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Cited by 597Immunotherapy and Immune ResponsesCancer Immunotherapy and BiomarkersT-cell and B-cell Immunology

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Therapeutic cancer vaccines: Advancements, challenges, and prospects

Open access
Fan, Ting, Zhang, Mingna, Yang, Jingxian, Zhu, Zhounan, Cao, Wanlu, Dong, Chunyan·2023·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-023-01674-3PMC PMC10716479
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Abstract

With the development and regulatory approval of immune checkpoint inhibitors and adoptive cell therapies, cancer immunotherapy has undergone a profound transformation over the past decades. Recently, therapeutic cancer vaccines have shown promise by eliciting de novo T cell responses targeting tumor antigens, including tumor-associated antigens and tumor-specific antigens. The objective was to amplify and diversify the intrinsic repertoire of tumor-specific T cells. However, the complete realization of these capabilities remains an ongoing pursuit. Therefore, we provide an overview of the current landscape of cancer vaccines in this review. The range of antigen selection, antigen delivery systems development the strategic nuances underlying effective antigen presentation have pioneered cancer vaccine design. Furthermore, this review addresses the current status of clinical trials and discusses their strategies, focusing on tumor-specific immunogenicity and anti-tumor efficacy assessment. However, current clinical attempts toward developing cancer vaccines have not yielded breakthrough clinical outcomes due to significant challenges, including tumor immune microenvironment suppression, optimal candidate identification, immune response evaluation, and vaccine manufacturing acceleration. Therefore, the field is poised to overcome hurdles and improve patient outcomes in the future by acknowledging these clinical complexities and persistently striving to surmount inherent constraints.

