A microRNA Signature Predicts Response to Anti-CD19 Therapy (MEDI-551) in B-Cell Malignancies

• Published in: Blood 2014-12, Vol.124 (21), p.2198-2198
• Main Authors: Streicher, Katie, Brohawn, Philip, Kuziora, Mike, Pilataxi, Fernanda, Higgs, Brandon, Lehmann, Kim, McKeever, Kathleen, Goswami, Trishna, Herbst, Ronald, Yao, Yihong, Ranade, Koustubh
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.2198.2198

Background: microRNAs (miRNA, miR) are a class of highly conserved short noncoding, 17–25 nucleotide long RNA products (Ambros; Nature, 2004) that regulate gene expression at the posttranscriptional level (Bartel; Cell, 2004). Specific miRNA expression signatures can distinguish cancer from benign tissues and may provide the basis for developing new diagnostic and therapeutic strategies (Nelson et al.; Mol Can Ther, 2008). Despite numerous studies focused on understanding the regulation of miRNA in cancer development and progression, the relationship between miRNA expression and response to B-cell therapy has not been fully explored; therefore, we sought to identify microRNAs that would identify patients with B cell malignancies who may derive improved benefit from MEDI-551, an afucosylated, affinity-optimized anti–CD19 antibody with enhanced antibody dependent cell cytotoxicity (ADCC). Methods: A miRNA signature was found to be highly differentially expressed between cell lines of high sensitivity (n = 4) versus low sensitivity (n = 3) to in vitro ADCC with MEDI-551. miRNA expression patterns were confirmed across four broad profiling platforms to ensure their reproducibility. This miRNA signature was pre-specified for testing in a Phase 1 and Phase 2 trials of MEDI-551 in B-cell malignancies to assess its clinical utility in predicting patient response to MEDI-551 treatment. For this analysis, quantitative PCR (TaqMan) was utilized on pre-treatment (baseline) whole blood or PBMC samples. Results: In patient samples, we found that the miRNA signature displayed consistent results between in vitro and in vivo experiments. The in vitro data showed a 12-fold (p < 0.001) lower median miRNA signature in cell lines highly sensitive to in vitro ADCC with MEDI-551 compared to those with lower sensitivity. In a Phase I trial evaluating multiple doses of MEDI-551, diffuse large B cell lymphoma (DLBCL) patients who responded to MEDI-551 (CR/PR, n = 5) had significantly lower (7-fold; p < 0.0001) median miRNA signature expression compared to patients who did not respond (PD, n = 10) (Figure 1). Similar results were observed in patients (n=34) with follicular lymphoma (FL) included in the Phase I trial and a Phase II trial for chronic lymphocytic leukemia (CLL) patients (n=160). Importantly, the microRNA signature did not appear to predict response to rituximab. Correlation of the miRNA signature with prognostic factors is covered in an abstract titled “MEDI-551 MicroR