Date: 2015-09-02
Type of information: Publication of results in a medical journal
phase:
Announcement: publication of results in Science Translational Medicine
Company: University of Pennsylvania (USA - PA) Novartis (Switzerland)
Product: CTL019 - tisagenlecleucel-T
Action mechanism: cell therapy/CAR-T cell therapy. CTL019 is an investigational, personalized T cell therapy, which was pioneered by Carl June and his team at Penn. In a CTL019 treatment cycle, immune cells (T cells) are drawn from a patient's blood. Then, using CAR technology, the T cells are reprogrammed to "hunt" cancer cells that express specific proteins, called CD19. CD19 is associated with a number of B-cell malignancies including ALL, CLL, diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. When the T cells are re-introduced into the patient's blood, the cells proliferate and bind to the targeted cancer cells and destroy them. These autologous T cells transduced with lentiviral vector containing a chimeric antigen receptor directed against CD19 were previously known as CART19. Novartis and Penn have an exclusive global agreement to research, develop and commercialize personalized CAR T cell therapies for the treatment of cancers. Novartis holds the worldwide rights to CARs developed through the collaboration for all cancer indications, including the lead program CTL019.
Disease: chronic lymphocytic leukemia (CLL)
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest news: * On September 2, 2015, eight of 14 patients in the first trial of the University of Pennsylvania's personalized cellular therapy for chronic lymphocytic leukemia (CLL) responded to the therapy, with some complete remissions continuing past four and a half years. These results, published in Science Translational Medicine, represent the most mature data from clinical trials of an approach known as CTL019, developed by a team from Penn's Abramson Cancer Center and the Perelman School of Medicine. In 2011, the research team published initial findings from the first three patients to enroll in the trial. Two of those patients had complete responses, and their leukemia remains in remission today, more than four and a half years after receiving the therapy. The first patient to receive the therapy recently marked five years cancer-free. The new study details the completed, 14-patient pilot trial of CTL019 for CLL, which began in the summer of 2010. The overall response rate was 57 percent. All patients who received the experimental therapy, which is made from their own immune cells, had cancer that had relapsed or continued to progress after receiving multiple conventional FDA-approved therapies, and few were eligible for bone marrow transplants. Four patients (29 percent) in the study 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 percent) 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 percent) 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. CTL019 begins with each patient's own T cells, collected through a procedure similar to dialysis. The cells are then reprogramed to hunt and potentially kill cancer cells in the patient's body. After the patient undergoes lymphodepleting chemotherapy, 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. 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. This condition included varying degrees of flu-like symptoms, with high fevers, nausea, and muscle pain, and 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. A laboratory experiment using CAR-modified T cells isolated from one of the first patients to receive the therapy confirmed the potential for long-term function of these cells: At nearly three years after infusion, the patient's CTL019 cells demonstrated immediate and specific reactivity against cells expressing CD19. Typically, patients whose healthy B cells disappear after treatment receive regular immunoglobulin infusions. This study did not identify demographic or disease-related factors, such as age or types of prior therapies, that could be used to predict response to the therapy, and no association between T-cell dose and response was observed. An ongoing dose-optimization study is exploring this relationship in greater detail. Further future areas of study may include strategies to combine CTL019 with immune checkpoint inhibitor drugs or other therapies to stimulate T cell recognition of tumor cells. Funding for the study was supported in part by a grant from Novartis, by grants from the Leukemia and Lymphoma Society (Specialized Center of Research Award), the National Institutes of Health (R01CA165206, K24 CA117879, R01CA102646 and R01CA116660).
