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Evolution of Cancer Vaccines—Challenges, Achievements, and Future Directions

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Tay, Ban Qi, Wright, Quentin, Ladwa, Rahul, Perry, Christopher, Leggatt, Graham, Simpson, Fiona, Wells, James W., Panizza, Benedict J., Frazer, Ian H., Cruz, Jazmina L. G.·2021·Vaccines
DOI 10.3390/vaccines9050535PMC PMC8160852
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Abstract

The development of cancer vaccines has been intensively pursued over the past 50 years with modest success. However, recent advancements in the fields of genetics, molecular biology, biochemistry, and immunology have renewed interest in these immunotherapies and allowed the development of promising cancer vaccine candidates. Numerous clinical trials testing the response evoked by tumour antigens, differing in origin and nature, have shed light on the desirable target characteristics capable of inducing strong tumour-specific non-toxic responses with increased potential to bring clinical benefit to patients. Novel delivery methods, ranging from a patient’s autologous dendritic cells to liposome nanoparticles, have exponentially increased the abundance and exposure of the antigenic payloads. Furthermore, growing knowledge of the mechanisms by which tumours evade the immune response has led to new approaches to reverse these roadblocks and to re-invigorate previously suppressed anti-tumour surveillance. The use of new drugs in combination with antigen-based therapies is highly targeted and may represent the future of cancer vaccines. In this review, we address the main antigens and delivery methods used to develop cancer vaccines, their clinical outcomes, and the new directions that the vaccine immunotherapy field is taking.

