A gene therapy that uses infusions of patients’ own T cells genetically engineered to attack their tumors enjoyed its first successful and sustained demonstration of clinical-trial success in nine of 12 leukemia patients—two of whom have been in remission for more than two years.
The therapy was pioneered by the University of Pennsylvania’s Perelman School of Medicine, whose researchers will present latest results from the study today at the American Society of Hematology (ASH)'s Annual Meeting and Exposition in Atlanta.
According to Penn Perelman, the results pave the way for a potential paradigm shift in the treatment of these types of blood cancers, which in advanced stages have the possibility of a cure only with bone marrow transplants. Transplantations require lengthy hospitalizations and carry at least a 20% mortality risk, with only a limited chance of cure for patients whose disease has not responded to other treatments.
“Chimeric antigen receptor-modified T cells have great promise to improve the treatment of leukemia and lymphoma," the trial's leader, Carl June, M.D., the Richard W. Vague professor in immunotherapy in the department of pathology and laboratory medicine and director of translational research in Penn's Abramson Cancer Center. "It is possible that in the future, this approach may reduce or replace the need for bone marrow transplantation."
The new treatment uses an apheresis process similar to blood donation to remove patients' cells, then modify them in Penn's cell and vaccine production facility. There, scientists apply a gene modification technique to target tumor cells by reprogramming patients' T cells using a HIV-derived lentivirus vector. The vector encodes a chimeric antigen receptor (CAR), an antibody-like protein expressed on the surface of the T cells, and designed to bind to the protein CD19.
Modified cells are infused back into the patient's body following lymphodepleting chemotherapy. Once T cells start expressing the CAR, they focus all of their killing activity on cells that express CD19, which includes CLL and ALL tumor cells, and normal B cells. All other cells are ignored by the modified T cells, thus limiting the side effects typically experienced during traditional therapies.
A signaling molecule built into the CAR also spurs the cell to produce cytokines that trigger other T cells to multiply until all target cells in the tumor are destroyed.
In patients experiencing complete remissions after treatment, CAR T cells exhibited vigorous proliferation after infusion, with the strongest expansion activity usually occurring between 10 and 31 days after infusion. Each of these patients developed a cytokine release syndrome—marked by fever, nausea, hypoxia, and low blood pressure—which doctors treated with tocilizumab.
Ultimately, the modified T-cell treatment eradicated large amounts of tumors in these patients, as well as normal B cells used by the body's immune system to fight infection. Patients were given regular gamma globulin treatments as a preventive measure.
Clinical trial participants included 10 adult patients with chronic lymphocytic leukemia treated at the Hospital of the University of Pennsylvania, and two children with acute lymphoblastic leukemia treated at the Children's Hospital of Philadelphia.
At the ASH annual meeting, abstracts about the new research will be presented later today by David Porter, M.D., director of blood and marrow transplantation in the Abramson Cancer Center; Michael Kalos, Ph.D., director of the translational and correlative studies laboratory at Penn; and Stephan Grupp, M.D., Ph.D., director of translational research in the Center for Childhood Cancer Research at the Children's Hospital of Philadelphia.