CC-122 is more potent but transcriptionally mirrors Lenalidomide in Chronic Lymphocytic Leukemia
The Journal of Immunology(2017)
摘要
Abstract Lenalidomide (Len) is an immune modulatory drug for the treatment of hematological malignancies which contrasts with a large repertoire of immunosuppressive treatments. Len is FDA approved for Multiple Myeloma (MM), yet its development in Chronic Lymphocytic Leukemia (CLL) has been hampered by a potentially fatal, dose-limiting toxicity known as tumor flare. Tumor flare consists of enlarged, painful lymph nodes (LN) and cytokine release and is managed by lower dosage/prophylactic measures. Len and next-generation reagent CC-122, target cereblon, leading to degradation of transcription factors IKZF1/IKZF3. We compared CC-122 to Len using primary CLL B and T cells and CLL-derived cell line, OSU-CLL. We present a key difference between CC-122 and Len treated activated CLL T cells. CC-122 0.1–10uM or 1uM Len are not directly cytotoxic to primary CLL B cells (avg. fold change 0.94–1.49 normalized to vehicle, N=8). CC-122 was more potent than Len by degradation of IKZF1/IKZF3, and immune activation measured by CD86 induction (7.2% more CD86+ induction, p=0.0026, N=12). RNA-seq analysis of the OSU-CLL cell line showed that at physiologically relevant doses, CC-122 (0.1uM) and Len (1uM) have no significant differences. Microarray analysis of 0.1uM CC-122 v. 1uM Len on αCD3 activated CLL T cells showed only two significantly different genes: CXCL13 and HLADQ-A1, p<0.0001. CXCL13, a B cell chemoattractant in CLL, was ≥ 3 fold increased with 1uM Len v. 0.1–1uM CC-122 (N=3). Overexpression of the CXCL13 receptor, CXCR5, in CLL but not MM may contribute to migration of CLL cells to the LN and potentially tumor flare. Retaining the anti-tumor activity of Len while mitigating tumor flare is of clinical interest and critical to the development of CC-122.
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