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Cancer Vaccines: Research and Applications
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Cancer Vaccines: Research and Applications

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 November 2018) | Viewed by 107375

Special Issue Editor

Prof. Dr. Vasso Apostolopoulos

E-Mail Website
Guest Editor
Institute for Health and Sport, Victoria University, Melbourne, VIC 3011, Australia
Interests: immunology; protein crystallography; medicinal chemistry; cellular and molecular biology; extensive translational research; clinical trials; vaccines; drugs; healthy ageing; chronic diseases; inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Designing cancer vaccines has been at the forefront of cancer research for over 2 decades. In particular delivery methods used to stimulate effective and long lasting immune responses has been the major focus. This special issue will focus on delivery methods used for cancer vaccines and their outcomes in preclinical studies and clinical trials.

Prof. Dr. Vasso Apostolopoulos
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cancer vaccines
  • Delivery methods
  • Dendritic cells
  • Particulate vaccines
  • Adjuvants
  • Peptide based vaccines
  • DNA vaccines
  • T cell responses
  • Clinical outcomes
  • Clinical trials
  • Antigen processing
  • Antigen presentation
  • MHC-T cell interaction

Published Papers (18 papers)

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Editorial

Jump to: Research, Review

5 pages, 4602 KiB  
Editorial
Cancer Vaccines: Research and Applications
by Vasso Apostolopoulos
Cancers 2019, 11(8), 1041; https://doi.org/10.3390/cancers11081041 - 24 Jul 2019
Cited by 17 | Viewed by 10155
Abstract
Designing cancer vaccines has been at the forefront of cancer research for over two-and-a-half decades. In particular, delivery methods used to stimulate effective and long-lasting immune responses have been the major focus. This special issue presents new tumor associated antigens, delivery methods, combination [...] Read more.
Designing cancer vaccines has been at the forefront of cancer research for over two-and-a-half decades. In particular, delivery methods used to stimulate effective and long-lasting immune responses have been the major focus. This special issue presents new tumor associated antigens, delivery methods, combination immune therapies, methods of measuring immunity induced following cancer vaccinations, and mechanisms in understanding tumor microenvironments and immunosuppression—all beneficial for the design of improved cancer vaccines. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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Research

