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Monoclonal Antibody Therapy Directed Against Human Acute Myeloid Leukemia Stem Cells

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Monoclonal Antibody Therapy Directed Against Human Acute Myeloid Leukemia Stem Cells Oncogene (2011) 30, 1009–1019 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc REVIEW Monoclonal antibody therapy directed against human acute myeloid leukemia stem cells R Majeti Division of Hematology, Department of Internal Medicine, Cancer Center, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, CA, USA Accumulating evidence indicates that many human this model (Kelly et al., 2007; Quintana et al., 2008), cancers are organized as a cellular hierarchy initiated there is strong evidence for the existence of cancer stem and maintained by self-renewing cancer stem cells. This cells in several human malignancies, including acute cancer stem cell model has been most conclusively myeloid leukemia (AML) (Bonnet and Dick, 1997; established for human acute myeloid leukemia (AML), Dick, 2008). Within a tumor, it is only these cancer stem although controversies still exist regarding the identity cells that are able to transplant the disease and of human AML stem cells (leukemia stem cell (LSC)). differentiate into the heterogeneous cells composing A major implication of this model is that, in order to the tumor. This model postulates that one reason eradicate the cancer and cure the patient, the cancer stem for the relative ineffectiveness of current cancer che- cells must be eliminated. Monoclonal antibodies have motherapy regimens is that these therapies target the emerged as effective targeted therapies for the treatment rapidly proliferating tumor cells, which do not include of a number of human malignancies and, given their target all of the cancer stem cells (Reya et al., 2001). Thus, antigen specificity and generally minimal toxicity, are well tumors often shrink in response to chemotherapy, but positioned as cancer stem cell-targeting therapies. One almost universally recur due to sparing of some cancer strategy for the development of monoclonal antibodies stem cells. A key implication of this cancer stem cell targeting human AML stem cells involves first identifying model is that in order to eradicate the tumor and cure cell surface antigens preferentially expressed on AML the patient, therapies must target and eliminate the LSC compared with normal hematopoietic stem cells. cancer stem cells. In recent years, a number of such antigens have been Monoclonal antibodies have emerged as a potent and identified, including CD123, CD44, CLL-1, CD96, CD47, effective molecularly targeted therapy for human cancer, CD32, and CD25. Moreover, monoclonal antibodies usually in combination with chemotherapy (Adams and targeting CD44, CD123, and CD47 have demonstrated Weiner, 2005; Finn, 2008). Such antibodies have been efficacy against AML LSC in xenotransplantation demonstrated to be effective in the treatment of a models. Hopefully, these antibodies will ultimately prove number of human cancers, including rituximab for to be effective in the treatment of human AML. B-cell non-Hodgkin lymphoma, trastuzumab for HER2- Oncogene (2011) 30, 1009–1019; doi:10.1038/onc.2010.511; positive breast carcinomas, cetuximab for colorectal published online 15 November 2010 carcinomas and head and neck squamous cell carcino- mas, alemtuzumab for chronic lymphocytic leukemia Keywords: acute myeloid leukemia; cancer stem cells; (CLL) and T-cell lymphoma, and others (Adams and monoclonal antibodies Weiner, 2005; Finn, 2008). Antibodies effective against cancer are believed to function by several mechanisms including, antibody-dependent cellular cytotoxicity, stimulation of complement-dependent cytotoxicity, Introduction inhibition of signal transduction, or direct induction of apoptosis (Cheson and Leonard, 2008). In some cases, A growing body of evidence indicates that many human an individual therapeutic antibody may function cancers are organized as cellular hierarchies initiated through several of these mechanisms simultaneously. and maintained by a small pool of self-renewing cancer Because of their target antigen specificity and mechan- stem cells (Reya et al., 2001; Jordan et al., 2006; Dalerba isms of action, monoclonal antibodies are able to deliver et al., 2007). Although some controversy still surrounds their therapeutic effects with minimal toxicity. Given the need to develop agents that can target and eliminate Correspondence: Dr R Majeti, Division of Hematology, Department cancer stem cells, and the antigen specificity and efficacy of Internal Medicine, Cancer Center, Stanford Institute for Stem Cell of monoclonal antibodies, recent investigation has Biology and Regenerative Medicine, Stanford University School of focused on the development of monoclonal antibodies Medicine, 