Therapeutic Efficacy of Cancer Stem Cell Vaccines in the Adjuvant Setting

Abstract

Dendritic cell (DC)-based vaccine strategies aimed at targeting cancer stem-like cells (CSC) may be most efficacious if deployed in the adjuvant setting. In this study, we offer preclinical evidence this is the case for a CSC-DC vaccine as tested in murine models of SCC7 squamous cell cancer and D5 melanoma. Vaccination of mice with an ALDHhigh SCC7 CSC-DC vaccine after surgical excision of established SCC7 tumors reduced local tumor relapse and prolonged host survival. This effect was augmented significantly by simultaneous administration of anti-PD-L1, an immune checkpoint inhibitor. In the minimal disease setting of D5 melanoma, treatment of mice with ALDHhigh CSC-DC vaccination inhibited primary tumor growth, reduced spontaneous lung metastases and increased host survival. In this setting, CCR10 and its ligands were downregulated on ALDHhigh D5 CSCs and in lung tissues respectively after vaccination with ALDHhigh D5 CSC-DC. RNAi-mediated attenuation of CCR10 blocked tumor cell migration in vitro and metastasis in vivo. T cells harvested from mice vaccinated with ALDHhigh D5 CSC-DC selectively killed ALDHhigh D5 CSCs, with additional evidence of humoral immunological engagement and a reduction in ALDHhigh cells in residual tumors. Overall, our results offered a preclinical proof of concept for the use of ALDHhigh CSC-DC vaccines in the adjuvant setting to more effectively limit local tumor recurrence and spontaneous pulmonary metastasis, as compared with traditional DC vaccines, with increased host survival further accentuated by simultaneous PD-L1 blockade.

Integrin β4–Targeted Cancer Immunotherapies Inhibit Tumor Growth and Decrease Metastasis

“…The most recent testing was 8 months ago. All cell lines were grown in complete medium (CM) consisting of RPMI1640 and supplements (30).…”

“…This effect was mediated by cytotoxic CD8 T cells as well as antibodies that specifically targeted the CSC population. Furthermore, the therapeutic efficacy of ALDH high head and neck CSC-DC vaccine was significantly augmented by anti-PD-L1 administration (30). This immunotherapeutic augmentation was apparent in tumor models of advanced disease as well as those simulating the adjuvant setting (30).…”

“…Furthermore, the therapeutic efficacy of ALDH high head and neck CSC-DC vaccine was significantly augmented by anti-PD-L1 administration (30). This immunotherapeutic augmentation was apparent in tumor models of advanced disease as well as those simulating the adjuvant setting (30). Although these studies demonstrated the feasibility of generating immune responses against the CSCs, the clinical application of this approach is limited by the need to obtain tumor tissue to isolate CSCs from patient.…”

Concise Review: Prostate Cancer Stem Cells: Current Understanding

“…Studies for other tumor types such as murine squamous cell cancer, murine melanoma and human colorectal cancer demonstrated anti-tumor efficiency of other types of CSC vaccines such as dendritic cells loaded with cell lysates of ALDH positive sorted tumor cells [182,183]. These studies demonstrated that anti-tumor efficiency of the CSC-based vaccine can be significantly improved in combination with an immune checkpoint inhibitor such as anti-PD-L1 antibody which blocks the immunosuppressive effect of the tumor microenvironment [182]. An ongoing Phase I/II clinical trial is testing this novel ALDH CSCderived vaccine for patients with metastatic colorectal cancer (ClinicalTrials.gov Identifier: NCT02176746).…”

Expression levels of a gene signature in hiPSC associated with lung adenocarcinoma stem cells and its capability in eliciting specific antitumor immune‐response in a humanized mice model

“…Immunization with embryonic materials to generate antitumor responses has been developed for some time, but the lack of suitable materials and ethical challenges limits its application . Previous studies have proved that CSC‐based vaccines elicit more effective antitumor responses compared with unselected tumor cells . However, the isolation and identification of CSCs are challenging.…”