Jump to: Editorial, Review

21 pages, 1318 KiB  
Article
The Complex Interaction between the Tumor Micro-Environment and Immune Checkpoints in Breast Cancer
by Vanessa Barriga, Nyanbol Kuol, Kulmira Nurgali and Vasso Apostolopoulos
Cancers 2019, 11(8), 1205; https://doi.org/10.3390/cancers11081205 - 19 Aug 2019
Cited by 55 | Viewed by 12651
Abstract
The progression of breast cancer and its association with clinical outcome and treatment remain largely unexplored. Accumulating data has highlighted the interaction between cells of the immune system and the tumor microenvironment in cancer progression, and although studies have identified multiple facets of [...] Read more.
The progression of breast cancer and its association with clinical outcome and treatment remain largely unexplored. Accumulating data has highlighted the interaction between cells of the immune system and the tumor microenvironment in cancer progression, and although studies have identified multiple facets of cancer progression within the development of the tumor microenvironment (TME) and its constituents, there is lack of research into the associations between breast cancer subtype and staging. Current literature has provided insight into the cells and pathways associated with breast cancer progression through expression analysis. However, there is lack of co-expression studies between immune pathways and cells of the TME that form pro-tumorigenic relationships contributing to immune-evasion. We focus on the immune checkpoint and TME elements that influence cancer progression, particularly studies in molecular subtypes of breast cancer. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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12 pages, 1592 KiB  
Article
Cancer Vaccines Co-Targeting HER2/Neu and IGF1R
by Carla De Giovanni, Lorena Landuzzi, Arianna Palladini, Marianna Lucia Ianzano, Giordano Nicoletti, Francesca Ruzzi, Augusto Amici, Stefania Croci, Patrizia Nanni and Pier-Luigi Lollini
Cancers 2019, 11(4), 517; https://doi.org/10.3390/cancers11040517 - 11 Apr 2019
Cited by 7 | Viewed by 3049
Abstract
(1) Background: Human epidermal growth factor receptor 2 (HER2)/neu-driven carcinogenesis is delayed by preventive vaccines able to elicit autochthonous antibodies against HER2/neu. Since cooperation between different receptor tyrosine kinases (RTKs) can occur in human as well as in experimental tumors, we investigated the [...] Read more.
(1) Background: Human epidermal growth factor receptor 2 (HER2)/neu-driven carcinogenesis is delayed by preventive vaccines able to elicit autochthonous antibodies against HER2/neu. Since cooperation between different receptor tyrosine kinases (RTKs) can occur in human as well as in experimental tumors, we investigated the set-up of DNA and cell vaccines to elicit an antibody response co-targeting two RTKs: HER2/neu and the Insulin-like Growth Factor Receptor-1 (IGF1R). (2) Methods: Plasmid vectors carrying the murine optimized IGF1R sequence or the human IGF1R isoform were used as electroporated DNA vaccines. IGF1R plasmids were transfected in allogeneic HER2/neu-positive IL12-producing murine cancer cells to obtain adjuvanted cell vaccines co-expressing HER2/neu and IGF1R. Vaccination was administered in the preneoplastic stage to mice prone to develop HER2/neu-driven, IGF1R-dependent rhabdomyosarcoma. (3) Results: Electroporated DNA vaccines for murine IGF1R did not elicit anti-mIGF1R antibodies, even when combined with Treg-depletion and/or IL12, while DNA vaccines carrying the human IGF1R elicited antibodies recognizing only the human IGF1R isoform. Cell vaccines co-expressing HER2/neu and murine or human IGF1R succeeded in eliciting antibodies recognizing the murine IGF1R isoform. Cell vaccines co-targeting HER2/neu and murine IGF1R induced the highest level of anti-IGF1R antibodies and nearly significantly delayed the onset of spontaneous rhabdomyosarcomas. (4) Conclusions: Multi-engineered adjuvanted cancer cell vaccines can break the tolerance towards a highly tolerized RTK, such as IGF1R. Cell vaccines co-targeting HER2/neu and IGF1R elicited low levels of specific antibodies that slightly delayed onset of HER2/neu-driven, IGF1R-dependent tumors. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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13 pages, 1515 KiB  
Article
Exploratory Study of the Effect of IMA950/Poly-ICLC Vaccination on Response to Bevacizumab in Relapsing High-Grade Glioma Patients
by Emma Boydell, Eliana Marinari, Denis Migliorini, Pierre-Yves Dietrich, Anna Patrikidou and Valérie Dutoit
Cancers 2019, 11(4), 464; https://doi.org/10.3390/cancers11040464 - 02 Apr 2019
Cited by 19 | Viewed by 3157
Abstract
Immunotherapy, including therapeutic vaccines, is increasingly being developed for patients with high-grade glioma, and combinations of immunotherapies and synergy with standard of care are being investigated. In this regard, bevacizumab (BEV) has been shown to synergize with immunotherapy in preclinical studies of glioma [...] Read more.
