Treatment with genetically engineered T cells produces sustained responses in patients with acute lymphoblastic leukemia (ALL) or chronic lymphocytic leukemia (CLL), according to research presented in December 2013 at the 55th American Society of Hematology (ASH) Annual Meeting, held in New Orleans, LA.
In this investigational treatment, developed by a research team from the University of Pennsylvania and Children’s Hospital of Philadelphia, patients’ T cells are removed by apheresis and reprogrammed with a gene transfer technique employing a lentivirus vector. The T cells are redesigned to use an antibody-like protein called a chimeric antigen receptor (CAR), which is expressed on their surface, to bind to the CD19 protein found on the surface of B cells associated with both ALL and CLL.
After lymphodepleting chemotherapy, the modified T cells are infused back into the patient’s body, where they and their progeny attack and kill leukemia cells. The infused adoptive T cells have been called “serial killers” because each cell and its offspring eliminate an average of 1,000 leukemia cells. Cells that do not express CD19 are unaffected, thus limiting the adverse effects associated with the treatment.
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The research team from Pennsylvania presented three studies at the ASH meeting detailing their results.
In the first study, 16 children and four adults with relapsed, refractory ALL were infused with CAR-modified T cells. After 1 month, 14 patients had achieved a complete response. After median follow-up of 2.6 months (range, 1 to 15 months), 11 of those 14 patients had a sustained complete response and three relapsed.1
In the second study, 14 patients with a median age of 67 years with relapsed, refractory CLL received infusions of modified T cells. After median follow-up of 9.4 months, three patients achieved a complete response, five achieved a partial response, and six had no response. No patient with a complete response relapsed during follow-up, although two patients with a partial response progressed within 4 months after the infusion.2
The third study is a phase 2 trial that involves two doses of modified T cells that has so far enrolled 27 patients with relapsed, refractory CLL. Ten patients with a median age of 63 years have been treated. Four patients have been randomly assigned to receive 5 x 108 CTL019 cells and six patients to receive 5 x 107 CTL019 cells. After median follow-up of 3 months, two patients have achieved a complete response and two have achieved a partial response. Preliminary analysis has not suggested that dose is directly related to response rate or degree of toxicity.3
In all three studies, the majority of patients who responded to the therapy developed a delayed cytokine release syndrome, which manifested as fever, myalgia, nausea, and anorexia, and in some cases, hypotension and hypoxia. This syndrome was associated with elevated concentrations of interleukin-6 (IL-6) during the expansion phase of the T cells. In about half of the cases, treatment for hemodynamic or respiratory instability was required. Treatment with tocilizumab, which suppresses elevated IL-6, produced rapid relief.
Michael Kalos, PhD, adjunct associate professor, Pathology and Laboratory Medicine at the University of Pennsylvania Perelman School of Medicine, also in Philadelphia, was involved with all three studies, and called the therapy a “game changer” for patients with ALL and CLL. Dr. Kalos added that the research team will now focus on determining why some patients respond to treatment with genetically modified T calls and others do not.
References
- Grupp SA, Frey NV, Aplenc R, et al. T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) produce significant in vivo proliferation, complete responses and long-term persistence without Gvhd in children and adults with relapsed, refractory ALL. Presented at the 55th American Society of Hematology Annual Meeting; December 8, 2013; New Orleans, LA. Abstract 67.
- Porter DL, Kalos M, Frey NV, et al. Chimeric antigen receptor modified T cells directed against CD19 (CTL019 cells) have long-term persistence and induce durable responses in relapsed, refractory CLL. Presented at the 55th American Society of Hematology Annual Meeting; December 9, 2013; New Orleans, LA. Abstract 4162.
- Porter DL, Kalos M, Frey NV, et al. Randomized, phase II dose optimization study of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL. Presented at the 55th American Society of Hematology Annual Meeting; December 10, 2013; New Orleans, LA. Abstract 873.
