Dataset Information

A novel cancer vaccine strategy based on HLA-A*0201 matched allogeneic plasmacytoid dendritic cells.

ABSTRACT:

Background

The development of effective cancer vaccines still remains a challenge. Despite the crucial role of plasmacytoid dendritic cells (pDCs) in anti-tumor responses, their therapeutic potential has not yet been worked out. We explored the relevance of HLA-A*0201 matched allogeneic pDCs as vectors for immunotherapy.

Methods and findings

Stimulation of PBMC from HLA-A*0201(+) donors by HLA-A*0201 matched allogeneic pDCs pulsed with tumor-derived peptides triggered high levels of antigen-specific and functional cytotoxic T cell responses (up to 98% tetramer(+) CD8 T cells). The pDC vaccine demonstrated strong anti-tumor therapeutic in vivo efficacy as shown by the inhibition of tumor growth in a humanized mouse model. It also elicited highly functional tumor-specific T cells ex-vivo from PBMC and TIL of stage I-IV melanoma patients. Responses against MelA, GP100, tyrosinase and MAGE-3 antigens reached tetramer levels up to 62%, 24%, 85% and 4.3% respectively. pDC vaccine-primed T cells specifically killed patients' own autologous melanoma tumor cells. This semi-allogeneic pDC vaccine was more effective than conventional myeloid DC-based vaccines. Furthermore, the pDC vaccine design endows it with a strong potential for clinical application in cancer treatment.

Conclusions

These findings highlight HLA-A*0201 matched allogeneic pDCs as potent inducers of tumor immunity and provide a promising immunotherapeutic strategy to fight cancer.

SUBMITTER: Aspord C

PROVIDER: S-EPMC2864288 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Publications

A novel cancer vaccine strategy based on HLA-A*0201 matched allogeneic plasmacytoid dendritic cells.

Aspord Caroline C Charles Julie J Leccia Marie-Therese MT Laurin David D Richard Marie-Jeanne MJ Chaperot Laurence L Plumas Joel J

PloS one 20100504 5

<h4>Background</h4>The development of effective cancer vaccines still remains a challenge. Despite the crucial role of plasmacytoid dendritic cells (pDCs) in anti-tumor responses, their therapeutic potential has not yet been worked out. We explored the relevance of HLA-A*0201 matched allogeneic pDCs as vectors for immunotherapy.<h4>Methods and findings</h4>Stimulation of PBMC from HLA-A*0201(+) donors by HLA-A*0201 matched allogeneic pDCs pulsed with tumor-derived peptides triggered high levels ...[more]

PMID: 20454561

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Project description:Minor histocompatibility antigens (mHAs), recipient-derived peptide epitopes presented on the cell surface, are known to mediate graft-versus-host disease (GVHD); however, there are no current methods to associate mHA features with GVHD risk. This deficiency is due in part to the lack of technological means to accurately predict, let alone confirm, the tremendous number of potential mHAs in each individual transplant. Previous studies have shown that different HLA molecules present varying fractions of candidate peptide epitopes; however, the genetic "distance" between HLA-matched donors and recipients is relatively constrained. From these 2 observations, it is possible that the HLA type for a donor-recipient pair (DRP) would provide a surrogate measurement of the number of predicted mHAs, which could be related to GVHD risk. Because different HLA molecules present variable numbers of peptide antigens, a predicted cumulative peptide-binding efficiency can be calculated for individual DRP based on the pair's HLA type. The purpose of this study was to test whether cumulative peptide-binding efficiency is associated with the risk of acute GVHD (aGVHD) or relapse. In this retrospective Center for International Blood and Marrow Transplant Research study, a total of 3242 HLA-matched DRPs were analyzed for predicted cumulative peptide-binding efficiency using their HLA types and were divided into tertiles based on their scores. Univariable and multivariable analyses was performed to test for associations between cumulative peptide-binding efficiency for DRPs, divided into the HLA-matched related donor (MRD) and HLA-matched unrelated donor (MUD) cohorts, and the primary outcomes of aGVHD and relapse. Secondary outcomes investigated included overall survival, disease-free survival, and transplantation-related mortality. Using a computationally generated peptidome as a test dataset, the tested series of HLA class I displayed peptide-binding frequencies ranging from 0.1% to 3.8% of the full peptidome, and HLA class II molecules had peptide-binding frequencies of 12% to 77% across the HLA-DRB1 allotypes. By increasing binding efficiency tertile, the cumulative incidence of aGVHD at 6 months for MUD patients was 41%, 41%, and 45% for HLA class I (P = .336) and 44%, 41%, and 42% for HLA class II (P = .452). The cumulative incidences of relapse at 3 years for MUD transplant recipients were 36%, 38%, and 38% for HLA class I (P = .533) and 37%, 37%, and 38% for HLA class II (P = .896). The findings were similar for MRD transplant recipients. Multivariable analysis did not identify any impact of peptide-binding efficiency on aGVHD or relapse in MUD or MRD transplant recipients. Whereas GVHD is mediated by minor antigen mismatches in the context of HLA-matched allo-HCT, peptide-binding efficiency, which was used as a surrogate measurement for predicted number of binding antigens, did not provide additional clinical information for GVHD risk assessment. The negative result may be due to the limitations of this surrogate marker, or it is possible that GVHD is driven by a subset of immunogenic mHAs. Further research should be directed at direct mHA epitope and immunogenicity prediction.

Dataset Information

A novel cancer vaccine strategy based on HLA-A*0201 matched allogeneic plasmacytoid dendritic cells.

Background

Methods and findings

Conclusions

Publications

A novel cancer vaccine strategy based on HLA-A*0201 matched allogeneic plasmacytoid dendritic cells.

Similar Datasets

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