Phase I clinical study of anti-apoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer

Abstract

Survivin is a member of the inhibitor of apoptosis protein (IAP) family containing a single baculovirus IAP repeat domain. It is expressed during fetal development but becomes undetectable in terminally differentiated normal adult tissues. We previously reported that survivin and its splicing variant survivin-2B was expressed abundantly in various types of tumor tissues as well as tumor cell lines and was suitable as a target antigen for active-specific anti-cancer immunization. Subsequently, we identified an HLA-A24-restricted antigenic peptide, survivin-2B80-88 (AYACNTSTL) recognized by CD8+ cytotoxic T lymphocytes (CTLs). We, therefore, started a phase I clinical study assessing the efficacy of survivin-2B peptide vaccination in patients with advanced or recurrent colorectal cancer expressing survivin. Vaccinations with survivin-2B peptide were given subcutaneously six times at 14-day intervals. Of 15 patients who finished receiving the vaccination schedule, three suffered slight toxicities, including anemia (grade 2), general malaise (grade 1), and fever (grade 1). No severe adverse events were observed in any patient. In 6 patients, tumor marker levels (CEA and CA19-9) decreased transiently during the period of vaccination. Slight reduction of the tumor volume was observed in one patient, which was considered a minor responder. No changes were noted in three patients while the remaining eleven patients experienced tumor progression. Analysis of peripheral blood lymphocytes of one patient using HLA-A24/peptide tetramers revealed an increase in peptide-specific CTL frequency from 0.09% to 0.35% of CD8+ T cells after 4 vaccinations. This phase I clinical study indicates that survivin-2B peptide-based vaccination is safe and should be further considered for potential immune and clinical efficacy in HLA-A24-expression patients with colorectal cancer.

Prime-Boost Vaccination with SA-4-1BBL Costimulatory Molecule and Survivin Eradicates Lung Carcinoma in CD8+ T and NK Cell Dependent Manner

“…However, vaccines based on SVN as TAA have shown limited therapeutic efficacy in preclinical models [23], [24] and no therapeutic, but limited immunogenic efficacy in the clinic [19], [20], [25]. Although there are various factors that may affect the limited efficacy of SVN based vaccines, the lack of an adjuvant with potent immune stimulatory activity along with the ability to concomitantly overcome various immune evasion mechanisms employed by the progressing tumor may provide a potential explanation.…”

Tumor priming enhances siRNA delivery and transfection in intraperitoneal tumors

“…Survivin was selected because (a) it is highly and selectively expressed in a majority of human cancers including gastric and colorectal cancer and peritoneal metastases, compared with most differentiated adult normal tissues including liver [19–25], (b) high survivin expression is correlated with more extensive peritoneal metastases (depth of invasion, lymph node metastasis) and shorter overall survival of patients with gastric and colorectal cancer [26–29], (c) high level survivin expression correlates with chemo/radio-resistance in multiple tumor types and its inhibition enhances cell death induced by chemo/radio-therapy [30,31], and (d) paclitaxel induces survivin expression whereas survivin siRNA (siSurvivin) significantly increases paclitaxel-induced cell death [32]. …”

The Central Role of Survivin in Proliferation and Apoptosis of Malignant Pleural Mesothelioma

“…Low molecular weight chemical inhibitors, such as YM155 (Nakahara et al, 2007), and immunogenic peptides, such as survivin-2B80-88 (Tsuruma et al, 2004) are being tested in the preclinical and early-phase clinical setting for breast, lung and colorectal cancer. Promising results of such antisurvivin therapies, applied to other cancer types (Hansen et al, 2008;Olie et al, 2000;Tsuruma et al, 2008), further confirm the feasibility and effectiveness of antisurvivin therapeutic approaches for the treatment of malignant pleural mesothelioma patients.…”