Therapeutic effect of a T helper cell supported CTL response induced by a survivin peptide vaccine against murine cerebral glioma

Abstract

Survivin is a tumor-associated antigen (TAA) that has significant potential for use as a cancer vaccine target. To identify survivin epitopes that might serve as targets for CTL-mediated, anti-tumor responses, we evaluated a series of survivin peptides with predicted binding to mouse H2-K b and human HLA-A201 antigens in peptide-loaded dendritic cell (DC) vaccines. H2-K b -positive, C57BL/ 6 mice were vaccinated using syngeneic, peptide-loaded DC2.4 cells. Splenocytes from vaccinated mice were screened by flow cytometry for binding of dimeric H2-K b :Ig to peptide-specific CD8+ T cells. Two survivin peptides (SVN 57-64 and SVN 82-89 ) generated specific CD8+ T cells. We chose to focus on the SVN 57-64 peptide because that region of the molecule is 100% homologous to human survivin. A larger peptide (SVN 53-67 ), containing multiple class I epitopes, and a potential class II ligand, was able to elicit both CD8+ CTL and CD4+ T cell help. We tested the SVN 53-67 15-mer peptide in a therapeutic model using a peptide-loaded DC vaccine in C57BL/6 mice with survivinexpressing GL261 cerebral gliomas. This vaccine produced significant CTL responses and helper T cell-associated cytokine production, resulting in a significant prolongation of survival. The SVN 53-67 vaccine was significantly more effective than the SVN 57-64 core epitope as a cancer vaccine, emphasizing the potential benefit of incorporating multiple class I epitopes and associated cytokine support within a single peptide.

Oral administration of a soluble 1–3, 1–6 β-glucan during prophylactic survivin peptide vaccination diminishes growth of a B cell lymphoma in mice

“…The survivin protein is a member of the inhibitor-of-apoptosis (IAP) gene family and is expressed in almost all malignant tissues, but is not present in normal differentiated adult tissues [27]. In syngeneic tumor models immunization with DC loaded with survivin-derived peptides induced specific CTL and significantly prolonged survival or induced protective immunity against tumor challenge [28,29]. Furthermore, the presence of survivin-specific CTL has been detected in patients with various cancers, and vaccination with a HLA-A2 restricted survivin peptide was successful in a patient suffering from pancreatic cancer leading to complete remission of liver metastasis [30,31].…”

Identification and characterization of survivin‐derived H‐2Kb‐restricted CTL epitopes

“…The availability of multiple survivin epitopes presented by different HLA restriction elements further reduces the risk of immune escape and thereby might improve therapeutic effectiveness. While several survivin-derived CTL epitopes are known in humans [19,20,31,32], there are only limited reports for the murine system [27,33].…”

“…The availability of multiple survivin epitopes presented by different HLA restriction elements further reduces the risk of immune escape and thereby might improve therapeutic effectiveness. While several survivin-derived CTL epitopes are known in humans [19,20,31,32], there are only limited reports for the murine system [27,33].In the present study, we identified two H-2K were carried out as described [36]. The assembly assay is based on stabilization of the class I molecule after loading of peptide to the peptide transporter-deficient cell line RMA-S.…”

“…3A), with significant differences in tumor volumes being observed between Msur 57/97-treated and control mice at day 29. Additionally, we found significant differences for Msur 97-peptide at every time point we measured and for Msur 57 on day 13, 21, and 29.Thus, the availability of K b -restricted epitopes from mouse survivin protein is likely to facilitate the characterization and optimization of anti-tumor vaccination approaches, particularly since the best-characterized melanoma model is syngeneic to Indeed, in a recent study using a murine cerebral glioma model, it has been demonstrated that a larger survivin-derived peptide (SVN 53-67 DLAQCFFCFKELEGW), containing multiple class I epitopes -including the herein described Msur 57 -as well as a potential class II ligand, was able to elicit both CD8 and CD4 1 T-cell responses in vivo, which resulted in a significant prolongation of survival of the animals [27]. The authors speculated that incorporation of CD4 1 helper-cell support associated with a specific survivin-derived CD8 1 T-cell response may lead to a more effective peptide anti-tumor vaccine.…”

Survivin minigene DNA vaccination is effective against neuroblastoma

“…This method was also applied for the development of a survivin-based immunotherapy against tumors such as breast cancer, colorectal cancer, gastric cancer or glioma. [40][41][42][43] We have previously shown that the syfpeithi prediction algorhithm 26 was reliable for the development of a minigene DNA vaccine encoding for murine tyrosine hydroxylase (mTH)-derived peptides. 21 In this report, the isolation of peptides presented by MHC class I molecules and the bioinformatical approach led to the generation of mTH minigene DNA vaccines equally effective in the induction of CTL-mediated antineuroblastoma immune responses.…”