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Harnessing the Power of Modified T Cells to Treat Cancer
Personalized immunotherapy treatments help 90% of acute lymphoblastic leukemia patients achieve remission in a new study.
New data from the University of Pennsylvania and The Children’s Hospital of Philadelphia reveal that an immunotherapy, named CTL019, helped 90% of children and adults with acute lymphoblastic leukemia (ALL) who had failed to respond to prior treatments or relapsed multiple times achieve remission. Personalized cellular therapy CTL019 received a Breakthrough Therapy designation in July 2014 and is the first of its kind to receive this designation. The therapy harnesses the power of a patient’s own cells, where the manufacture of CTL019 begins.
To incorporate cancer-fighting genetic material into the host cells of each cancer patient, researchers from Penn’s Clinical Cell and Vaccine Production Facility extracted some of each patient’s T cells through apheresis, a practice in which the blood of the patient is passed through an apparatus that separates out one or more blood components and returns red cells and platelets to the circulation. The researchers exposed the cells to a modified strain of HIV-1 (the viral vector), and the virus containing the anticancer genes invaded the T cells. The T cells propagated, and then the reprogrammed T cells were reintroduced into the patient’s body. The engineered cells contained an antibody-like protein known as a chimeric antigen receptor (CAR) that is designed to bind to a protein called CD19 found on the surface of cancerous B cells. Simply put, the researchers reprogrammed the cells to deliver cancer-fighting genetic information into the DNA of the cancer patient’s host cells. This DNA, once incorporated back into the patient’s genome, trained the patient’s immune system to recognize and kill cancer cells.
Twenty-seven of the 30 patients in the study achieved complete remission after receiving the engineered cells, and 78% of patients were alive six months after treatment. Nineteen patients in the study currently remain in remission. Seven patients, however, relapsed between six weeks and eight-and-a-half months after their infusions, and three of these patients had cancers return as CD19-negative leukemia, which would not have been targeted by the modified cells.
A drawback of the treatment is that all those who achieved remission also had their normal, non-cancerous B cells eliminated along with their tumors. As a result, patients would need to receive immunoglobulin replacement therapies to maintain healthy immune systems. Despite this fact, the researchers note in a press release that “absence of normal B cells following CTL019 treatment indicates continued activity of the gene-modified T cells, which are thought to provide long-term, vaccine-like activity preventing tumor recurrence.”
The research on CAR therapies was funded partially by Novartis, an early supporter of this type of research. An alliance between the pharma company and Penn’s research team was formed in 2012 to study and commercialize novel cellular immunotherapies using CAR technologies. As a result of the partnership, Penn granted Novartis “an exclusive worldwide license to the technologies used in an ongoing trial of patients with chronic lymphocytic leukemia (CLL) as well as future CAR-based therapies developed through the collaboration,” according to a press release. Novartis has reportedly enlisted gene therapy specialist Oxford BioMedica to assist with the development of lentiviral vectors expressing CTL019; the partnership is valued at $90 million and will last three years.
The new research builds on prior research in 2011 wherein Penn researchers, led by Carl June, MD, the Richard W. Vague Professor in Immunology in the department of pathology and laboratory medicine in the Perelman School of Medicine and director of translational research at Penn's Abramson Cancer Center, concluded that two chronic lymphocytic leukemia patients treated with this gene-transfer therapy achieved remission more than a year after treatment. The current study, supported by Novartis, was also supported by the National Institutes of Health, the Leukemia and Lymphoma Society, and Stand Up to Cancer.
There were no treatment options left for many of the patients included in the study, says Stephan Grupp, MD, PhD, director of translational research in the Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia and professor of pediatrics in Penn’s Perelman School of Medicine. “The patients who participated in these trials had relapsed as many as four times, including 60% whose cancers came back after stem cell transplants,” he says in a press release. “The durable responses we have observed with CTL019 therapy are unprecedented.”
Penn Medicine
http://www.uphs.upenn.edu/news/News_Releases/2012/08/novartis/http://www.uphs.upenn.edu/news/News_Releases/2014/10/ctl019/