In:
The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 120.14-120.14
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 & lt;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.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.198.Supp.120.14
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2017
detail.hit.zdb_id:
1475085-5