Immunotherapy, including therapeutic vaccines, is increasingly being developed for patients with high-grade glioma, and combinations of immunotherapies and synergy with standard of care are being investigated. In this regard, bevacizumab (BEV) has been shown to synergize with immunotherapy in preclinical studies of glioma and in other tumour entities. Here, we conducted a post-hoc exploratory study to evaluate the effect of the IMA950/poly-ICLC peptide vaccine on subsequent BEV administration in high-grade glioma patients. 16 IMA950-vaccinated and 40 non-vaccinated patients were included. At initial diagnosis, patients benefited from surgery and chemoradiation. At first or subsequent recurrence, patients received 10mg/kg of BEV every 2–3 weeks. Primary endpoints were overall survival (OS) and progression-free survival (PFS) from BEV initiation. IMA950-vaccinated patients did not show improved response to BEV as compared to non-vaccinated patients: there was no difference in median PFS (2.6 vs. 4.2 months for vaccinated and control patients, respectively, p = 0.50) nor in median OS (7.8 vs. 10.0 months for vaccinated and control patients, respectively, p = 0.69). In conclusion, potential synergy of BEV and therapeutic vaccines, when administered sequentially, has yet to be established in the clinical setting of GBM recurrence. Potential synergy of concomitant administration should be tested in future trials. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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14 pages, 1591 KiB  
Article
Identification of Novel HLA Class II-Restricted Neoantigens Derived from Driver Mutations
by Susumu Iiizumi, Junya Ohtake, Naoko Murakami, Taku Kouro, Mamoru Kawahara, Fumiko Isoda, Hiroshi Hamana, Hiroyuki Kishi, Norihiro Nakamura and Tetsuro Sasada
Cancers 2019, 11(2), 266; https://doi.org/10.3390/cancers11020266 - 24 Feb 2019
Cited by 23 | Viewed by 7677
Abstract
Neoantigens derived from tumor-specific genetic mutations might be suitable targets for cancer immunotherapy because of their high immunogenicity. In the current study, we evaluated the immunogenicity of 10 driver mutations that are frequently expressed in various cancers using peripheral blood mononuclear cells from [...] Read more.
Neoantigens derived from tumor-specific genetic mutations might be suitable targets for cancer immunotherapy because of their high immunogenicity. In the current study, we evaluated the immunogenicity of 10 driver mutations that are frequently expressed in various cancers using peripheral blood mononuclear cells from healthy donors (n = 25). Of the 10 synthetic peptides (27-mer) derived from these mutations, the six peptides from KRAS-G12D, KRAS-G12R, KRAS-G13D, NRAS-Q61R, PIK3CA-H1047R, and C-Kit-D816V induced T cell responses, suggesting that frequent driver mutations are not always less immunogenic. In particular, immune responses to PIK3CA-H1047R, C-Kit-D816V, KRAS-G13D, and NRAS-Q61R were observed in more than 10% of the donors. All six peptides induced human leukocyte antigen (HLA) class II-restricted CD4+ T cell responses; notably, PIK3CA-H1047R contained at least two different CD4+ T cell epitopes restricted to different HLA class II alleles. In addition, PIK3CA-H1047R and C-Kit-D816V induced antigen-specific CD8+ T cells as well, indicating that they might contain both HLA class I- and class II-restricted epitopes. Since the identified neoantigens might be shared by patients with various types of cancers and are not easily lost due to immune escape, they have the potential to be promising off-the-shelf cancer immunotherapy targets in patients with the corresponding mutations. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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17 pages, 4179 KiB  
Article
Activation of CD8+ T Cell Responses after Melanoma Antigen Targeting to CD169+ Antigen Presenting Cells in Mice and Humans
by Dieke van Dinther, Miguel Lopez Venegas, Henrike Veninga, Katarzyna Olesek, Leoni Hoogterp, Mirjam Revet, Martino Ambrosini, Hakan Kalay, Johannes Stöckl, Yvette van Kooyk and Joke M. M. den Haan
Cancers 2019, 11(2), 183; https://doi.org/10.3390/cancers11020183 - 05 Feb 2019
Cited by 22 | Viewed by 5731
Abstract
The lack of tumor-reactive T cells is one reason why immune checkpoint inhibitor therapies still fail in a significant proportion of melanoma patients. A vaccination that induces melanoma-specific T cells could potentially enhance the efficacy of immune checkpoint inhibitors. Here, we describe a [...] Read more.
The lack of tumor-reactive T cells is one reason why immune checkpoint inhibitor therapies still fail in a significant proportion of melanoma patients. A vaccination that induces melanoma-specific T cells could potentially enhance the efficacy of immune checkpoint inhibitors. Here, we describe a vaccination strategy in which melanoma antigens are targeted to mouse and human CD169 and thereby induce strong melanoma antigen-specific T cell responses. CD169 is a sialic acid receptor expressed on a subset of mouse splenic macrophages that captures antigen from the blood and transfers it to dendritic cells (DCs). In human and mouse spleen, we detected CD169+ cells at an equivalent location using immunofluorescence microscopy. Immunization with melanoma antigens conjugated to antibodies (Abs) specific for mouse CD169 efficiently induced gp100 and Trp2-specific T cell responses in mice. In HLA-A2.1 transgenic mice targeting of the human MART-1 peptide to CD169 induced strong MART-1-specific HLA-A2.1-restricted T cell responses. Human gp100 peptide conjugated to Abs specific for human CD169 bound to CD169-expressing monocyte-derived DCs (MoDCs) and resulted in activation of gp100-specific T cells. Together, these data indicate that Ab-mediated antigen targeting to CD169 is a potential strategy for the induction of melanoma-specific T cell responses in mice and in humans. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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Graphical abstract

