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CTL019 therapy induced response in CLL, ALL
NEW ORLEANS — Chimeric antigen receptor-expressing T cells that target CTL019 induced clinical response and long-term B-cell aplasia in patients with advanced, refractory and high-risk chronic lymphocytic leukemia, as well as adult and pediatric patients with relapsed, refractory pre-B-cell acute lymphoblastic leukemia, according to study results presented at the ASH Annual Meeting and Exposition.
Michael Kalos, PhD, of the University of Pennsylvania School of Medicine in Philadelphia, and colleagues sought to analyze the functional persistence, trafficking and bioactivity of infused CTL019 cells.
“The advantage of chimeric antigen receptors (CARs) is that they involve major histocompatibility complex (MHC)-independent target recognition,” Kalos said during a press conference. “T cells usually require appropriate MHC; they’re actually an HLA match. Thus, every therapy that you develop is limited. However, CARs are not matched by MHC. As long as it expresses the molecule, it’s targeted. Every surface molecule is a target epitope.”
Kalos and colleagues evaluated data from three cohorts. The first cohort included 24 adults with CLL, the second included 14 pediatric patients with ALL, and the third included three adults with ALL.
They engineered the CTL019 cells to express CD137 and T-cell receptor-zeta signaling domains.
In the CLL cohort, five patients achieved ongoing complete response and seven patients achieved partial response within 3 months post-infusion. Twelve patients did not respond to treatment.
In the pediatric ALL cohort, eight patients achieved ongoing complete response. Four patients relapsed. Of them, two had CD19-negative disease and two were nonresponders.
All patients in the adult ALL cohort achieved ongoing complete response. One patient went into an allogeneic transplant while in complete response.
Molecular and flow cytometric analyses showed robust in vivo expansion followed by contraction of CTL019 cells in all patients who achieved complete response.
Researchers observed stable persistence of engineered cells, elimination of tumor B cells and ongoing B-cell aplasia in blood and marrow in all but one of the complete responders. They also noted the peak marking exceeded 5% of total CD3+ in these patients.
Among partial responders, in vivo expansion was less robust and was accompanied by transient B-cell elimination. Nonresponders demonstrated minimal in vivo expansion.
All complete responders experienced on-target cytokine release syndrome and macrophage activation syndrome. Researchers also noted a broad pro-inflammatory signature with significant elevation in soluble immune modulators such as interferon gamma, interleukin (IL)-6 and IL-2 receptor alpha with multiplex cytokine analysis.
“These new and expanded data provide significant proof that T cells engineered to express cancer-targeting chimeric antigen receptors not only work, but work dramatically and in a sustained manner in patients with relapsed, treatment-resistant leukemia, and further demonstrate the potential of this approach to help these patients achieve complete response,” Kalos said in a press release. “Further, our results show that we can potentially measure and track the activity of these engineered cells in the body as a way to monitor treatment, an exciting finding considering that this treatment is often the last hope for these patients.”
For more information:
Kalos M. Abstract #163. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2013; New Orleans.
Disclosure: The researchers report advisory board roles with, research funding from, and royalties on CART19 and cell and gene therapy IP patents licensed to Novartis.
Perspective
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Here we’re talking about the chimeric antigen receptor (CAR) that previously has been known as the T body. This is an engineering process that occurs ex vivo, in which T cells that are extracted from the blood are engineered to latch on to the tumor cells and destroy them. Then they’re infused back into patients, many of whom have exhausted every other treatment. Kalos has provided an overview of patient response in a clinical research program that evaluated treatment of both pediatric and adult leukemia patients with these CAR-modified T cells, finding significant proof that this method not only works, but — importantly — that it works for a sustained period of time.