265 Campus Drive, G3021B, Stanford, CA 94305, USA. E-mail: [email protected] targeting cancer stem cell antigens. This review will Received 11 May 2010; revised 26 August 2010; accepted 29 September focus on the pre-clinical investigation of monoclonal 2010; published online 15 November 2010 antibodies targeting human AML stem cells. Antibody therapy for AML LSC R Majeti 1010 Human AML stem cells that the Lin–CD34 þ CD38ÀCD90À fraction of human cord blood contains a non-HSC multipotent progenitor, Human AML is a clonal malignancy characterized by and hypothesize that this multipotent progenitor is the the accumulation of immature myeloid cells defective in cell of origin for human AML (Majeti et al., 2007), their maturation and function. Much is now known although it is possible that loss of CD90 expression about the biology of AML, including chromosomal occurs as a consequence of leukemic transformation of translocations resulting in gene fusions, chromosomal HSC. Similar to the normal hematopoietic differentia- and subchromosomal deletions of putative tumor tion pathway, these LSC in turn give rise to leukemia suppressor genes, dysregulation of programmed cell progenitor cells with the surface immunophenotype of death, single-gene mutations correlating with leukemia, CD34 þ CD38 þ , which further differentiate into the and derangements of the telomere/telomerase system bulk leukemic blast population defined as CD34À. (Gilliland et al., 2004). A model has been proposed AML affects 13,000 adults annually in the United that AML results from the combination of mutations States, most of them over the age of 65 years (Low- that fall into two broad categories: (1) stimulators of enberg et al., 1999; Estey and Dohner, 2006). Current proliferation (for example, Ras, FLT3 and c-kit) and (2) standard of care includes treatment with several cycles inhibitors of differentiation (for example, CBF, CEBPA of high-dose chemotherapy and often includes allo- and MLL) (Gilliland and Griffin, 2002; Gilliland et al., geneic hematopoietic cell transplantation. Even with 2004). In order for AML to develop, cells must acquire these aggressive treatments, which have significant side at least one mutation from each category; however, in effects, 5-year overall survival is between 30–40%, and most cases of human AML, the molecular identity of much lower for those over age of 65 years (Lowenberg such mutations is unknown. et al., 1999; Estey and Dohner, 2006). AML is a Recent experiments have added to our fundamental heterogeneous disorder with several different patholo- knowledge by demonstrating that AML, similar to gical classification schemes, including the French– normal hematopoiesis, is composed of a hierarchy of American–British and the more recent World Health cells that is maintained by a small pool of leukemia stem Organization classification (Bennett et al., 1976; Vardi- cells (LSC) (Tan et al., 2006; Dick, 2008). Stem cells in man et al., 2009). The World Health Organization any biological process are defined by the properties of scheme was developed to reflect the molecular under- self-renewal, which is the ability to give rise to progeny standing of several subtypes of AML and to take into identical to the parent through cell division, and account the prognostic importance of cytogenetic multipotency, which is the ability to give rise to all the abnormalities. Immunophenotyping by flow cytometry differentiated cells of that biological process (Reya et al., is routinely performed on clinical specimens and shows 2001). Most of the cells within AML do not possess that most, but not all, human AML samples are these properties, which are restricted to the infrequent predominantly CD34 positive (Vardiman et al., 2009). LSC that are able to maintain the leukemia. Both In published reports assaying a variety of subtypes of in vitro and in vivo experimental approaches using CD34-positive AML samples, LSC have been demon- fluorescence-activated cell sorting-purified subpopula- strated to reside in the Lin–CD34 þ CD38À subpopula- tions of leukemia cells were utilized to identify human tion of cells. The clinical significance of the cancer stem AML LSC. Culture of AML subpopulations on bone cell model for AML is suggested by a study that marrow feeder cells identified long-term culture-initiat- correlated the percentage of CD34 þ CD38À LSC at the ing activity in the CD34 þ CD38À leukemia fraction of time of diagnosis with the duration of relapse free most samples assayed (Ailles et al., 1997; Blair et al., survival in 92 AML patients (van Rhenen et al., 2005). 1998). Dick and colleagues were the first to establish Those patients with 43.5% AML LSC had a median xenotransplantation models for human AML, and used relapse free survival of 5.6 months compared to those this assay to identify long-term engrafting
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