11 pages, 2768 KiB  
Article
Treatment Combining CD200 Immune Checkpoint Inhibitor and Tumor-Lysate Vaccination after Surgery for Pet Dogs with High-Grade Glioma
by Michael R. Olin, Elisabet Ampudia-Mesias, Christopher A. Pennell, Aaron Sarver, Clark C. Chen, Christopher L. Moertel, Matthew A. Hunt and G. Elizabeth Pluhar
Cancers 2019, 11(2), 137; https://doi.org/10.3390/cancers11020137 - 24 Jan 2019
Cited by 26 | Viewed by 5229
Abstract
Recent advances in immunotherapy have included inhibition of immune checkpoint proteins in the tumor microenvironment and tumor lysate-based vaccination strategies. We combined these approaches in pet dogs with high-grade glioma. Administration of a synthetic peptide targeting the immune checkpoint protein, CD200, enhanced the [...] Read more.
Recent advances in immunotherapy have included inhibition of immune checkpoint proteins in the tumor microenvironment and tumor lysate-based vaccination strategies. We combined these approaches in pet dogs with high-grade glioma. Administration of a synthetic peptide targeting the immune checkpoint protein, CD200, enhanced the capacity of antigen-presenting cells to prime T-cells to mediate an anti-glioma response. We found that in canine spontaneous gliomas, local injection of a canine-specific, CD200-directed peptide before subcutaneous delivery of an autologous tumor lysate vaccine prolonged survival relative to a historical control treated with autologous tumor lysate alone (median survivals of 12.7 months and 6.36 months, respectively). Antigen-presenting cells and T-lymphocytes primed with this peptide suppressed their expression of the inhibitory CD200 receptor, thereby enhancing their ability to initiate immune reactions in a glioblastoma microenvironment replete with the immunosuppressive CD200 protein. These results support consideration of a CD200 ligand as a novel glioblastoma immunotherapeutic agent. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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12 pages, 1524 KiB  
Article
A DNA Vaccine Encoding SA-4-1BBL Fused to HPV-16 E7 Antigen Has Prophylactic and Therapeutic Efficacy in a Cervical Cancer Mouse Model
by Rodolfo Garza-Morales, Jose J. Perez-Trujillo, Elvis Martinez-Jaramillo, Odila Saucedo-Cardenas, Maria J. Loera-Arias, Aracely Garcia-Garcia, Humberto Rodriguez-Rocha, Esma Yolcu, Haval Shirwan, Jorge G. Gomez-Gutierrez and Roberto Montes-de-Oca-Luna
Cancers 2019, 11(1), 96; https://doi.org/10.3390/cancers11010096 - 15 Jan 2019
Cited by 16 | Viewed by 4788
Abstract
The SA-4-1BBL, an oligomeric novel form of the natural ligand for the 4-1BB co-stimulatory receptor of the tumor necrosis factor (TNF) superfamily, as a recombinant protein has potent pleiotropic effects on cells of innate, adaptive, and regulatory immunity with demonstrated therapeutic efficacy in [...] Read more.
The SA-4-1BBL, an oligomeric novel form of the natural ligand for the 4-1BB co-stimulatory receptor of the tumor necrosis factor (TNF) superfamily, as a recombinant protein has potent pleiotropic effects on cells of innate, adaptive, and regulatory immunity with demonstrated therapeutic efficacy in several tumor models. However, the production of soluble form of SA-4-1BBL protein and quality control is time and resource intensive and face various issues pertinent to clinical development of biologics. The present study sought to take advantage of the simplicity and translatability of DNA-based vaccines for the production and delivery of SA-4-1BBL for cancer immune prevention and therapy. A chimeric HPV-16 E7 DNA vaccine (SP-SA-E7-4-1BBL) was constructed that contains the signal peptide (SP) of calreticulin (CRT), streptavidin (SA) domain of SA-4-1BBL, HPV-16 E7 double mutant gene, and the extracellular domain of mouse 4-1BBL. Immunization by gene gun with SP-SA-E7-4-1BBL induced greater prophylactic as well as therapeutic effects in C57BL/6 mice against TC-1 tumor model compared with immunization with E7wt, SP-SA-4-1BBL or reference-positive control CRT-E7wt. The therapeutic efficacy of the DNA vaccine was associated with increased frequency of E7-specific T cells producing interferon (IFN)-γ. Overall, our data suggest that this DNA-based vaccine strategy might represent a translational approach because it provides a simpler and versatile alternative to a subunit vaccine based on SA-4-1BBL and E7 proteins. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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21 pages, 7614 KiB  
