Efficacy of an ALDH peptide-based dendritic cell vaccine targeting cancer stem cells

Cancer immunotherapies may be limited by their failure to target cancer stem cells (CSCs). We previously described an approach to target these cells using a dendritic cell (DC) vaccine primed with lysates of CSCs identified by aldehyde dehydrogenase (ALDH). However, its clinical application is limited by the difficulty of obtaining adequate amounts of tumor from patient to make CSC lysate for vaccine preparation. To address this issue, we evaluated targeting ALDH^high CSCs using two antigenic peptides derived from ALDH in D5 melanoma model in both protection and therapeutic settings. ALDH 1A1 or 1A3 peptide-DC vaccines primed cytotoxic T lymphocytes (CTLs) that specifically killed ALDH^high D5 CSCs, with ALDH 1A1 + 1A3 dual peptides-DC vaccine mediating an additive CTL effect compared to single peptide-DC vaccines. In a tumor challenge model, ALDH peptide-DC vaccines induced significant protective immunity suppressing D5 tumor growth with the dual peptides-DC vaccine being superior to each peptide individually. In a therapeutic model, dual peptide-DC vaccine resulted in significant tumor growth suppression with anti-PD-L1 administration significantly augmenting this effect. Immune monitoring studies revealed that ALDH dual peptides-DC vaccination elicited strong T cell (CTL & IFNγ Elispot) and antibody immunity targeting ALDH^high CSCs, resulting in significant reduction of ALDH^high D5 CSCs. ALDH dual peptides-DC vaccination plus anti-PD-L1 administration resulted in increased recruitment of CD3⁺ TILs in the residual tumors and further reduction of ALDH^high D5 CSCs. ALDH peptide(s)-based vaccine may allow for clinical translation via immunological targeting of ALDH^high CSCs. Furthermore, this vaccine augments the efficacy of immune checkpoint blockade.