Randomized phase <scp>II</scp> trial of survivin 2B peptide vaccination for patients with <scp>HLA</scp>‐A24‐positive pancreatic adenocarcinoma

Shima, Hiroaki; Tsurita, Giichiro; Wada, Satoshi; Hirohashi, Yoshihiko; Hayashi, Hiroshi; Miyakoshi, Tatsuyoshi; Watanabe, Kazue; Murai, Aiko; Asanuma, Hiroko; Tokita, Serina; Kubo, Terufumi; Nakatsugawa, Munehide; Kanaseki, Takayuki; Tsukahara, Tomohide; Nakae, Yutaka; Sugita, Osamu; Ito, Yoichi M.; Ota, Yasunori; Kimura, Yasutoshi; Kutomi, Goro; Hirata, Koichi; Mizuguchi, Toru; Imai, Kohzoh; Takemasa, Ichiro; Sato, Noriyuki; Torigoe, Toshihiko

doi:10.1111/cas.14106

Cited by 41 publications

(39 citation statements)

References 18 publications

(21 reference statements)

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“…In fact, the overexpression of survivin has been a target of cancer vaccination by using survivin 2B peptides in combination with interferon-β. While this therapy did not improve progression-free survival, there was a significantly enhanced immune reaction following treatment with this vaccine [45]. Overall, continued evaluation of survivin as a therapeutic target with our novel inhibitor has the potential to provide more therapeutic options and enhance overall benefits to patients with PDAC.…”

Section: Discussionmentioning

confidence: 94%

The role of survivin in the progression of pancreatic ductal adenocarcinoma (PDAC) and a novel survivin-targeted therapeutic for PDAC

et al. 2020

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Treating pancreatic ductal adenocarcinoma (PDAC) remains a major hurdle in the field of oncology. Less than half of patients respond to frontline chemotherapy and the pancreatic tumor microenvironment limits the efficacy of immunotherapeutic approaches. Targeted therapies could serve as effective treatments to enhance the clinical response rate. One potential therapeutic target is survivin, a protein that is normally expressed during embryonic and fetal development and has a critical impact on cell cycle control and apoptosis. In adulthood, survivin is not present in most normal adult cells, but is significantly re-expressed in tumor tissues. In PDAC, elevated survivin expression is correlated with treatment resistance and lower patient survival, although the underlying mechanisms of survivin's action in this type of cancer is poorly understood. Using patient derived xenografts of PDAC and their corresponding primary pancreatic cancer lines (PPCL-46 and PPCL-LM1) possessing increased expression of survivin, we aimed to evaluate the therapeutic response of a novel survivin inhibitor, UFSHR, with respect to survivin expression and the tumorigenic characteristics of PDAC. Cell viability and apoptosis analyses revealed that repressing survivin expression by UFSHR or YM155, a well-known inhibitor of survivin, in PPCLs effectively reduces cell proliferation by inducing apoptosis. Tumor cell migration was also hindered following treatment with YM155 and UFSHR. In addition, both survivin inhibitors, particularly UFSHR, effectively reduced progression of PPCL-46 and PPCL-LM1 tumors, when compared to the untreated cohort. Overall, this study provides solid evidence to support the critical role of survivin in PDAC progression and proposes a novel survivin inhibitor UFSHR that can become an alternative strategy for this type of cancer.

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Section: Discussionmentioning

confidence: 94%

The role of survivin in the progression of pancreatic ductal adenocarcinoma (PDAC) and a novel survivin-targeted therapeutic for PDAC

et al. 2020

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“…Additionally, some patients participated in a subsequent round of 4 treatments with survivin-2B80-88 plus IFN-β (Step 2). Those patients who had received survivin-2B80-88 plus IFN-β in Step 1 and Step 2 showed better overall survival (OS) compared with those who had received placebo in Step 1 [161]. Based on this result, a longer survivin-2B80-88 plus IFN-β vaccination protocol might confer survival benefit.…”

Section: Survivin-2b80-88mentioning

confidence: 98%

“…Based on these promising results, a multicenter randomized phase II study in patients with advanced pancreatic adenocarcinoma was conducted [161]. Specifically, patients after gemcitabine and/or tegafur-gimeracil-oteracil (TS-1) were randomly assigned into 3 groups and treated with (i) survivin-2B80-88 plus IFNβ (n=30), (ii) survivin-2B80-88 only (n=34), or (iii) placebo (n=19) until the patients showed disease progression.…”

