Application of Cancer Stem Cell-Targeted Vaccine in Cancer Immunotherapy
Accumulating evidence shows that tumours contain a distinct subpopulation of cancer stem cells (CSCs) which are capable of self-renewal, differentiation, and tumour-initiation. Previous studies have demonstrated that cancer stem cells are relatively resistant to chemo-and radio-therapies, and play an essential role in tumour recurrence and metastasis. Since multiple human malignancies are associated with quantitative and qualitative deficiencies in the immune system, immunotherapies are potentially ejective for cancer treatment. Vaccination is believed to have advantages over traditional treatments due to its potential to possibly eradicate the micrometastases that tend to linger after standard treatments. However, to date, experimental evidence remains limited on direct targeting of cancer stem cells by vaccination-induced immunotherapy.
In recent years, multiple studies have demonstrated that aldehyde dehydrogenase (ALDH) can serve as a specific marker for cancer stem cells in a variety of cancers [5-10]. We first characterized the tumourigenicity and stemness of ALDH (high) enriched cancer cells in immunocompetent animal models and developed a dendritic-cell based cancer stem cell vaccine (CSC-DC) in murine melanoma (D5) and murine squamous cell carcinoma (SCC7) tumour models. DC-based CSC vaccine is generated by using dendritic cells harvested from syngeneic mice and pulsing them with ALDH (high) cancer stem cells lysates. CSC-DC vaccine-primed CTLs and antibodies can then recognize and attack the CSCs. Our early study clearly showed that the CSC-DC vaccination could confer significant protective immunity against tumour cell challenges by selectively targeting cancer stem cells.
For a vaccine to be clinically relevant, it needs to be examined in the therapeutic models. Since solid tumours harbour only a small number of cancer stem cells, therapies that combine cancer stem cell vaccination with traditional treatments such as surgery, chemotherapy, and/or radiotherapy may optimize the therapeutic effects against cancer. We postulate that the initial therapy of established tumours with traditional treatments may result in tumour shrinkage, and CSC targeted vaccination may eliminate microscopic residual disease, resulting in reduced/delayed local tumour recurrence and distant metastasis. In two recent studies, we administrated DC-based cancer stem cell vaccination after localized radiotherapy of established tumours or after surgical excision of the established tumours in immunocompetent mouse models. CSC-DC vaccination significant\reduced local tumour relapse inhibited spontaneous lung metastases and prolonged host survival. No significant toxicities or adverse events were observed in these animal studies. However, to translate these findings into clinical, several critical problems remain to be solved. For example, the identification of any potential CSC antigen(s) recognized by CSC-DC vaccine-primed T cells and antibodies has yet to be characterized, and the mechanisms that are involved in CSC-DC vaccine-mediated therapeutic efficacy have to be fully defined.
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Journal of Vaccines & Vaccination