Abstract. to test the safety and immune responses of a novel peptide vaccine derived from RNF43 (ring finger protein 43) and tOmm34 (34-kda translocase of the outer mitochondrial membrane) administered in combination with chemotherapy in patients with metastatic colorectal cancer, a phase I clinical trial with 21 HLA-A2402-positive metastatic colorectal cancer patients was conducted. Patients received a weekly peptide vaccine (1 mg of each peptide in incomplete Freund's adjuvant) in combination with oral UFT (300 mg/m 2 /day) and UZEL (75 mg/day) for 4 weeks, followed by 1 week of rest. The protocol consisted of at least two cycles of this regimen. After the 2nd cycle, vaccinations were given biweekly or monthly, depending on the condition of the patient. Clinical responses were judged 10 weeks after the 2nd cycle by performing computed tomography (CT) scans and assessing the cytotoxic T lymphocyte (CTL) responses against RNF43 and TOMM34 in peripheral lymphocytes. The vaccinations were well tolerated without any serious adverse events. CTL responses were induced against both antigens in 8 patients and against one antigen in 12 patients, while 1 patient had no CTL response. The rate of stable disease was 83%. The group with CTL responses against both antigens had the most long-term survivors, followed by the group showing CTL responses against one antigen (p=0.0079). The patients with no CTL responses had the lowest survival. The safety and immunological responsiveness of the present combination therapy suggests that it is clinically beneficial for metastatic colorectal cancer. Further clinical trials are warranted.

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.

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 colorectal cancer (CRC), and demonstrated the safety and immunological responsiveness of this combination therapy. In this study, we evaluated vaccination‐induced immune responses to clarify the survival benefit of the combination therapy as adjuvant treatment. We enrolled 44 patients initially in an HLA‐masked fashion. After the disclosure of HLA, 28 patients were in the HLA‐A*2402‐matched and 16 were in the unmatched group. In the HLA‐matched group, 14 patients had positive CTL responses specific for the RNF43 and/or TOMM34 peptides after 2 cycles of treatment and 9 had negative responses; in the HLA‐unmatched group, 10 CTL responses were positive and 2 negative. In the HLA‐matched group, 3‐year relapse‐free survival (RFS) was significantly better in the positive CTL subgroup than in the negative‐response subgroup. Patients with negative vaccination‐induced CTL responses showed a significant trend towards shorter RFS than those with positive responses. Moreover, in the HLA‐unmatched group, the positive CTL response subgroup showed an equally good 3‐year RFS as in the HLA‐matched group. In conclusion, vaccination‐induced CTL response to peptide vaccination could predict survival in the adjuvant setting for stage III CRC.

Objectives: To elucidate the efficacy of adjuvant vaccine monotherapy using 3 Human Leukocyte Antigen (HLA)-A Ã 24-restricted tumor-specific peptide antigens for ESCC, upregulated lung cancer 10, cell division cycle associated 1, and KH domain-containing protein overexpressed in cancer 1. Summary of Background Data: ESCC patients with pathologically positive nodes (pN(þ)) have a high risk for postoperative recurrence, despite curative resection after preoperative therapy. Subclinical micrometastases are an appropriate target for cancer vaccine. Methods: This is a non-randomized prospective phase II clinical trial (UMIN000003557). ESCC patients curatively resected after preoperative therapy with pN(þ) were allocated into the control and vaccine groups (CG and VG) according to the HLA-A status. One mg each of three epitope peptides was postoperatively injected 10 times weekly followed by 10 times biweekly to the VG. The primary and secondary endpoints were relapse-free survival (RFS) and esophageal cancer-specific survival (ECSS), respectively. Results: Thirty were in the CG and 33 in the VG. No significant difference was observed in RFS between the CG and VG (5-year RFS: 32.5% vs 45.3%), but the recurrence rate significantly decreased with the number of peptides which induced antigen-specific cytotoxic T lymphocytes. The VG showed a significantly higher 5-year ECSS than the CG (60.0% vs 32.4%, P ¼ 0.045) and this difference was more prominent in patients with CD8 þ and programmed death-ligand 1 double negative tumor (68.0% vs 17.7%, P ¼ 0.010). Conclusions: Our cancer peptide vaccine might improve the survival of ESCC patients, which is warranted to be verified in the phase III randomized controlled study.

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