufficiently different from the original CD45 that CAR T cells that are designed to fight against CD45 do not detect it and attack it.

“It’s essentially a blood stem cell transplant paired with CAR T cell therapy,” said 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.”

The method could potentially be used as a milder form of chemotherapy conditioning, which is given to patients prior to a bone marrow transplant to suppress the immune system, because it replaces the stem cells that produce new blood cells.

The approach was put to the test by the researchers using a wide range of cell culture and mouse model tests. They demonstrated that the new strategy allows for the quick eradication of blood cell malignancies while also preventing anti-CD45 CAR T cells from targeting stem cells or other cells. In one experiment, the anti-CD45 CAR T cells killed leukemia cells three weeks after injection and continued to exist and be able to do so more than two months later.

Prior to entering Phase I clinical trials, more toxicity and modeling investigations are being conducted in preparation for an investigational new drug application.

Source Link