Personalized peptide vaccination for advanced biliary tract cancer: IL-6, nutritional status and pre-existing antigen-specific immunity as possible biomarkers for patient prognosis

Abstract

Considering that the prognosis of patients with advanced biliary tract cancer (BTC) remains very poor, with a median survival of less than 1 year, new therapeutic approaches need to be developed. In the present study, a phase II clinical trial of personalized peptide vaccination (PPV) was conducted in advanced BTC patients to evaluate the feasibility of this treatment and to identify potential biomarkers. A maximum of 4 human leukocyte antigen-matched peptides, which were selected based on the pre-existing host immunity prior to vaccination, were subcutaneously administered (weekly for 6 consecutive weeks and bi-weekly thereafter) to 25 advanced BTC patients without severe adverse events. Humoral and/or T cell responses specific to the vaccine antigens were substantially induced in a subset of the vaccinated patients. As shown by multivariate Cox regression analysis, lower interleukin-6 (IL-6) and higher albumin levels prior to vaccination and greater numbers of selected vaccine peptides were significantly favorable factors for overall survival [hazard ratio (HR)=1.123, 95% confidence interval (CI) 1.008-1.252, P=0.035; HR=0.158, 95% CI 0.029-0.860, P=0.033; HR=0.258, 95% CI 0.098-0.682, P=0.006; respectively]. Based on the safety profile and substantial immune responses to vaccine antigens, PPV could be a promising approach for refractory BTC, although its clinical efficacy remains to be investigated in larger-scale prospective studies. The identified biomarkers are potentially useful for selecting BTC patients who would benefit from PPV.

IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4+ T cells

“…Therefore, improving the immune status of cancer patients is required for effective cancer immunotherapies. Prospective and retrospective studies have shown that serum IL-6 levels are related to tumor stage and size, metastasis, survival of colon cancer patients [19], chemotherapy efficacy for advanced pancreatic cancer [20], advanced stage and metastasis-related morbidity of breast cancer [21], and the efficacy of personalized peptide vaccination for advanced biliary tract cancer [22]. Results from these studies suggest that IL-6 levels in cancer are not simply useful as promising prognostic biomarkers, but are also related to tumorigenesis and anti-tumor immune responses.…”

Change in Palliative Performance Scale (PPS) Predicts Survival in Patients with Terminal Cancer

“…Limited data demonstrated that as the progression of primary cancer and metastasis gradually promote activation of inflammatory cytokines and interleukins, systemic symptoms such as fatigue, cachexia-anorexia, and decreased performance status are developing. Poor immune system and physical status are associated with complications such as severe sepsis, hemorrhage, embolism, and multiple organ failure which were known as major cause of death (28)(29)(30)(31)(32)(33)(34)(35)(36). By previous studies, rapid declining of patient's performance status appears to be a result of cancer progression, imbalanced immune system and unexpected complications.…”

Current status of immunotherapy for the treatment of biliary tract cancer

“…31 Recently, we conducted a phase II clinical trial of PPV for 25 chemo-resistant BTC patients (gallbladder carcinomas, n = 7; extrahepatic cholangiocarcinomas, n = 11; intrahepatic cholangiocarcinomas, n = 6; and periampullary carcinoma, n = 1) to evaluate the feasibility of this treatment and to identify potential biomarkers. 32 A maximum of 4 peptides were selected in consideration of the pre-existing host immunity before vaccination, as assessed by the titers of IgGs specific to each of the 31 different vaccine candidates [12 peptides for HLA-A2, 16 peptides for HLA-A24, 9 peptides for HLA-A3 supertypes (-A3, -A11, -A31, and -A33), and 4 peptides for HLA-A26], whose safety and immunological effects for other Downloaded by [Seton Hall University] at 15: 33 29 March 2015 …”