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Figures

Figure 1 Basic neoantigen vaccine pipeline. 1. Sample collection. Tumour biopsy and healthy tissue from blood or the surrounding area of the lesion are the starting material for DNA and RNA extraction. 2. Whole exome and transcriptome sequencing. DNA and RNA are used to sequence the whole-exome and transcriptome of the healthy and tumour samples. 3. Tumour-specific non-synonymous mutations. Exome data is processed, and tumour non-synonymous mutations derived from different mutational sources are annotated using specialized packages, such as GATK, VarScan2, FACTERA and ANNOVAR [148,149,150,151]. Comparison of these mutations with the corresponding healthy tissue sequence will pinpoint somatic mutations restricted to the tumour. 4. Selection of transcribed sequences. One of the most important quality control points is the verification that the identified exome mutations have been translated to mRNA and the evaluation of the abundance of the mutated mRNA respect to the wild-type variant. 5. 4-digit HLA-typing. Neoantigens are HLA-type specific. Therefore, patient’s individual HLA-typing are commonly performed using DNA extracted from blood with commercial protocols such as Illumina TruSight HLA v2 Sequencing Panel®. 6. HLA-specific peptides. Long peptides (~19 mer) containing the mutated regions are the input of software such as netMHCpan and netMHCIIpan that predict HLA binding of 8-10-mer sequences for each patient’s HLA-type [152]. 7. Neoantigen validation. Some neoantigen pipelines include the use of software to predict neoantigen immunogenicity based on parameters that include strength of binding to their specific HLA or recognition by the TCR (i.e., NAseek [153], Luksza’s algorithm [154]). Additional wet-lab work can be done to ease the selection of the most promising candidates. For example, DNA barcoded MHC-I multimers can be used to detect neoantigen-specific CD8+ T cells in clinical samples [146]. Unique DNA barcodes (up to 1000) are bound to peptide-loaded-HLA molecules (pHLA) and joined to a fluorescently labelled backbone to generate HLA multimers. Patient’s samples are incubated with a mix of HLA multimers, and HLA multimer+ T cells are sorted based on the fluorescent label. Then, DNA barcodes are sequenced, and the relative number of DNA barcode counts is used to determine the composition of neaontigen-specific T cells in the patient’s sample. Ex vivo stimulation of patient’s cells with APC loaded with the neoantigens of interest, is a common validation protocol [155]. T cell proliferation and cytokine release are two of the major readouts of this method. Often, the immunogenicity of the neoantigen is compare with the one exhibited by the wild-type sequence. 8. Neoantigen vaccine formulation. Patient-specific neoantigen vaccine will be formulated with the selected candidates using the most convenient adjuvants and delivery platforms. (Created in BioRender.com).
Figure 1 Basic neoantigen vaccine pipeline. 1. Sample collection. Tumour biopsy and healthy tissue from blood or the surrounding area of the lesion are the starting material for DNA and RNA extraction. 2. Whole exome and transcriptome sequencing. DNA and RNA are used to sequence the whole-exome and transcriptome of the healthy and tumour samples. 3. Tumour-specific non-synonymous mutations. Exome data is processed, and tumour non-synonymous mutations derived from different mutational sources are annotated using specialized packages, such as GATK, VarScan2, FACTERA and ANNOVAR [148,149,150,151]. Comparison of these mutations with the corresponding healthy tissue sequence will pinpoint somatic mutations restricted to the tumour. 4. Selection of transcribed sequences. One of the most important quality control points is the verification that the identified exome mutations have been translated to mRNA and the evaluation of the abundance of the mutated mRNA respect to the wild-type variant. 5. 4-digit HLA-typing. Neoantigens are HLA-type specific. Therefore, patient’s individual HLA-typing are commonly performed using DNA extracted from blood with commercial protocols such as Illumina TruSight HLA v2 Sequencing Panel®. 6. HLA-specific peptides. Long peptides (~19 mer) containing the mutated regions are the input of software such as netMHCpan and netMHCIIpan that predict HLA binding of 8-10-mer sequences for each patient’s HLA-type [152]. 7. Neoantigen validation. Some neoantigen pipelines include the use of software to predict neoantigen immunogenicity based on parameters that include strength of binding to their specific HLA or recognition by the TCR (i.e., NAseek [153], Luksza’s algorithm [154]). Additional wet-lab work can be done to ease the selection of the most promising candidates. For example, DNA barcoded MHC-I multimers can be used to detect neoantigen-specific CD8+ T cells in clinical samples [146]. Unique DNA barcodes (up to 1000) are bound to peptide-loaded-HLA molecules (pHLA) and joined to a fluorescently labelled backbone to generate HLA multimers. Patient’s samples are incubated with a mix of HLA multimers, and HLA multimer+ T cells are sorted based on the fluorescent label. Then, DNA barcodes are sequenced, and the relative number of DNA barcode counts is used to determine the composition of neaontigen-specific T cells in the patient’s sample. Ex vivo stimulation of patient’s cells with APC loaded with the neoantigens of interest, is a common validation protocol [155]. T cell proliferation and cytokine release are two of the major readouts of this method. Often, the immunogenicity of the neoantigen is compare with the one exhibited by the wild-type sequence. 8. Neoantigen vaccine formulation. Patient-specific neoantigen vaccine will be formulated with the selected candidates using the most convenient adjuvants and delivery platforms. (Created in BioRender.com).CC BY · PubMed Central
Figure 2 Cancer vaccine delivery methods. Various delivery strategies used to expose patients to immunogenic tumour antigens. (A) DNA Plasmid Vaccine. (1) DNA plasmids encoding cancer antigens are injected intramuscularly or pushed into myocytes using electrical pulses from a gene gun. (2) The host cells transcribe and (3) translate the given tumour antigens. (4) Tumour antigens peptides will be presented to immune cells on MHC-I molecules or alternatively secreted and then taken by APCs. (B) Naked mRNA and Lipid Nanoparticle (LNP) mRNA. (1) LNP mRNA is delivered to host cells via systemic or intramuscular injection and uptaken by the cells through specific ligand/receptor interactions. Naked mRNA is administered via intra-lymph node or intra-muscular injection. (2) Lower endosomal pH triggers LNPs to release mRNA cargo in the cytosol of the cell. (3) mRNAs are translated by the cell ribosomal machinery. (4) Tumour antigen peptides will be presented to immune cells as pMHC-I and/or pMHC-II (only on APCs) complexes. (C) Dendritic Cell Vaccines. (1) Ex vivo differentiation of patient’s blood cells into APCs. (2) APCs will be loaded with the tumour antigens of interest using either electroporation, where electrical pulses make cells temporarily permeable, or cell squeezing, where a microfluidic flow temporarily deforms the cell plasma membrane to create pores enabling the passage of therapy into cells. (3) Modified cells can then be transfused back into the donor patient. (D) Whole Cell Vaccines. (1-2) Subcutaneous injected allogenic or autologous tumour cells will be uptaken and processed by APCs. (3) Activated APCs secreting cytokines and expressing co-stimulatory molecules, will mediate the recognition of pMHC-II by T-cells (E) Viral Vectors. (1-3) Injected viral particles, enter the cell by receptor mediated endocytosis and released into the cytosol. (4) In the case of DNA life attenuated viruses, viral genome containing the encoded tumour antigens is transferred into the host nucleus and (5) transcribed into mRNA. (6) The therapeutic mRNA is translated in the cytosol to protein(s)/peptide(s). (7) mRNA products will be secreted either/or presented by MHC complexes on the surface of the cell. (Created in BioRender.com).
Figure 2 Cancer vaccine delivery methods. Various delivery strategies used to expose patients to immunogenic tumour antigens. (A) DNA Plasmid Vaccine. (1) DNA plasmids encoding cancer antigens are injected intramuscularly or pushed into myocytes using electrical pulses from a gene gun. (2) The host cells transcribe and (3) translate the given tumour antigens. (4) Tumour antigens peptides will be presented to immune cells on MHC-I molecules or alternatively secreted and then taken by APCs. (B) Naked mRNA and Lipid Nanoparticle (LNP) mRNA. (1) LNP mRNA is delivered to host cells via systemic or intramuscular injection and uptaken by the cells through specific ligand/receptor interactions. Naked mRNA is administered via intra-lymph node or intra-muscular injection. (2) Lower endosomal pH triggers LNPs to release mRNA cargo in the cytosol of the cell. (3) mRNAs are translated by the cell ribosomal machinery. (4) Tumour antigen peptides will be presented to immune cells as pMHC-I and/or pMHC-II (only on APCs) complexes. (C) Dendritic Cell Vaccines. (1) Ex vivo differentiation of patient’s blood cells into APCs. (2) APCs will be loaded with the tumour antigens of interest using either electroporation, where electrical pulses make cells temporarily permeable, or cell squeezing, where a microfluidic flow temporarily deforms the cell plasma membrane to create pores enabling the passage of therapy into cells. (3) Modified cells can then be transfused back into the donor patient. (D) Whole Cell Vaccines. (1-2) Subcutaneous injected allogenic or autologous tumour cells will be uptaken and processed by APCs. (3) Activated APCs secreting cytokines and expressing co-stimulatory molecules, will mediate the recognition of pMHC-II by T-cells (E) Viral Vectors. (1-3) Injected viral particles, enter the cell by receptor mediated endocytosis and released into the cytosol. (4) In the case of DNA life attenuated viruses, viral genome containing the encoded tumour antigens is transferred into the host nucleus and (5) transcribed into mRNA. (6) The therapeutic mRNA is translated in the cytosol to protein(s)/peptide(s). (7) mRNA products will be secreted either/or presented by MHC complexes on the surface of the cell. (Created in BioRender.com).CC BY · PubMed Central

