Pilot Clinical Trial Shows Engineered Autologous T-Cell Therapy Eradicates CLL
Pennsylvania School of Medicine investigators say tumors were "blown away."!--h2>
Patients treated in an early clinical trial evaluating engineered autologous T cell therapy for advanced chronic lymphocytic leukemia (CLL) have had their tumors “blown away,” according to the trial investigators at the University of Pennsylvania School of Medicine. The trial involved therapy with patients’ own expanded T cells that had been engineered to express an anti-CD19 chimeric antigen receptor (CAR) including both CD3-ζ and the 4-1BB costimulatory domain (CART19 cells) to target CD19+ malignancies.
The resulting trial data, reported in Science Translational Medicine and NEJM, showed the engineered T cells expanded >1,000-fold in vivo, trafficked to bone marrow, and continued to express functional CARs at high levels for at least six months. A CD19-specific immune response was demonstrated in the blood and bone marrow, accompanied by complete remission in two of three patients, which has lasted for at least 10 months. A portion of the transplanted cells have also persisted as memory CAR+ T cells and retain anti-CD19 effector functionality.
Reporting on the trial results, Carl H. June, M.D., at the University of Pennsylvania’s Abramson Cancer Center and colleagues calculated that each infused CAR-expressing T cell eradicated, on average, at least 1,000 CLL cells. Some of the data from one patient in the trial is published in NEJM in a paper titled"Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid Leukemia." In the Science Translational Medicine paper published simultaneously, the investigators describe the T cell expansion and engineering process, and report further results from all three patients. This paper is titled “T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia.”
All three enrolled patients had been heavily pretreated for their CLL using standard therapies, and their only other option was a bone marrow transplant. When treated using the trial T cell therapy, the patients developed short-term toxic side effects within the first three weeks of receiving their first T cell infusion, but these effects, including high fever, transient cardiac dysfunction in one patient, and transient hypotension, were reversible, and appeared to be linked with clearance of leukemic cells. For the patient detailed in the NEJM paper, T cell therapy appeared to have little effect for the first two weeks, but the patient then developed a raft of symptoms including chills, nausea, and fever, which tests showed were associated with tumor lysis syndrome. By day 28 the patient had recovered, and his blood and bone marrow were also free from leukemic cells.
“Within three weeks, the tumors had been blown away, in a way that was much more violent than we ever expected,” Dr. June claims. “It worked much better than we thought it would...In addition to an extensive capacity for self-replication, the infused T cells are serial killers. On average, each infused T cell led to the killing of thousands of tumor cells and overall, destroyed at least two pounds of tumor in each patient."
The researchers claim their initial trial provides direct proof of principal for their approach, and they plan to test the same CD19 CAR construct in patients with other types of CD19-positive tumors, including non-Hodgkin lymphoma and acute lymphocytic leukemia, and in pediatric leukemia patients who have failed standard therapy.
Their work has in addition extended to the development of a CAR vector that binds to mesothelin, which is expressed on mesothelioma cancer cells, and on ovarian and pancreatic cancer cells.