Preclinical modeling of novel therapeutics in chronic lymphocytic leukemia: the tools of the trade

Herman, Sarah E. M.; Wiestner, Adrian

doi:10.1053/j.seminoncol.2016.02.007

Cited by 26 publications

(19 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(2, 26) In order to investigate the anti-leukemic effects of combined BTK and PI3Kδ inhibition with acalabrutinib and ACP-319, we chose a murine model that recapitulate the contribution of the microenvironment to CLL progression. (27) The TCL1-192 adoptive transfer model corresponds to a rapidly progressive CLL with fatal outcome and is therefore well suited for the comparison of multiple treatments in a controlled manner, with overall survival as a final endpoint. (18) The TCL1-192 cells do not proliferate in vitro , thus demonstrating dependency on the microenvironment similarly to primary CLL cells.…”

Section: Discussionmentioning

confidence: 99%

Combined BTK and PI3Kδ Inhibition with Acalabrutinib and ACP-319 Improves Survival and Tumor Control in CLL Mouse Model

Niemann

Mora-Jensen

Dadashian

et al. 2017

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose Targeting the B-cell receptor (BCR) pathway with inhibitors of BTK and PI3K-delta is highly effective for the treatment of chronic lymphocytic leukemia (CLL). However, deep remissions are uncommon and drug resistance with single-agent therapy can occur. In vitro studies support the effectiveness of combing PI3K-delta and BTK inhibitors. Experimental design As CLL proliferation and survival depends on the microenvironment, we used murine models to assess the efficacy of the BTK inhibitor acalabrutinib combined with the PI3K-delta inhibitor ACP-319 in vivo. We compared single-agent with combination therapy in TCL1-192 cell-injected mice, a model of aggressive CLL. Results We found significantly larger reductions in tumor burden in the peripheral blood and spleen of combination-treated mice. While single-agent therapy improved survival compared with control mice by a few days, combination therapy extended survival by over two weeks compared to either single agent. The combination reduced tumor proliferation, NF-KB signaling and expression of BCL-xL and MCL-1 more potently than single-agent therapy. Conclusion The combination of acalabrutinib and ACP-319 was superior to single-agent treatment in a murine CLL model, warranting further investigation of this combination in clinical studies.

show abstract

Section: Discussionmentioning

confidence: 99%

Combined BTK and PI3Kδ Inhibition with Acalabrutinib and ACP-319 Improves Survival and Tumor Control in CLL Mouse Model

Niemann

Mora-Jensen

Dadashian

et al. 2017

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…When CLL cells are cultured in vitro, they undergo rapid apoptosis due to a lack of microenvironmental support. However, CLL cells can be rescued from spontaneous apoptosis when cultured in conditions that mimic microenvironmental signaling (6). Microenvironmental signals are initiated by communications with accessory cells including stromal cells, macrophages, and T cells.…”

Section: Introductionmentioning

confidence: 99%

TLR Signaling Is Activated in Lymph Node–Resident CLL Cells and Is Only Partially Inhibited by Ibrutinib

et al. 2019

Self Cite

View full text Add to dashboard Cite

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells driven by B-cell receptor (BCR) signaling and activated primarily in the lymph node. The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib effectively inhibits BCR-dependent proliferation and survival signals and has emerged as a breakthrough therapy for CLL. However, complete remissions are uncommon and are achieved only after years of continuous therapy. We hypothesized that other signaling pathways that sustain CLL cell survival are only partially inhibited by ibrutinib. In normal B cells, Toll-like receptor (TLR) signaling cooperates with BCR signaling to activate prosurvival NF-kB. Here, we show that an experimentally validated gene signature of TLR activation is overexpressed in lymph node-resident CLL cells compared with cells in the blood. Consistent with TLR activation, we detected phosphorylation of NF-kB, STAT1, and STAT3 in lymph node-resident CLL cells and in cells stimulated with CpG oligonucleotides in vitro. CpG promoted IRAK1 degradation, secretion of IL10, and extended survival of CLL cells in culture. CpG-induced TLR signaling was significantly inhibited by both an IRAK1/4 inhibitor and ibrutinib. Although inhibition of TLR signaling was incomplete with either drug, the combination achieved superior results, including more effective inhibition of TLRmediated survival signaling. Our data suggest an important role for TLR signaling in CLL pathogenesis and in sustaining the viability of CLL cells during ibrutinib therapy. The combination of ibrutinib with a TLR pathway inhibitor could provide superior antitumor activity and should be investigated in clinical studies. Significance: CLL relies on the concomitant cooperation of B-cell receptor and Toll-like receptor signaling; inhibition of both pathways is superior to inhibition of either pathway alone.

show abstract

“…Mice were euthanized on day 36 to avoid any possibility of graft‐versus‐host disease (GVHD)‐like symptoms, which could impact the results of the study, particularly in mice that received healthy donor PBMCs. This phenomenon is commonly observed in partially humanized mouse models (Herman & Wiestner, ).…”

Section: Methodsmentioning

confidence: 67%

“…Notably, we did not observe any significant weight loss up to day 34 (Fig C). Mice were euthanized after day 34 because of development of GVHD‐like symptoms, which is common after administration of human PBMCs (Herman & Wiestner, ). Altogether, our data demonstrate that Dara significantly prohibited WM cell growth in mice and was well tolerated, with no observable drug‐related toxicities.…”

Section: Resultsmentioning

confidence: 99%

Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells

et al. 2018

View full text Add to dashboard Cite

CD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti-CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells. In vitro Dara treatment of WM cells (including ibrutinib-resistant lines) elicited antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cell phagocytosis (ADCP) and direct apoptosis. In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI-WM1-xenografted mice. CD38 is reported to augment B-cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib-resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single-agent Dara or ibrutinib. In summary, we are the first to report the in vitro and in vivo anti-WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co-targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib.

show abstract

Preclinical modeling of novel therapeutics in chronic lymphocytic leukemia: the tools of the trade

Cited by 26 publications

References 99 publications

Combined BTK and PI3Kδ Inhibition with Acalabrutinib and ACP-319 Improves Survival and Tumor Control in CLL Mouse Model

Combined BTK and PI3Kδ Inhibition with Acalabrutinib and ACP-319 Improves Survival and Tumor Control in CLL Mouse Model

TLR Signaling Is Activated in Lymph Node–Resident CLL Cells and Is Only Partially Inhibited by Ibrutinib

Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells

Contact Info

Product

Resources

About