Article
IL-15 and a Two-Step Maturation Process Improve Bone Marrow-Derived Dendritic Cell Cancer Vaccine
by Ananda Mookerjee, Michele Graciotti and Lana E. Kandalaft
Cancers 2019, 11(1), 40; https://doi.org/10.3390/cancers11010040 - 04 Jan 2019
Cited by 7 | Viewed by 7028
Abstract
In the last 20 years, dendritic cells (DCs) have been largely used as a platform for therapeutic vaccination in cancer patients. However, despite its proven safety and ability to induce cancer specific immune responses, the clinical benefits of DC-based immunotherapy are currently very [...] Read more.
In the last 20 years, dendritic cells (DCs) have been largely used as a platform for therapeutic vaccination in cancer patients. However, despite its proven safety and ability to induce cancer specific immune responses, the clinical benefits of DC-based immunotherapy are currently very limited. Thus, novel approaches are still needed to boost its efficacy. Our group recently showed that squaric acid treatment of antigens is an important adjuvant that can increase vaccine-induced downstream immune responses and therapeutic outcomes. Here we further improved this dendritic cell vaccine formulation by developing a new method for differentiating and maturing DCs from their bone marrow precursors. Our data demonstrate that bone marrow-derived DCs differentiated with GM-CSF and IL-15 and matured with a maturation cocktail in two steps present a more mature and immunogenic phenotype, compared to standard DC preparations. Further suppression of the prostaglandin E2 pathway achieved even more immunogenic DC phenotypes. This vaccine was more potent at delaying tumor growth, improved animal survival and induced a more immunogenic and Th1-skewed T cell response in an ovarian cancer mouse model. These promising results support future efforts for the clinical translation of this approach. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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19 pages, 4600 KiB  
Article
Non-Invasive Fluorescent Monitoring of Ovarian Cancer in an Immunocompetent Mouse Model
by Amy L. Wilson, Kirsty L. Wilson, Maree Bilandzic, Laura R. Moffitt, Ming Makanji, Mark D. Gorrell, Martin K. Oehler, Adam Rainczuk, Andrew N. Stephens and Magdalena Plebanski
Cancers 2019, 11(1), 32; https://doi.org/10.3390/cancers11010032 - 31 Dec 2018
Cited by 14 | Viewed by 5169
Abstract
Ovarian cancers (OCs) are the most lethal gynaecological malignancy, with high levels of relapse and acquired chemo-resistance. Whilst the tumour–immune nexus controls both cancer progression and regression, the lack of an appropriate system to accurately model tumour stage and immune status has hampered [...] Read more.
Ovarian cancers (OCs) are the most lethal gynaecological malignancy, with high levels of relapse and acquired chemo-resistance. Whilst the tumour–immune nexus controls both cancer progression and regression, the lack of an appropriate system to accurately model tumour stage and immune status has hampered the validation of clinically relevant immunotherapies and therapeutic vaccines to date. To address this need, we stably integrated the near-infrared phytochrome iRFP720 at the ROSA26 genomic locus of ID8 mouse OC cells. Intrabursal ovarian implantation into C57BL/6 mice, followed by regular, non-invasive fluorescence imaging, permitted the direct visualization of tumour mass and