Multicenter, phase II clinical trial of peptide vaccination with oral chemotherapy following curative resection for stage�III colorectal cancer

Abstract

The safety and immunological responsiveness of a peptide vaccine of ring finger protein 43 and 34-kDa translocase of the outer mitochondrial membrane combined with uracil-tegafur/leucovorin (UFT/LV) was previously demonstrated in metastatic colorectal cancer (CRC) in a phase I clinical trial. To clarify the survival benefit of a peptide vaccine combined with UFT/LV as adjuvant treatment, a phase II clinical trial was conducted involving patients with stage III CRC. All enrolled patients, whose human leukocyte antigen (HLA)-A status was double-blinded, were administered the same regime of a peptide vaccine and UFT/LV chemotherapy. The primary objective of the study was to compare relapse-free survival (RFS) in patients with HLA-A*2402 vs. those without HLA-A*2402. Secondary objectives included comparisons between the two groups regarding overall survival, safety, tolerability and peptide-specific activities of cytotoxic T lymphocytes (CTLs) as measured by the ELISPOT assay. Between December 2009 and December 2014, a total of 46 patients were enrolled to the present study. Three-year RFS was not significantly different between HLA-A*2402 matched and unmatched groups [67.8 vs. 73.6%, respectively; hazard ratio (HR)=1.254, 95% confidence interval (CI): 0.48–4.63; P=0.706]. Three-year RFS was significantly better in patients with positive CTL responses in the HLA-A*2402 matched group compared with those without (85.7 and 33.3%, respectively; HR=0.159, 95% CI: 0.023–0.697; P=0.011). In conclusion, vaccination-induced immune responses combined with UFT/LV were positively associated with survival benefit in patients with HLA-A*2402-positive stage III CRC. Further study is required to clarify whether vaccination-induced immune responses shortly following the initiation of therapy can predict the therapeutic effect and help develop a promising therapeutic strategy for patients with stage III CRC.

A phase I study of multi-HLA-binding peptides derived from heat shock protein 70/glypican-3 and a novel combination adjuvant of hLAG-3Ig and Poly-ICLC for patients with metastatic gastrointestinal cancers: YNP01 trial

“…Approximately 70% of the patients in this trial showed specific CTL induction to each of the peptides. This finding is superior to those of previous reports [3][4][5]32]. Additionally, patients receiving dose level 3 (1.0 mg hLAG-3Ig + 1.4 mg Poly-ICLC/injection) had significantly faster and stronger peptide-specific CTL induction than those at dose levels 1 and 2.…”

Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer

“…Interestingly, only one patient failed to mount specific CD8 T cell responses against RNF43 and/or TOMM34 and 83% of patients had stable disease following the vaccination (165). After having demonstrated the safety and immunological responsiveness of this combination therapy, the same group showed that 3-years DFS was significantly better in the group of patients with CD8 T cell responses than in the group without (154,166). In order to improve clinical responses, Okuno et al added to this original combination therapy 5 other TAA-derived peptides to the vaccine.…”

“…In addition to depending on TAAs, vaccine immunogenicity also relies on the use of adjuvants that are crucial components to boost and enhance antigen-specific immune responses. Most TAA-based vaccines described above are combined with different adjuvants inducing the activation and recruitment of APCs (168), such as incomplete Freund's adjuvant (IFA) (165)(166)(167), TLR-3 agonist (161) or Flt3 ligand (160). The use of type I IFN as a second adjuvant in a survivin-2B-based vaccine already combined with IFA led to 50% of patients having stable disease versus 20% with IFA only (152).…”

Cytotoxic T lymphocyte response to peptide vaccination predicts survival in stage III colorectal cancer

“…Detailed information of the study design was described previously. 9 Briefly, this was a phase II, non-randomized, single-arm study in which the HLA-A status was double-blinded. The therapy consisted…”

“…[4][5][6] We previously reported a phase I clinical trial of a peptide vaccine ring finger protein 43 (RNF43) and 34-kDa translocase of the outer mitochondrial membrane (TOMM34) combined with uracil-tegafur (UFT)/LV for patients with metastatic CRC, and demonstrated the safety and immunological responsiveness of this combination therapy. [7][8][9] In this study, we evaluated vaccination-…”