B-precursor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood cancer. Although this disease can be successfully treated in 80 % of patients by chemotherapy, prognosis for primary refractory or relapsed patients is very poor. Even after allogeneic stem cell transplantation (SCT), relapse rates are considerable and correlate significantly with persistent minimal residual disease (MRD) prior to or after SCT. In an MRD constellation favorable effector-target ratios prevail and thus it is well suited for immunotherapy with therapeutic antibodies.
We developed a chimeric Fc-optimized third-generation CD19 antibody (4G7SDIE) and produced it in pharmaceutical quality. This antibody mediates markedly enhanced antibody dependent cellular cytotoxicity (ADCC) through its improved capability to recruit FcγRIIIa-bearing effector cells. In this study, 4G7SDIE was applied on a compassionate need basis to pediatric patients with relapsed or refractory BCP-ALL in an MRD situation (n=14) or in relapse (n=2) (initial refractory disease, n=3; 1st relapse, n=7; ≥ 2nd relapse, n=6; 12/16 patients had previous SCT). Side effects were negligible. In all patients complete CD20+ B-cell depletion was observed during therapy. After discontinuation of 4G7SDIE therapy B cell counts recovered rapidly to normal levels. Both patients in relapse did not respond to 4G7SDIE treatment. In 9/14 MRD-positive patients, MRD was reduced by ≥ 1 log or fell below MRD-detection threshold of 10-4 over the course of treatment. 2/9 responders were receiving additional treatment.
In CD107a assays primary NK cells and γδ T cells were identified as main effector cell populations. The FcγRIIIA-V158F polymorphism had no influence on ADCC mediated by 4G7SDIE. Cytotoxicity assays confirmed sustained functionality of patient effector cells over the course of 4G7SDIE treatment. In vitro cytotoxicity assays were performed using PBMC from transplanted patients obtained at different time points of 4G7SDIE treatment. Lysis of autologous leukemic blasts was increased when 4G7SDIE or autologous patient serum taken after antibody infusion was added. After infusion of 20 mg/m2 4G7SDIE serum half-life was 34 ± 13 hours (n=3) and serum levels of 4G7SDIE remained above saturating concentrations of ≥ 700 ng/ml (EC50=65 ng/ml) at day 13 and following treatment cycle, respectively.
Notably, in 3/3 analyzed patients under 4G7SDIE therapy, a transient down modulation of CD19 surface expression on the leukemic blasts was observed. In vitro antigenic shift assays on primary leukemic blasts showed considerable but very heterogeneous shift of CD19 surface expression. Furthermore, a positive correlation between CD19 surface expression levels and 4G7SDIE mediated lysis was observed. These observations hint at in vivo tumor escape mechanisms and furthermore indicate selective pressure exerted by immunotherapy with 4G7SDIE, underlining its therapeutic potential, but also delineating possible limitations.
In conclusion, promising anti-leukemic effects of the 4G7SDIE antibody have been observed in vitro and in vivo. We are currently preparing a phase I/IIa trial.
Citation Format: Ursula Joerdis Eva Seidel, Ludger Grosse-Hovest, Patrick Schlegel, Martin Hofmann, Friedhelm R. Schuster, Roland Meisel, Kai-Erik Witte, Steffen Aulwurm, Elwira Pyz, Hans-Georg Rammensee, Gundram Jung, Rupert Handgretinger, Peter Lang. Reduction of minimal residual disease in pediatric B-precursor acute lymphoblastic leukemia by an Fc-optimized CD19 antibody. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B144.
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