A phase I study of combination vaccine treatment of five therapeutic epitope-peptides for metastatic colorectal cancer; safety, immunological response, and clinical outcome

Abstract

BackgroundTo evaluate the safety of combination vaccine treatment of multiple peptides, phase I clinical trial was conducted for patients with advanced colorectal cancer using five novel HLA-A*2402-restricted peptides, three peptides derived from oncoantigens, ring finger protein 43 (RNF43), 34 kDa-translocase of the outer mitochondrial membrane (TOMM34), and insulin-like growth factor–II mRNA binding protein 3 (KOC1), and the remaining two from angiogenesis factors, vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2.MethodsEighteen HLA- A*2402-positive colorectal cancer patients who had failed to standard therapy were enrolled in this study. 0.5 mg, 1.0 mg or 3.0 mg each of the peptides was mixed with incomplete Freund’s adjuvant and then subcutaneously injected at five separated sites once a week. We also examined possible effect of a single site injection of “the cocktail of 5 peptides” on the immunological responses. ELISPOT assay was performed before and after vaccinations in the schedule of every 4 weeks.ResultsThe vaccine treatment using multiple peptides was well tolerated without any severe treatment-associated systemic adverse events. Dose-dependent induction of peptide-specific cytotoxic T lymphocytes was observed. The single injection of “peptides cocktail” did not diminish the immunological responses. Regarding the clinical outcome, one patient achieved complete response and 6 patients revealed stable disease for 4 to 7 months. The median overall survival time (MST) was 13.5 months. Patients, in which we detected induction of cytotoxic T lymphocytes specific to 3 or more peptides, revealed significantly better prognosis (MST; 27.8 months) than those with poorer immune responses (MST; 3.7 months) (p = 0.032).ConclusionOur cancer vaccine treatment using multiple peptides is a promising approach for advanced colorectal cancer with the minimum risk of systemic adverse reactions.Clinical trial registrationUMIN-CTR number UMIN000004948.

A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study)

“…We selected five HLA-A*2402-restricted peptides derived from RNF43, TOMM34, KOC1, VEGFR1, and VEGFR2 for the clinical trial due to the abundance of the HLA-A*2402 allele in the Japanese population (an allelic frequency of approximately 60%) [17]. We previously performed a phase Ι study of a combination vaccine treatment for mCRC, and confirmed the safety and the promising potential of our five-peptide-cocktail treatment to improve the prognosis of advanced CRC [18]. …”

Personalized immunotherapy in colorectal cancer

“…For treatment of CRC patients, short or long peptides derived from various TAAs, including carcinoembryonic antigen (CEA) [11], heat shock protein (HSP) [12], melanoma antigen family (MAGE)-A4 [13], p53 [14,15], squamous cell carcinoma antigen recognized by T cells (SART) 3 [16], Survivin-2B [17,18] and many other antigens [19,20], have been used for vaccination. Since vaccination with a single short peptide showed only limited clinical responses, several modified approaches, such as long peptide [14,15], hybrid peptide [13], and multi-peptide cocktail vaccines [21], have been tried.…”

“…Therefore, employment of multiple vaccine antigens for vaccination might be recommended to reduce the risk of emergence of antigennegative variants [29,30]. In a phase I clinical trial, 18 patients with advanced CRC received a cocktail of five HLA-A*2402-restricted peptides, including those derived from ring finger protein 43 (RNF43), 34 kDa-translocase of the outer mitochondrial membrane (TOMM34), KH-domain containing protein overexpressed in cancer 1 (KOC1), vascular endothelial growth factor receptor 1 (VEGFR1), and VEGFR2, without severe vaccine-associated adverse events [21]. One of these 18 patients showed complete response (CR), and six patients maintained SD for 4-7 months.…”

Cancer vaccine therapy based on peptides

“…Multi-peptides cocktail vaccine is a strategy to overcome not only the low rate immunological responders of single vaccine, but also the heterogeneity of antigen expression on tumor cells, even though phase III trial of multi-peptides (IMA901) for advanced/metastatic RCC (IMPRINT) and phase III trial of multipeptides (OCV-C01) for advanced pancreatic cancer failed to prove survival benefits [49][50][51][52][53] .…”