CTL019-targeting T-cell Therapy Promising Against Advanced, Refractory CLL, ALL
NEW ORLEANS—CTL019 T cells engineered to express chimeric antigen receptor (CAR), which targets CD19, show promise against advanced, refractory chronic lymphoblastic leukemia (CLL) and pediatric pre-B-cell acute lymphoblastic leukemia (ALL), despite a strong association between complete remission and cytokine release syndrome (CRS) and macrophage activation syndrome (MAS), researchers reported at the 55th American Society of Hematology Annual Meeting and Exposition.
“Adoptive transfer of CTL019 cells engineered to express CD137 and TCR-zeta signaling domains can result in in-vivo expansion, homing to marrow, and long-term functional persistence of engineered cells, accompanied by ongoing complete clinical responses and long-term B-cell aplasia in a substantial fraction of patients with advanced, refractory, and high-risk CLL and relapsed refractory pre-B-cell ALL,” reported lead study author Michael Kalos, PhD, of the University of Pennsylvania School of Medicine in Philadelphia, PA, and colleagues. “A single treatment with engineered gene-modified T cells has the potential to generate potent and long-lasting anti-tumor immunity.”
“This is synthetic biology coming of age,” Dr. Kalos said, likening infused CTL019 cells to ‘serial killers'. “Each infused CTL019 cell or its progeny kills on average more than 1,000 leukemia cells,” he explained. After one of the cells kills a tumor cell, “it goes on its merry way” to kill other cancer cells, he explained.
Recent advances in T-cell engineering allow for clinical trials to evaluate adoptive transfer of T cells to target leukemia, explained Kalos. The authors and their colleagues previously reported initial results for a cohort of patients with advanced, refractory CLL and ALL who were treated with T cells engineered to express CAR.
“The initial cohort of patients is now disease free between 1 and 3 years post-infusion,” the authors reported.
In the new report, the authors presented data on functional persistence, trafficking, and bioactivity of CTL019 cells from initial cohorts of 32 adult patients with advanced relapsed or treatment-refractory CLL, 22 pediatric patients with treatment-refractory ALL, and an initial cohort of five adults with relapsed and/or refractory ALL.
A total of seven patients with CLL had achieved ongoing complete remission (CR), eight patients have achieved partial remission, and 17 did not achieve remission within 3 months post-infusion. Of the 22 evaluable children with ALL in the cohort, 14 have ongoing CR, and three have had no remission. Among the five adults with ALL, four have ongoing CR.
“In all patients with CR, robust in vivo expansion of CTL019 cells was observed, as assessed by both molecular and flow cytometric analysis, followed by contraction and in all but one patient, ongoing stable persistence of engineered cells, elimination of tumor B cells and ongoing B cell aplasia in blood and marrow at all evaluated time points,” the coauthors reported.
“We're talking about profoundly deep molecular responses,” Dr. Kalos said, describing long-term 3-year long CTL019 persistence and ongoing B-cell aplasia in the study's first CR patients. “If 6% of cells are CAR-positive, the patient is almost destined to become a complete responder.”
All patients who experienced CR experienced on-target CRS and MAS, the authors reported—potentially life-threatening conditions.
“Elevation of cytokines coincided with expansion of CTL019 cells, elimination of B cells, and toxicity suggesting the potential for a cytokine-based diagnostic signature to monitor CTL019 treatment efficacy,” the authors reported.