The first of its kind personalized cellular therapy trial at University of Pennsylvania has yielded promising results with eight of 14 patients responding to the therapy, with some complete remissions continuing past four and a half years.
The findings of the trial published in Science Translational Medicine, is pegged as one of the most mature data set from a clinical trial for an approach known as CTL019.
The trial began in summer of 2010 with 14 patients who have had their chronic lymphocytic leukemia (CLL) relapse or continued to progress after receiving multiple conventional Food and Drug Administration-approved therapies. Few of these patients were even eligible for bone marrow transplants. Researchers revealed in their report that the overall response rate of the therapy was 57 per cent.
The approach of therapy dubbed CTL019 begins with collection of each patient’s own T cells. These collected cells are reprogrammed to hunt and potentially kill cancer cells in the patient’s body. Patients are first administered lymphodepleting chemotherapy, after which they receive an infusion of their newly engineered cells.
The modified T cells contain an antibody-like protein known as a chimeric antigen receptor (CAR), which is designed to target the CD19 protein found on the surface of B cells, including the cancerous B cells that characterize several types of leukemia and lymphoma.
Researchers revealed in their finding that all patients who responded to the investigational T cell therapy developed cytokine release syndrome (CRS) within several weeks after their infusions, typically during the time when the modified cells expanded to their greatest number in the body.
However, there were varying levels of side effects ranging from flu-like symptoms, with high fevers, nausea, and muscle pain, to neurologic symptoms including hallucinations and delirium. Four patients experienced more severe symptoms, including low blood pressure and breathing difficulties, which required intensive care.
Prior CAR studies have shown that CRS can be a very serious and life-threatening toxicity. The Penn team has developed a management strategy to treat these side effects, including the antibody drug tocilizumab, which was used in four patients, and two patients received steroids. All recovered from their CRS.
According to researchers four patients (29 per cent) achieved a complete remission. One patient died while in remission at 21 months after the therapy due to infectious complications that occurred after removal of a basal cell carcinoma on his leg. The three other patients remained alive at the time of this analysis with no evidence of leukemia at 28, 52, and 53 months after receiving their infusions, with no further therapy.
An additional four patients (29 per cent) achieved partial responses to the therapy, with responses lasting a median of seven months. During the period analyzed, two of these patients had died of disease progression at 10 and 27 months after receiving CTL019, and one died after suffering a pulmonary embolism six months after T cell infusion. One patient’s disease progressed at 13 months but remained alive on other therapies at 36 months after receiving the therapy.
Six patients (43 per cent) did not respond to the therapy and progressed within one to nine months; tests revealed that the modified T cells did not expand as robustly in these patients as in those who experienced remissions. Two of these subjects later died from their disease or complications of other therapies, and four are receiving other types of treatment.
“The durability of the remissions we have observed in this study are remarkable and have given us great hope that personalized cell therapies are going to be important options for patients whose cancers are no longer treatable with standard approaches,” said lead author David L. Porter, MD, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and director of Blood and Marrow Transplantation in Penn’s Abramson Cancer Center.
“Importantly, our tests of patients who experienced complete remissions showed that the modified cells remain in patients’ bodies for years after their infusions, with no sign of cancerous or normal B cells,” said the study’s senior author, Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy in Penn’s department of Pathology and Laboratory Medicine and director of Translational Research in the Abramson Cancer Center. “This suggests that at least some of the CTL019 cells retain their ability to hunt for cancerous cells for long periods of time.”
