Long-term Vaccination with Multiple Peptides Derived from Cancer-Testis Antigens Can Maintain a Specific T-cell Response and Achieve Disease Stability in Advanced Biliary Tract Cancer

Abstract

Purpose: The prognosis of patients with advanced biliary tract cancer (BTC) is extremely poor and there are only a few standard treatments. We conducted a phase I trial to investigate the safety, immune response, and antitumor effect of vaccination with four peptides derived from cancer-testis antigens, with a focus on their fluctuations during long-term vaccination until the disease had progressed.Experimental Design: Nine patients with advanced BTC who had unresectable tumors and were refractory to standard chemotherapy were enrolled. HLA-A Ã 2402-restricted epitope peptides, lymphocyte antigen 6 complex locus K, TTK protein kinase, insulin-like growth factor-II mRNA-binding protein 3, and DEP domain containing 1 were vaccinated subcutaneously once a week at doses of 0.5, 1, or 2 mg and continued until disease progression. The adverse events were assessed by Common Terminology Criteria for Adverse Events and the immune response was monitored by an enzyme-linked immunospot assay or by flow cytometry. The clinical effects observed were tumor response, progression-free survival (PFS), and overall survival (OS).Results: Four-peptide vaccination was well tolerated. No grade 3 or 4 adverse events were observed. Peptide-specific T-cell immune responses were observed in seven of nine patients and clinical responses were observed in six of nine patients. The median PFS and OS were 156 and 380 days. The injection site reaction and CTL induction seemed to be prognostic factors of both PFS and OS.Conclusions: Four-peptide vaccination was well tolerated and seemed to provide some clinical benefit to some patients. These immunologic and clinical responses were maintained over the long term through continuous vaccinations.

TTK is a favorable prognostic biomarker for triple-negative breast cancer survival

“…Moreover, because TTK is expressed in all proliferating human cells [27], these inhibitors should be used cautiously to avoid severe adverse effects. TTK-567(SYRNEIAYL) epitope peptide was also used to elicit cytotoxic T lymphocytes to establish cancer vaccines in lung, esophageal and advanced biliary tract cancers [28, 29]. …”

Immunotherapy: Pancreatic Cancer and Extrahepatic Biliary Tract Cancer

“…Clinical responses were observed in 6 of 9 patients with a median OS of 380 days. The injection site reaction and cytotoxic T cell induction seemed to be prognostic factors for survival [93]. …”

Immunotherapy as a treatment for biliary tract cancers: A review of approaches with an eye to the future

“…Quadruple peptide vaccine therapy incorporating lymphocyte antigen 6 complex locus K (LY6K), TTK protein kinase, insulin like growth factor II mRNA binding protein 3 (IGF2BP3), and DEP domain-containing 1 (DEPDC1) were administered to 9 patients with unresectable BTC in a phase 1 study. 29 Peptide-specific T cell responses were observed in 78% of patients and these responses in addition to developing a grade 2 local skin reaction at the vaccination site, were associated with a longer progression-free survival (PFS) and OS. 29 The same group performed a phase I trial of vaccine with 3-peptide combination including: cell division cycle associated protein 1 (CDC1), cadherin 3 (CDH3), and kinesin family member 20A (KIF20A) in patients with advanced BTC.…”

“…29 Peptide-specific T cell responses were observed in 78% of patients and these responses in addition to developing a grade 2 local skin reaction at the vaccination site, were associated with a longer progression-free survival (PFS) and OS. 29 The same group performed a phase I trial of vaccine with 3-peptide combination including: cell division cycle associated protein 1 (CDC1), cadherin 3 (CDH3), and kinesin family member 20A (KIF20A) in patients with advanced BTC. 30 This triple peptide combination vaccine was well tolerated and resulted in peptide-specific T cell responses in all patients.…”