New Therapy Triggers Remission in Leukemia Patients

Chronic lymphocytic leukemia treatment reprograms T cells to hunt and kill cancer cells.

Eight out of 14 patients with chronic lymphocytic leukemia (CLL) responded to a new therapeutic regimen that left some patients in remission passed four and a half years, a recent study indicates. These results represent the most mature data from clinical trials of a treatment known as CTL019, developed by a team from Penn’s Abramson Cancer Center and the Perelman School of Medicine.

In 2011, researchers published initial findings from the first 3 patients to enroll in the trial. Two of the patients achieved complete remission and remain in remission today; the first patient to be enrolled recently celebrated 5 years in remission.

“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. “The patients in this study are pioneers, whose participation has given us a foundation of knowledge and experience on which to build this new approach to help more patients.”

The study began in 2010 and included a 14-patient pilot trial of CTL019 for CLL. Overall, the response rate was 57% and all the patients who received the therapy had relapsed cancer or cancer that continued to progress despite receiving multiple conventional FDA-approved therapies. Few patients were eligible for bone marrow transplants.

Twenty-nine percent of patients in the study achieved complete remission. One patient died while in remission at 21 months due to complications from the removal of basal cell carcinoma on his leg. The 3 other patients remained alive at the time of the analysis with no evidence of leukemia at 28, 52, and 53 months after receiving their infusions with no further therapy.

Additionally, 29% of patients in the study achieved partial remission, with responses lasting a median of 7 months. Of the 4 patients who achieved partial remission, 2 died due to disease progression at 10 and 27 months after receiving CTL019. An additional patient died from a pulmonary embolism 6 months after T cell infusion. The remaining patient had disease progression but lived and is now on other therapies at 36 months after receiving the initial therapy.

Forty-three percent of patients involved in the study had no response to treatment and progressed within 1 to 9 months. Tests revealed that the modified T cells did not expand as robustly in these patients as in those who experienced remissions. Two of the 6 patients died from their disease or complications of other therapies and 4 are receiving other types of treatment.

CTL019 is similar to dialysis in the way it initially collects patients’ T cells to be reprogrammed into hunter cells that potentially kill cancer cells in the body. After going through lymphodepleting chemotherapy, patients receive an infusion of the newly engineered cells. The modified T cells contain an antibody-like protein called 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 the patients who responded to treatment during the study developed cytokine release syndrome (CRS) within several weeks after the infusions. The condition included various degrees of flu-like symptoms such as high fever, nausea and muscle pain, and neurologic symptoms including hallucinations and delirium.

Four patients experienced more severe symptoms such as low blood pressure and breathing difficulties, requiring intensive care. Prior studies have shown CRS to be a serious and potentially life-threatening degree of toxicity. The Penn team developed a management strategy to treat these side effects, including the antibody drug tocilizumab, which was used in 4 patients, while 2 patients received steroids. All recovered from their CRS.

“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 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.”

In 1 of the patients involved in a laboratory experiment using CAR-modified T cells isolated from the patient’s body, nearly 3 years after infusion the patient’s CTL019 cells demonstrated immediate and specific reactivity against cells expressing CD19.

Limitations of the study included not involving demographic or disease-related factors, such as age or types of prior therapies that could be used to predict response to the therapy. No association between T-cell dose and response was observed. Instead, a separate study is evaluating this relationship in greater detail. Future areas of study involve strategies to combine CTL019 with immune checkpoint inhibitor drugs or other therapies to stimulate T cell recognition of tumor cells.