A promising antitumor method: Targeting CSC with immune cells modified with CAR

Abstract

Tumors pose a great threat to human health; as a subgroup of tumor cells, cancer stem cells (CSCs) contribute to the genesis, development, metastasis, and recurrence of tumors because of their enhanced proliferation and multidirectional differentiation. Thus, a critical step in tumor treatment is to inhibit CSCs. Researchers have proposed many methods to inhibit or reduce CSCs, including monoclonal antibodies targeting specific surface molecules of CSCs, signal pathway inhibitors, and energy metabolic enzyme inhibitors and inducing differentiation therapy. Additionally, immunotherapy with immune cells engineered with a chimeric antigen receptor (CAR) showed favorable results. However, there are few comprehensive reviews in this area. In this review, we summarize the recent CSC targets used for CSC inhibition and the different immune effector cells (T cells, natural killer (NK) cells, and macrophages) which are engineered with CAR used for CSC therapy. Finally, we list the main challenges and options in targeting CSC with CAR-based immunotherapy. The design targeting two tumor antigens (one CSC antigen and one mature common tumor antigen) should be more reasonable and practical; meanwhile, we highlight the potential of CAR-NK in tumor treatment.

Keywords: CAR; CAR-NK; CSC; immunotherapy; targeted strategy.

Figure 1

Different generations of CAR design. The intracellular domain of the first CAR only consists of one signaling domain (CD3ζ). The second CAR adds one co-stimulatory molecule (CD28/4-1BB/OX40/ICOS) to the intracellular domain of the first CAR. The third CAR contains two costimulatory molecules in the intracellular domain. The fourth CAR is designed by adding NFAT or suicide gene based on the second or third CAR. The fifth CAR uses a “third-party” intermediate system to separate the antigen-binding domain of CAR from the T-cell signaling unit.

Figure 2

Different methods to target CSC with immune effector cells modified with CAR. (A) One target CAR-effector cell targeting a CSC antigen located on CSCs; (B) Dual-target CAR-effector cell targeting two different antigens, including one common tumor antigen and one CSC antigen located on common tumor cells and CSCs, respectively. (C) Dual-target CAR-effector cell targeting two different antigens, including one common tumor antigen and one CSC antigen located on one CSC simultaneously.