Phase I clinical trial of a novel peptide vaccine in combination with UFT/LV for metastatic colorectal cancer

Abstract

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.

RNF43 Inhibits Cancer Cell Proliferation and Could be a Potential Prognostic Factor for Human Gastric Carcinoma

“…These results suggest that RNF43 might play a suppressive role in the development and progression of these tumors. Because the combination therapy of peptide vaccines and anti-cancer drugs for colorectal cancer is associated with increased expression of RNF43 [23,24], a novel therapeutic strategy based on RNF43 might be used in the future for patients with gastric carcinomas. Additionally, we analyzed the reason that we observed that there was no statistical association between pTNM and survival in the Cox proportional hazard model and found that the number of samples might have been insufficient.…”

Colorectal Clinical Trials: What is on the Horizon?

“…Since these agents are derived from tumor-specific antigens, they have a decreased risk of inducing autoimmunity. Several peptide vaccines for CRC have reached Phase I trials, demonstrating promising signs of clinical activity [18,19]. With HER2 overexpression present in a proportion of CRC [20,21], HER2 peptide vaccines and their potential roles as a therapeutic agent in CRC are currently being investigated (NCT01376505).…”

RT-qPCR analysis of the tumor antigens TOMM34 and RNF43 in samples extracted from paraffin-embedded specimens of colorectal cancer

“…TOMM34 and RNF43 are considered to be associated with cell proliferation, and clinical studies of vaccine therapy with an artificially synthesized cancer peptide based on the amino acid sequence of tumor antigens such as TOMM34 and RNF43 are ongoing (3–6). A tumor antigen inoculated by vaccine is used for antigen presentation from dendritic cells to lymphocytes, and cytotoxic T-lymphocytes (CTLs) are induced in vivo .…”