Section: Survivin-2b80-88mentioning

confidence: 99%

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Aljahdali

Ling

2019

J Exp Clin Cancer Res

179

171

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Survivin (also named BIRC5) is a well-known cancer therapeutic target. Since its discovery more than two decades ago, the use of survivin as a target for cancer therapeutics has remained a central goal of survivin studies in the cancer field. Many studies have provided intriguing insight into survivin's functional role in cancers, thus providing promise for survivin as a cancer therapeutic target. Despite this, moving survivin-targeting agents into and through the clinic remains a challenge. In order to address this challenge, we may need to rethink current strategies in order to develop a new mindset for targeting survivin. In this Review, we will first summarize the current survivin mechanistic studies, and then review the status of survivin cancer therapeutics, which is classified into five categories: (i) survivin-partner protein interaction inhibitors, (ii) survivin homodimerization inhibitors, (iii) survivin gene transcription inhibitors, (iv) survivin mRNA inhibitors and (v) survivin immunotherapy. We will then provide our opinions on cancer therapeutics using survivin as a target, with the goal of stimulating discussion that might facilitate translational research for discovering improved strategies and/or more effective anticancer agents that target survivin for cancer therapy.

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“…However, the vaccine did not improve progression‐free survival, as reported by Shima et al. in this issue . Development of the next generation of tumor‐specific immunotherapy requires an understanding of the local effect in tumor tissue after administration of this vaccine.…”

Section: Introductionmentioning

confidence: 52%

“…All patients were found to have the HLA‐A24 allele and expression of HLA class I and survivin on examination of biopsy specimens. The protocol for this trial is described in detail in the parallel publication by Shima et al . Autopsies were carried out in 7 of these patients; the vaccination schedule for each of these patients is shown in Figure A.…”

Section: Methodsmentioning

confidence: 99%

Immunohistological analysis of pancreatic carcinoma after vaccination with survivin 2B peptide: Analysis of an autopsy series

et al. 2019

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Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer by providing new options in addition to existing therapies. However, peptide vaccination therapies still represent an attractive approach, because of the antigen specificity. We identified survivin 2B peptide (SVN‐2B), a 9‐mer antigenic peptide encoded by survivin, and an SVN‐2B peptide vaccine‐based phase II randomized clinical trial targeting unresectable and refractory pancreatic carcinoma was undertaken. The SVN‐2B peptide vaccine did not have any statistically significant clinical benefits in that study. Therefore, we undertook an autopsy study to analyze the immune status of the pancreatic cancer lesions at the histological level. Autopsies were carried out in 13 patients who had died of pancreatic cancer, including 7 who had received SVN‐2B peptide vaccination and 6 who had not, as negative controls. The expression of immune‐related molecules was analyzed by immunohistochemical staining. Cytotoxic T lymphocytes were analyzed by tetramer staining and enzyme‐linked immunospot assay. Histological analysis revealed dense infiltration of CD8+ T cells in some lesions in patients who had received the SVN‐2B peptide vaccine. A high rate of programmed cell death ligand 1 expression in cancer cells was observed in these cases, indicating that CTLs were induced by SVN‐2B peptide vaccination and had infiltrated the lesions. The lack of a significant antitumor effect was most likely attributable to the expression of immune checkpoint molecules. These findings suggest that the combination of a tumor‐specific peptide vaccine and an ICI might be a promising approach to the treatment of pancreatic carcinoma in the future.

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Randomized phase II trial of survivin 2B peptide vaccination for patients with HLA‐A24‐positive pancreatic adenocarcinoma

Cited by 41 publications

References 18 publications

The role of survivin in the progression of pancreatic ductal adenocarcinoma (PDAC) and a novel survivin-targeted therapeutic for PDAC

The role of survivin in the progression of pancreatic ductal adenocarcinoma (PDAC) and a novel survivin-targeted therapeutic for PDAC

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Immunohistological analysis of pancreatic carcinoma after vaccination with survivin 2B peptide: Analysis of an autopsy series

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