Ninety percent of children and adults with acute lymphoblastic leukemia (ALL) who had relapsed multiple times or failed to respond to standard therapies went into remission after receiving an investigational personalized cellular therapy, CTL019, developed at the Perelman School of Medicine at the University of Pennsylvania. Twenty-seven of the 30 patients in the studies achieved a complete remission after receiving an infusion of these engineered “hunter” cells, and 78 percent of the patients were alive six months after treatment.
New York Times reports that other hospitals around the country will soon test the experimental treatment in children with advanced acute lymphoblastic leukemia. Similar research, also with encouraging results, is being done at the National Cancer Institute and Memorial Sloan Kettering Cancer Center in New York. Each year in the United States, acute lymphoblastic leukemia affects about 2,400 people older than 20, and 3,600 younger. It has a cure rate in adults of only about 40 percent, compared with 80 percent to 90 percent in children. About 1,170 adults die from the disease each year, compared with 270 people under age 20.
CTL019 manufacturing begins with a patient’s own T cells, which are collected via an apheresis process similar to blood donation, then reprogrammed in Penn’s Clinical Cell and Vaccine Production Facility with a gene transfer technique that teaches the T cells to target and kill tumor cells. The engineered cells contain an antibody-like protein known as a chimeric antigen receptor (CAR), which is designed to bind to a protein called CD19 found on the surface of B cells, including the cancerous B cells that characterize several types of leukemia. The modified “hunter” cells are then infused back into the patient’s body, where they both multiply and attack the cancer cells. A signaling domain built into the CAR promotes rapid multiplication of the “hunter” cells, building an army of tumor-killing cells that tests reveal can grow to more than 10,000 new cells for each single engineered cell patients receive.
Nineteen patients in the study remain in remission, 15 with this therapy alone, including a 9 year old who was the first ALL patient to receive the therapy more than two years ago. The follow-up periods reported in the study are more than six months for most patients, with a range from 1.4 to 24 months. Five patients went off-study for alternate therapy, three of whom proceeded to allogeneic stem cell transplants while in remission. Seven patients relapsed, between 6 weeks and 8.5 months after their infusions, including three whose cancers returned as CD19-negative leukemia that would not have been targeted by the modified cells.
All patients who received the CTL019 “hunter” cells experienced a cytokine release syndrome (CRS) within a few days after receiving their infusions – a key indicator that the engineered cells have begun proliferating and killing tumor cells in the body. During this time, 22 of 30 patients experienced mild to moderate CRS, which included varying degrees of flu-like symptoms, with high fevers, nausea, and muscle pain. Eight patients developed severe CRS, which required treatment for low blood pressure and breathing difficulties. Nine patients were treated with tocilizumab, an immunosuppressant drug that blocks the effects of the inflammatory cytokine IL-6, which have been found to spike during the most robust phase of the engineered cells’ expansion in the body. Six patients also received short courses of steroids to combat CRS symptoms. Tests of all patients who experienced complete remissions also showed that their normal, non-cancerous B cells, which also express the CD19 protein, had been eliminated along with their tumors. The researchers note that persistent 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. Since B cells play a role in helping fight infection, patients typically receive immunoglobulin replacement to maintain healthy immune function. “Our results support that CTL019 can produce long-lasting remissions for certain heavily pre-treated ALL patients without further therapy,” Frey said. “For our patients who have already relapsed after stem cell transplants, or don’t have any options for donors, this option has provided new hope.”
Wikipedia backgrounder on Acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) or acute lymphoid leukemia is an acute form of leukemia, or cancer of the white blood cells, characterized by the overproduction of cancerous, immature white blood cells—known as lymphoblasts. In persons with ALL, lymphoblasts are overproduced in the bone marrow and continuously multiply, causing damage and death by inhibiting the production of normal cells—such as red and white blood cells and platelets—in the bone marrow and by spreading (infiltrating) to other organs. ALL is most common in childhood with a peak incidence at 2–5 years of age, and another peak in old age.
The symptoms of ALL are indicative of a reduced production of functional blood cells, because the leukemia wastes the resources of the bone marrow, which are normally used to produce new, functioning blood cells. These symptoms can include fever, increased risk of infection (especially bacterial infections like pneumonia, due to neutropenia; symptoms of such an infection include shortness of breath, chest pain, cough, vomiting, changes in bowel or bladder habits), increased tendency to bleed (due to thrombocytopenia) and signs indicative of anemia including pallor, tachycardia (high heart rate), fatigue and headache.
About 6,000 cases are reported in the US every year; statistics from other countries are difficult to come by, although it is known to be more common in the United States, Italy and Costa Rica. Cure is a realistic goal and is achieved in over 80% of affected children, although only 20-40% of adults can be cured. “Acute” refers to the relatively short time course of the disease to differentiate it from chronic lymphocytic leukemia, which has a potential time course of many year