Immunotargeting of Cancer Stem Cells

Simple Summary Tumor cells from the same specimen are functionally heterogeneous. Cancer stem cells (CSCs) are populations of tumor cells with self-renewal and differentiation properties. CSCs are found in nearly all solid and hematological tumors and are characterized by various surface or intracellular markers. These markers can be used to develop tumor-specific antibodies, cytotoxic immune cells, vaccines, and direct immune responses to the tumor cells, including CSC populations. This review discusses the emerging CSC-directed immunotherapies, the current state of their clinical development, the approaches to improve their safety and efficacy, and future strategies to strengthen anti-CSC immunotherapy. The generally accepted view is that CSCs hijack the signaling pathways attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is associated with significant challenges because CSC and normal stem cells share many important signaling mechanisms for their maintenance and survival. Furthermore, the efficacy of this therapy is opposed by tumor heterogeneity and CSC plasticity. While there have been considerable efforts to target CSC populations by the chemical inhibition of the developmental pathways such as Notch, Hedgehog (Hh), and Wnt/beta-catenin, noticeably fewer attempts were focused on the stimulation of the immune response by CSC-specific antigens, including cell-surface targets. Cancer immunotherapies are based on triggering the anti-tumor immune response by specific activation and targeted redirecting of immune cells toward tumor cells. This review is focused on CSC-directed immunotherapeutic approaches such as bispecific antibodies and antibody-drug candidates, CSC-targeted cellular immunotherapies, and immune-based vaccines. We discuss the strategies to improve the safety and efficacy of the different immunotherapeutic approaches and describe the current state of their clinical development.