The B cell malignancy Chronic Lymphocytic Leukemia (CLL) is associated with humoral and cellular immunodeficiencies, which result in recurrent opportunistic infections, contributing to patient morbidity and mortality. This profound immunodeficiency arises in part from impaired antigen presenting cell (APC) function, which is likely to impede the development of a robust anti-CLL T cell response. Therefore, we wanted to explore the ability of CLL-B cells treated with novel combination therapies to promote anti-CLL immune responses.
We investigated the therapeutic capacity of activated CLL-B cells to be licensed in vitro or in vivo in order to promote tumor antigen presentation and drive an anti-CLL immune response. We are testing the ability of novel combinations of new immunotherapies to activate CLL-B cells in untreated primary patient samples, or after samples from patients on treatment in selected clinical trials. We utilized novel combinations of the TLR agonists and Lenalidomide (Len), to activate both healthy donor B cells, and CLL-B cells. Activation of B cells was determined using flow cytometry to measure cell surface costimulatory protein expression (CD80, CD86, CD83), and secretion of cytokines (IL-6, IL-10, and TNFa) into the supernatant by cytokine bead array. CLL-B cells were profoundly defective in IL-6 and IL-10 secretion after stimulation with novel combination therapies, in comparison to healthy B cells. By contrast, costimulatory protein expression in CLL-B cells was upregulated to a similar level observed in healthy B cells. We are currently investigating if activated CLL-B cells can present the specific NKT ligand, aGalCer, to NKT cells, to expand autologous anti-CLL T cells in vitro.
The Bruton's Tyrosine Kinase inhibitor, Ibrutinib, inhibits T and NK cell function in CLL patients, in addition to inhibiting BCR and NF-kB signaling in CLL-B cells. Therefore, we tested the ability of CLL-B cells collected from patients prior to, and after Ibrutinib treatment, to respond to immunomodulatory stimuli. After 48 hours stimulation, the expression of CD80 was impaired in CLL-B cells collected post-Ibrutinib treatment, compared with the pre-treatment CLL-B cells. This warrants further investigation, in particular how pro-inflammatory cytokine secretion is regulated by Ibrutinib treatment, and if downregulation of CLL-B cell activation is associated with clinical outcome.
Citation Format: Joanne Davis, Kylie Mason, Chia Sharpe, Rachel Koldej, Brendon Chua, David Jackson, Paul Neeson, Constantine Tam, David Ritchie. Can CLL-B cells treated with novel combination therapies be used to promote anti-CLL immune responses? [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 B054.
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