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Research works printed but not linked: 3

  1. Higano, C. (2009, January 26–28). A phase III trial of GVAX immunotherapy for prostate cancer versus docetaxel plus prednisone in asymptomatic, castration-resistant prostate cancer (CRPC). Proceedings of the 2009 Genitourinary Cancer Symposium, American Society of Clinical Oncology (ASCO), Orlando, FL, USA.
  2. Small, E. (2009, January 26–28). A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel versus docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC). Proceedings of the 2009 Genitourinary Cancer Symposium, American Society of Clinical Oncology (ASCO), Orlando, FL, USA.
  3. Laus, 2001, Dendritic cell immunotherapy of prostate cancer: Preclinical models and early clinical experience, Cancer Res. Ther. Control., 11, 1

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Authors
Tay, B. Q., Wright, Q., Ladwa, R., Perry, C., Leggatt, G., Simpson, F., Wells, J. W., Panizza, B. J., Frazer, I. H., & Cruz, J. L. G.
Affiliations
The University of Queensland (AU)
Corresponding author
Cruz, Jazmina L. G.
ORCID
Venue
Vaccines
Publisher
MDPI AG
Published
2021-05-20
Volume
9
Issue
5
Pages
535
ISSN
2076-393X (ISSN-L)
DOI
10.3390/vaccines9050535
PMC
PMC8160852
OpenAlex
W3165800301
Cited by
76
References
246
Citations by year
2026: 8 · 2025: 15 · 2024: 15 · 2023: 22 · 2022: 12 · 2021: 4
FWCI
1.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Vaccines (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Garnett Passe and Rodney Williams Memorial Foundation (2019_CG_Gonzalez Cruz_Perry)
  • PA Research Foundation (Panizza_Cruz_2021)
  • National Health and Medical Research Council (Investigator grant_Frazer_2020)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Bacterial Cancer Therapy
Keywords
cancer vaccines, tumor antigens, vaccine delivery, dendritic cell vaccine, nanoliposomes, tumor immune evasion, antitumor immunity, combination immunotherapy

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