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Fig. 1 The mechanism of cancer vaccine in vivo. After the tumor antigens migrate into the body in different forms, they are phagocytosed, intracellularly expressed, and efficiently processed by specialized antigen-presenting cells (APCs). The major histocompatibility complex (MHC) of dendritic cells presents antigens to their surface, and the MHC complexes activate antigen-specific T-cells by binding to T-cell receptors (TCR) on the surface of T-cells, therefore safely, persistently, and specifically destroying tumor cells and inhibiting tumor growth
Fig. 1 The mechanism of cancer vaccine in vivo. After the tumor antigens migrate into the body in different forms, they are phagocytosed, intracellularly expressed, and efficiently processed by specialized antigen-presenting cells (APCs). The major histocompatibility complex (MHC) of dendritic cells presents antigens to their surface, and the MHC complexes activate antigen-specific T-cells by binding to T-cell receptors (TCR) on the surface of T-cells, therefore safely, persistently, and specifically destroying tumor cells and inhibiting tumor growthCC BY · PubMed Central
Fig. 2 The history and the key time points of therapeutic cancer vaccines
Fig. 2 The history and the key time points of therapeutic cancer vaccinesCC BY · PubMed Central
Fig. 3 Prediction of neoantigen candidates. a An overview of the bioinformatic characterization of neoantigens. b The somatic mutants originate from multiple sources, including single nucleotide variants, insertions/deletions, gene fusion, copy number variant, splice variant and microsatellite instability. c HLA typing from WES and RNA-seq could be found by the in-silico tools. d Peptide processing prediction with several algorithms. e Available bioinformatic pipelines for peptide-MHC binding prediction. f Available bioinformatic pipelines for T cell recognition. RNA-seq, RNA-sequencing; WES Whole exome sequencing, PBMC Peripheral blood mononuclear cell, HLA Human leukocyte antigen, MHC Major histocompatibility complex, APC Antigen presentation cell, TCR T cell receptor
Fig. 3 Prediction of neoantigen candidates. a An overview of the bioinformatic characterization of neoantigens. b The somatic mutants originate from multiple sources, including single nucleotide variants, insertions/deletions, gene fusion, copy number variant, splice variant and microsatellite instability. c HLA typing from WES and RNA-seq could be found by the in-silico tools. d Peptide processing prediction with several algorithms. e Available bioinformatic pipelines for peptide-MHC binding prediction. f Available bioinformatic pipelines for T cell recognition. RNA-seq, RNA-sequencing; WES Whole exome sequencing, PBMC Peripheral blood mononuclear cell, HLA Human leukocyte antigen, MHC Major histocompatibility complex, APC Antigen presentation cell, TCR T cell receptorCC BY · PubMed Central
Fig. 4 Overview of the factors involved in the different steps from the neoantigen cancer vaccine preparation to application. Following the tumor biopsy, deep sequencing was performed on tissue and blood samples to identify immunogenic neoantigens. A neoantigen-based cancer vaccine was subsequently developed using an appropriate design strategy and administered to the patient, with regular monitoring of the immune response and clinical outcomes. WES Whole exome sequencing, RNA-seq RNA-sequencing, MHC Major histocompatibility complex, ELISpot Interferon-γ Enzyme-Linked Immuno-Spot, ICS Intracellular cytokine staining
Fig. 4 Overview of the factors involved in the different steps from the neoantigen cancer vaccine preparation to application. Following the tumor biopsy, deep sequencing was performed on tissue and blood samples to identify immunogenic neoantigens. A neoantigen-based cancer vaccine was subsequently developed using an appropriate design strategy and administered to the patient, with regular monitoring of the immune response and clinical outcomes. WES Whole exome sequencing, RNA-seq RNA-sequencing, MHC Major histocompatibility complex, ELISpot Interferon-γ Enzyme-Linked Immuno-Spot, ICS Intracellular cytokine stainingCC BY · PubMed Central
Fig. 5 Direct delivery of antigen. TAA or TSA, which are the antigens with tumor immunogenicity, could be delivered directly into the body as DNA, RNA, or peptides using different adjuvants. DNA and RNA vaccines provide the potential for more efficient delivery and sustained expression of the target antigen, while peptide vaccines are generally easier to produce and have a strong safety profile. TAA Tumor-associated antigen, TSA Tumor-specific antigen, APC Antigen presentation cell, DC Dendritic cell, MHC-I Major histocompatibility complex-I, SLPs Synthetic long peptides; dsRNA, Double-stranded RNA
Fig. 5 Direct delivery of antigen. TAA or TSA, which are the antigens with tumor immunogenicity, could be delivered directly into the body as DNA, RNA, or peptides using different adjuvants. DNA and RNA vaccines provide the potential for more efficient delivery and sustained expression of the target antigen, while peptide vaccines are generally easier to produce and have a strong safety profile. TAA Tumor-associated antigen, TSA Tumor-specific antigen, APC Antigen presentation cell, DC Dendritic cell, MHC-I Major histocompatibility complex-I, SLPs Synthetic long peptides; dsRNA, Double-stranded RNACC BY · PubMed Central
