Abstract
Abstract 1821
Lenalidomide is an oral immune-modulating agent that has been shown to have clinical activity in patients with treatment-naive and previously treated chronic lymphocytic leukemia (CLL). In CLL, a disease-specific phenomenon of drug-induced tumor flare is often observed that results in lymph node enlargement, rash, and cytokine release. We and others have attributed both lenalidomide-induced tumor flare and cytokine release in part to CLL cell activation, with concomitant increase in surface co-stimulatory molecules including CD154. The potential consequences of such activation by lenalidomide in CLL are multiple. In symptomatic, previously untreated CLL, activation of tumor cells by lenalidomide likely contributes to reversal of hypogammaglobulinemia in a subset of patients. Additionally, activation of CLL cells increases their capacity for antigen presentation, potentially facilitating a clinically beneficial development of tumor-specific antibodies toward antigens such as ROR1. In patients with previously treated CLL, lenalidomide therapy does not reverse hypogammaglobulinemia. However, treatment has been documented to increase serum b-FGF and VEGF levels, which correlates with lack of response. Previous work demonstrates that CLL cells predominately utilize the PI3K p110δ isoform for activation following CD154 signaling. Given our prior findings of prominent lenalidomide induction of CD40-CD154 signaling in vitro and in vivo, we focused initially on molecular interrogation of isoforms responsible for this in CLL cells. Utilizing primary CLL cells, we demonstrated that inhibition of PI3K-δ signaling by CAL-101, a clinically relevant PI3K-δ isoform-specific inhibitor, abrogated lenalidomide-induced activation of CLL cells by directly reducing PI3K enzymatic activity and also reducing phosphorylation of the downstream PI3K target AKT. Parallel studies with siRNA targeted to the p110δ isoform of PI3K demonstrated antagonism of lenalidomide-induced AKT phosphorylation. Furthermore, we found that inhibition of PI3K-δ by CAL-101 at therapeutically relevant concentrations (1 μM) prevented up-regulation of CD40, CD154, and CD86 by lenalidomide and also antagonized production of IgM by normal B-cells co-cultured with CLL cells. Collectively, these data demonstrate the importance of PI3K-δ signaling in modulating the pharmacological effects of lenalidomide in CLL cell activation including up-regulation of CD40, CD154, CD86 and active CLL cell co-stimulation of normal B-cells. Our findings suggest that clinical evaluation of combination strategies of lenalidomide and CAL-101 in treatment-naive patients with CLL should be performed with careful pharmacodynamic monitoring of immune modulation and signaling to best preserve the clinical benefits of both drugs.
This work is supported by the Leukemia and Lymphoma Society, D. Warren Brown Foundation, and The OSU Leukemia SPORE grant funded by the NCI. CAL-101 was provided by Calistoga Pharmaceuticals, Inc.
Disclosures:
Jones: Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Lannutti:Calistoga Pharmaceutical Inc.: Employment. Byrd:Calistoga Pharmaceutical Inc.: Equity Ownership. Johnson:Calistoga Pharmaceutical Inc.: Research Funding.
Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia
