Tumor-derived Autophagosomes is a Potent Vaccine in Cancer Immunotherapy (41.33)

Abstract

Abstract Active immunotherapy (AIT) using vaccines has been exploited to eradicate primary tumors and metastases; however, overall clinical response rate of AIT is less than 4%. This disappointing result underscores the need for novel vaccines. We have developed an autophagosome-enriched vaccine (DRibble), and evaluated its efficiency in cross-presentation of tumor-associated antigens (TAA) and its anti-tumor efficacy. We found that autophagosomes can accumulate and be released from a number of tumor cell lines after prolonged inhibition of proteasome-mediated protein degradation. By transmission electron microscopy, we confirmed the presence of numerous double-membrane autophagosomes in DRibble preparations from tumor cells. The DRibbles sequestered long-lived and short-lived proteins, defective ribosomal products, as well as heat shock proteins HSP90 and HSP94, as evidenced by western blotting. Using CFSE dilution of labeled antigen-specific TCR transgenic CD8+ T cells as a read out, we showed that DRibbles were highly efficient in cross-presenting TAA in vitro and in vivo. Vaccination with DCs loaded with gp100-DRibbles resulted in a doubling of median survival time of mice bearing 6-day s.c. B16F10 tumors (59 days for vaccinated mice vs 26 days for untreated mice). Remarkably, 83% of mice bearing 6-day s.c. 3LL tumors were cured when they received DRibble vaccines, whereas all untreated mice succumbed to disease. Based on these strong preclinical results, our Institute has initiated a clinical trial for non-small cell lung cancer using autologous tumor-derived DRibbles. This work was supported by NIH grants CA 107243 (HMH), CA 123864 (WJU), ACS grant LIB-106810 (HMH), the Providence Medical Foundation, and the Kuui Foundation.