Abstract LB-153: Introduction of Th1 help by a novel cancer vaccine, helper/killer hybrid epitope long peptide (H/K-HELP): From basic to clinical study

Abstract

Abstract Using mouse tumor model, we have demonstrated that there are strong immunosuppressive tumor escape mechanisms in tumor-bearing hosts. Especially, we have emphasized the following three mechanisms; (i) CD133+ cancer-stem cells (CSC) produced high levels of active TGF-β and they are resistant to CD8+ T cell-mediated immunosurveillance via inducing regulatory T cells (Tregs); (ii) Immature myeloid cells (ImC), which are abnormally increased in tumor-bearing mice, are classified into three distinct populations and MΦ-ImC and NeutSeg-ImC, but not NeutStab-ImC act as myeloid-derived suppressor cells (MDSC); (iii) IL-17-producing γδ T cells act as protumor cells during carcinogenesis and tumor progression via promoting angiogenesis. We have proposed that Th1-dominant immunity played a critical role for overcoming such immunosuppressive tumor-escape mechanisms to induce tumor-specific memory and CTL, which are essential for the cure of tumor. In addition, we have reported rational strategies such as Th1 cell therapy and its combination with chemo or radiation therapy. To apply these basic findings to a clinical trial, we first identified a novel helper epitopes of MAGE-A4 and Survivin tumor antigens, which can activate tumor-specific Th1 cells by combination with Th1 adjuvant, OK-432. To induce an efficient Th1-dependent antitumor immunity, we further developed a novel cancer vaccine, artificial helper/killer hybrid epitope long peptide (H/K-HELP) of MAGE-A4 or Survivin. In phase I study, H/K-HELP consisted of both killer and helper epitopes was mixed with adjuvants (OK-432 and Oil adjuvant) and subcutaneously administered into cancer patients 4 times with 2 wks interval. Both MAGE-A4-H/K-HELP and Survivin-H/K-HELP induced tumor-specific Th1 and Tc1 immune responses and tumor-specific C-fixing antibody (IgG1 and IgG3) responses in cancer patients. H/K-HELP vaccination inhibited the growth of tumor in patients with melanoma and colon cancer. Moreover, H/K-HELP vaccination induced a complete regression of chemo and radio-resistant lateral deep cervical node recurrence of triple-negative breast cancer. Thus, our results propose that H/K-HELP vaccination or its combination with Th1 cells will become a promising tumor vaccine/cell therapy of human cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-153. doi:10.1158/1538-7445.AM2011-LB-153