Fig. 6 Mechanistic diagram of the different combination therapies after the immunization of cancer vaccine in patient. ICIs unblock immunosuppression and stimulate T cell activation by blocking signaling pathways on the surface of T cells and cancer cells. Conventional therapies, such as chemotherapy and radiotherapy, complement this process by directly affecting tumor cells or indirectly by eliminating immune suppressor cells. Different therapy combinations can activate effector T-cells, enhancing the clinical efficacy of neoantigen cancer vaccines. ICIs Immune checkpoint inhibitors, APC Antigen presentation cell, PD-1 Programmed cell death protein 1, PD-L1 Programmed cell death-ligand 1, CTLA4 Cytotoxic T-lymphocyte-associated antigen 4
Fig. 6 Mechanistic diagram of the different combination therapies after the immunization of cancer vaccine in patient. ICIs unblock immunosuppression and stimulate T cell activation by blocking signaling pathways on the surface of T cells and cancer cells. Conventional therapies, such as chemotherapy and radiotherapy, complement this process by directly affecting tumor cells or indirectly by eliminating immune suppressor cells. Different therapy combinations can activate effector T-cells, enhancing the clinical efficacy of neoantigen cancer vaccines. ICIs Immune checkpoint inhibitors, APC Antigen presentation cell, PD-1 Programmed cell death protein 1, PD-L1 Programmed cell death-ligand 1, CTLA4 Cytotoxic T-lymphocyte-associated antigen 4CC BY · PubMed Central
Fig. 7 Roles of cancer cells and immunosuppressive cells in tumor immune microenvironment. Immunosuppressive cells in the TME, such as Tregs, M2 macrophages, myeloid-derived suppressor cells, PD-L1-positive DCs, cancer-associated fibroblasts, and tumor cells form a suppressive ecological niche at the tumor site through the expression of immunosuppressive signals. TME Tumor microenvironment, Tregs Regulatory T cells, PD-L1 Programmed cell death-ligand 1, DC Dendritic cell, CTLA4 Cytotoxic T-lymphocyte-associated antigen 4, MHC Major histocompatibility complex, Teff, Effector T cell, IL Interleukin, ROS Reactive oxygen species, NK Natural killer cells, iNOS Inducible nitric oxide, Arg-1 Arginase 1, TGF-β Transforming growth factor-β, PEG2 Prostaglandinum E-2, CCL22, C-C motif chemokine ligand 22, EGFR Endothelial growth factor receptors, EMT Epithelial-mesenchymal transition, CXCL14 CXC-chemokine ligand 14, TAM Tumor-associated macrophage, VEGFR Vascular endothelial growth factor receptors
Fig. 7 Roles of cancer cells and immunosuppressive cells in tumor immune microenvironment. Immunosuppressive cells in the TME, such as Tregs, M2 macrophages, myeloid-derived suppressor cells, PD-L1-positive DCs, cancer-associated fibroblasts, and tumor cells form a suppressive ecological niche at the tumor site through the expression of immunosuppressive signals. TME Tumor microenvironment, Tregs Regulatory T cells, PD-L1 Programmed cell death-ligand 1, DC Dendritic cell, CTLA4 Cytotoxic T-lymphocyte-associated antigen 4, MHC Major histocompatibility complex, Teff, Effector T cell, IL Interleukin, ROS Reactive oxygen species, NK Natural killer cells, iNOS Inducible nitric oxide, Arg-1 Arginase 1, TGF-β Transforming growth factor-β, PEG2 Prostaglandinum E-2, CCL22, C-C motif chemokine ligand 22, EGFR Endothelial growth factor receptors, EMT Epithelial-mesenchymal transition, CXCL14 CXC-chemokine ligand 14, TAM Tumor-associated macrophage, VEGFR Vascular endothelial growth factor receptorsCC BY · PubMed Central

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Research works printed but not linked: 1

  1. Ott, P. et al. A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung. Cancer, or Bladder. Cancer 183, 347–362 (2020).

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Metadata

Authors
Fan, T., Zhang, M., Yang, J., Zhu, Z., Cao, W., & Dong, C.
Affiliations
  • Tongji University (CN)
  • Shanghai East Hospital (CN)
Corresponding author
  • Cao, Wanlu
  • Dong, Chunyan
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2023-12-13
Volume
8
Issue
1
Pages
450-450
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-023-01674-3
PMC
PMC10716479
OpenAlex
W4389639889
Cited by
597
References
235
Citations by year
2026: 187 · 2025: 292 · 2024: 116 · 2023: 2
FWCI
16.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81573008, 81860547, 82203861)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
therapeutic cancer vaccines, cancer immunotherapy, tumor-associated antigens, tumor-specific antigens, antigen delivery systems, antigen presentation, tumor immune microenvironment, vaccine production, clinical trials, antitumor efficacy, T cell response
MeSH terms
Antigens, Neoplasm, Humans, Immunity, Immunotherapy, Neoplasms, Cancer Vaccines, Tumor Microenvironment

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