Antibodies targeting cancer stem cells: A new paradigm in immunotherapy?

Abstract

Antibody targeting of cancer is showing clinical and commercial success after much intense research and development over the last 30 years. They still have the potential to delivery long-term cures but a shift in thinking towards a cancer stem cell (CSC) model for tumor development is certain to impact on how antibodies are selected and developed, the targets they bind to and the drugs used in combination with them. CSCs have been identified from many human tumors and share many of the characteristics of normal stem cells. The ability to renew, metabolically or physically protect themselves from xenobiotics and DNA damage and the range of locomotory-related receptors expressed could explain the observations of drug resistance and radiation insensitivity leading to metastasis and patient relapse.Targeting CSCs could be a strategy to improve the outcome of cancer therapy but this is not as simple as it seems. Targets such as CD133 and EpCAM/ESA could mark out CSCs from normal cells enabling specific intervention but indirect strategies such as interfering with the establishment of a supportive niche through anti-angiogenic or anti-stroma therapy could be more effective. This review will outline the recent discoveries for CSCs across the major tumor types highlighting the possible molecules for intervention. Examples of antibody-directed CSC therapies and the outlook for the future development of this emerging area will be given.Monoclonal antibodies are clinically and commercially-established therapeutics. 1,2 A great deal of progress has been made over the last 30 years in overcoming problems and translating the phenomenal amount of laboratory research into clinical products. However, antibodies or other molecular interventions against cancer do not necessarily cure. In many cases, they can increase survival and improve quality of life. So, have we been hitting the wrong targets? Certainly, receptors such as human epidermal growth factor-1 (HER1/EGFR), HER2, CD20 and growth factors such as vascular endothelial cell (VEGF) and Interleukin-6 (IL-6) are involved in the cancer process, but have we been overlooking the real culprits?This review aims to examine the biology of cancer stem cells considering the markers defining them and their survival and will describe the new antibody-focused strategies emerging to target them for more effective treatment of cancer. Introduction to Cancer Stem Cells (CSCs)The 'Seed and Soil' theory of the English surgeon Paget, in 1889, 3 significantly pre-dates the current cancer stem cell hypothesis and once again shows how many of the best theories were thought about many years ago, went generally unnoticed but were later supported by technological advances. Paget surveyed breast cancers in patients and was struck by the discrepancy between blood supply and site of metastasis in some organs. He concluded that cancer cells ('seeds') could only grow in congenial conditions ('soil'). This theory contradicted the previous view that tumor cells lodged in the vasculature, and was challenge...

Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example

“…However, their inherent traits, which allow them to escape conventional Targeting the human WT NCAM1 + cell fraction with an anti-NCAM1 antibody-toxin conjugate (HuN901-DMI) resulted in loss of the WT CSCs, followed by complete tumor degradation chemo/radiotherapies, necessitate the development of alternative treatment options directed at these highly malignant and therapy-resistant cancer cells. Although therapeutics aimed at CSC eradication have not yet reached clinical use, there are several novel reports of targeted CSC therapy in animal models or in clinical trials [62,63].…”

Application of Stem Cells in Targeted Therapy of Breast Cancer: A Systematic Review

“…No universal cell surface antigen, or combination of antigens, for the purification of breast CSCs by antibody techniques yet have been identified (Ablett et al, 2012). Many putative CSC markers are not merely restricted to CSCs, therefore the main goal in targeted therapy is specific destruction of CSCs while protecting normal cells (Deonarain et al, 2009).…”

“…A distinguished understanding of signaling pathways between normal and CSCs is required to prevent destroying normal stem cells, as this is the key point to perfect accomplishment of anti-CSC therapies (Deonarain et al, 2009).…”

“…The first one is targeting CSC markers or pathways involved in CSCs using monoclonal antibodies as a novel strategy to improve the outcome of cancer therapy (Deonarain et al, 2009). The second one applies stem cells particularly Mesenchymal Stem Cells (MSCs) as promising platform for cell and gene therapy of incurable cancers (Ozawa et al, 2008).…”

Cellular Stiffness as a Novel Stemness Marker in the Corneal Limbus

“…Antibodies against the ATPbinding cassettes subfamily G member 2 (ABCG2) and subfamily B member 5 (ABCB5) have been successfully used to enrich the LSC population, but they also enrich for other ABCG2-or ABCB5-expressing cells present in the limbus and cornea (11,(14)(15)(16). The use of antibodies to identify LSCs in the clinic is cumbersome, requiring~15 h of laborious cell processing, and can subsequently affect cellular physiology if the epitope is associated with a functionally important protein domain (17)(18)(19). A label-free microfluidic device that sorts based on cellular biomechanical properties offers cost and labor advantages over current methods and may provide sufficient enrichment to serve as an alternative or additional approach to antibody-based techniques.…”