Targeting Chronic Myeloid Leukemia Stem/Progenitor Cells Using Venetoclax-Loaded Immunoliposome

Abstract

CML is a hematopoietic stem-cell disorder emanating from breakpoint cluster region/Abelson murine leukemia 1 (BCR/ABL) translocation. Introduction of different TKIs revolutionized treatment outcome in CML patients, but CML LSCs seem insensitive to TKIs and are detectable in newly diagnosed and resistant CML patients and in patients who discontinued therapy. It has been reported that CML LSCs aberrantly express some CD markers such as CD26 that can be used for the diagnosis and for targeting. In this study, we confirmed the presence of CD26+ CML LSCs in newly diagnosed and resistant CML patients. To selectively target CML LSCs/progenitor cells that express CD26 and to spare normal HSCs/progenitor cells, we designed a venetoclax-loaded immunoliposome (IL-VX). Our results showed that by using this system we could selectively target CD26+ cells while sparing CD26− cells. The efficiency of venetoclax in targeting CML LSCs has been reported and our system demonstrated a higher potency in cell death induction in comparison to free venetoclax. Meanwhile, treatment of patient samples with IL-VX significantly reduced CD26+ cells in both stem cells and progenitor cells population. In conclusion, this approach showed that selective elimination of CD26+ CML LSCs/progenitor cells can be obtained in vitro, which might allow in vivo reduction of side effects and attainment of treatment-free, long-lasting remission in CML patients.

Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells

“…CD26 (DPPV) has also proved to be a novel, specific biomarker for CML LSCs, which is promising for the diagnosis and targeted treatment of CML (161)(162)(163). In a recent study, a venetoclax-loaded immunoliposome remarkably induced apoptosis in CD26+ cells in both stem cells and progenitor cells population (164). However, DPPIV blocker vildagliptin in combination with nilotinib did not exert a synergy effect, indicating insignificant effects of co-administration (165).…”

Targeting Leukemic Stem Cells in Chronic Myeloid Leukemia: Is It Worth the Effort?

“…BCL2 is overexpressed and hyperactivated in CML LSCs [48] and BCL2 targeting was indeed found to reduce LSC engraftment in mice [49]. Houshmand et al [47] found that their immunoliposome could indeed reduce cell growth and induce apoptosis in CD26+ cell lines, and co-administration with TKIs (imatinib, nilotinib) demonstrated synergistic effects. Moreover, they observed that their immunoliposome could dramatically reduce the percentage of CD26+ cells in primary patient samples.…”

“…However, a preclinical study evaluating the combination of TKIs (imatinib or nilotinib) with vildagliptin failed to evidence major cooperative effects on engraftment in mice models [46]. More recently, Houshmand et al [47] developed an innovative strategy based on a liposome loaded with the BCL2 inhibitor venetoclax exploiting begelomab (an anti-CD26 antibody) to selectively target CD26+ CML LSCs. BCL2 is overexpressed and hyperactivated in CML LSCs [48] and BCL2 targeting was indeed found to reduce LSC engraftment in mice [49].…”

Chronic myeloid leukemia stem cells: targeting therapeutic implications

“…Furthermore, BCL-2 inhibitors (subutoclax and venetoclax) can increase the eradication of CML LSCs by disrupting energy metabolic pathways [ 208 , 209 ]. Recently, an innovative strategy based on a liposome loaded with the BCL2 inhibitor (venetoclax) using an anti-CD26 antibody (begelomab) to selectively target CML LSCs showed that the immunoliposome could reduce cell growth and also induce apoptosis in CD26 + LSCs, along with synergistic effects by coadministration with imatinib or nilotinib [ 210 ]. Interestingly, inhibition of ALOX15 pathway involved in fatty acid metabolism with the BLT2-specific inhibitor triggered apoptosis and inhibited self-renewal in TKI-resistant CML cells in blast crisis phase [ 211 ].…”