Leukemia patients face a frightening reality: The cells that are supposed to protect them from disease are themselves the source of their life-threatening illness. City of Hope researchers Simon F. Lacey, Ph.D., and Don J. Diamond, Ph.D., may have found a path to changing that.
|Simon Lacey (Photo by p.cunningham)|
Diamond, director of the Division of Translational Vaccine Research (TVR), and Lacey, formerly of the TVR division and currently director of the Clinical Immunobiology Correlative Studies Laboratory, lead a team of scientists seeking a vaccine against chronic myeloid leukemia, or CML. They reported on an important step in their quest in the Aug. 25 issue of the journal Blood.
Vaccine researchers such as Diamond and Lacey look for small molecular targets called antigens. These antigens can guide the immune system’s T cells to seek and destroy diseased cells. When the scientists find an antigen that is especially plentiful on — or even unique to — diseased cells, they use it to create a vaccine that boosts T cells’ ability to detect and kill those diseased cells.
One antigen that fits this profile in CML is an enzyme called proteinase 3. CML cells produce far more of this enzyme than normal cells do.
Digging deeper, other researchers have found that T cells actually recognize and react to a specific piece of the proteinase 3 enzyme called PR1.
Lacey and Diamond, however, showed that another piece of proteinase 3, called PR2, may be equally important, if not more so.
“Scientists initially dismissed PR2’s importance because their tests showed it probably wouldn’t cause an immunological reaction,” Lacey said. “We found otherwise.”
Using genetically engineered mice that model the human immune system, the scientists injected a vaccine that encourages the growth of T cells that recognize proteinase 3. Then they studied the T cells that developed. To their surprise, they found that nearly all of the T cells were the type that recognizes PR2.
“We didn’t expect that,” Diamond said. “Since PR2 was believed to be weaker at activating T cells than PR1, we would expect PR1-specific T cells to dominate.” But the opposite was true.
The team next examined blood samples from CML patients and found both PR1-specific and PR2-specific T cells, indicating that both types of T cells are present to potentially fight CML.
The study results suggest that developing vaccines targeting both PR1 and PR2 could significantly boost a patient’s immune response to CML cells, according to the researchers.
Researchers also believe a vaccine could boost therapy in a different way. Physicians potentially could vaccinate healthy stem cell donors before hematopoietic cell transplantation, so their donated T cells are primed to attack diseased cells as soon as they are infused into the CML patient.
“Normal donors often have low levels of T cells that recognize proteinase 3, so a vaccine that boosted these levels prior to transplantation could help protect the transplant recipients against any CML cells that survive pretransplant treatment,” Lacey said.
Other researchers on the study include City of Hope’s Corinna La Rosa, Ph.D., Teodora Kaltcheva, Ph.D., Tumul Srivastava, Ph.D., Aprille Seidel, Ph.D., Wendi Zhou, M.D., Ph.D., Ravindra Rawal, Ph.D., Katharine Hagen, Aparna Krishnan, Jeff Longmate, Ph.D., Ravi Bhatia, M.D., Vinod Pullarkat, M.D., and Stephen J. Forman, M.D., as well as Jeff Molldrem, M.D., and Laurence Cooper, M.D., Ph.D., from M.D. Anderson Cancer Center in Houston.
The study was funded by the National Institutes of Health and the Bill and Melinda Gates Foundation.