distribution over the course of progression. Four distinct phases of tumour growth and dissemination were detectable over time that closely mimicked clinical OC progression. Progression-related changes in immune cells also paralleled typical immune profiles observed in human OCs. Specifically, we observed changes in both the CD8+ T cell effector (Teff):regulatory (Treg) ratio, as well as the dendritic cell (DC)-to-myeloid derived suppressor cell (MDSC) ratio over time across multiple immune cell compartments and in peritoneal ascites. Importantly, iRFP720 expression had no detectible influence over immune profiles. This new model permits non-invasive, longitudinal tumour monitoring whilst preserving host–tumour immune interactions, and allows for the pre-clinical assessment of immune profiles throughout disease progression as well as the direct visualization of therapeutic responses. This simple fluorescence-based approach provides a useful new tool for the validation of novel immuno-therapeutics against OC. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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15 pages, 6154 KiB  
Article
Tumor-Targeted Immunotherapy by Using Primary Adipose-Derived Stem Cells and an Antigen-Specific Protein Vaccine
by Jui-Hua Lu, Bou-Yue Peng, Chun-Chao Chang, Navneet Kumar Dubey, Wen-Cheng Lo, Hsin-Chung Cheng, Joseph R. Wang, Hong-Jian Wei and Win-Ping Deng
Cancers 2018, 10(11), 446; https://doi.org/10.3390/cancers10110446 - 15 Nov 2018
Cited by 17 | Viewed by 3971
Abstract
Cancer is a leading cause of mortality and a major public health problem worldwide. For biological therapy against cancer, we previously developed a unique immunotherapeutic platform by combining mesenchymal stem cells with an antigen-specific protein vaccine. However, this system possesses a few limitations, [...] Read more.
Cancer is a leading cause of mortality and a major public health problem worldwide. For biological therapy against cancer, we previously developed a unique immunotherapeutic platform by combining mesenchymal stem cells with an antigen-specific protein vaccine. However, this system possesses a few limitations, such as improperly immortalized mesenchymal stem cells (MSCs) along with transfected oncogenic antigens in them. To overcome the limitations of this platform for future clinical application, we freshly prepared primary adipose-derived stem cells (ADSCs) and modified the E7’ antigen (E7’) as a non-oncogenic protein. Either subcutaneously co-inoculated with cancer cells or systemically administered after tumor growth, ADSC labeled with enhanced green fluorescent protein (eGFP) and combined with modified E7’ (ADSC-E7’-eGFP) cells showed significant antitumor activity when combined with the protein vaccine in both colon and lung cancer in mice. Specifically, this combined therapy inhibited tumor through inducing cell apoptosis. The significantly reduced endothelial cell markers, CD31 and vascular endothelial growth factor (VEGF), indicated strongly inhibited tumor angiogenesis. The activated immune system was demonstrated through the response of CD4+ T and natural killer (NK) cells, and a notable antitumor activity might be contributed by CD8+ T cells. Conclusively, these evidences imply that this promising immunotherapeutic platform might be a potential candidate for the future clinical application against cancer. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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20 pages, 3381 KiB  
Article
In Vivo Evaluation of a New Recombinant Hyaluronidase to Improve Gene Electro-Transfer Protocols for DNA-Based Drug Delivery against Cancer
by Mariangela De Robertis, Lise Pasquet, Luisa Loiacono, Elisabeth Bellard, Luciano Messina, Susanna Vaccaro, Roberta Di Pasquale, Vito Michele Fazio, Marie-Pierre Rols, Justin Teissie, Muriel Golzio and Emanuela Signori
Cancers 2018, 10(11), 405; https://doi.org/10.3390/cancers10110405 - 28 Oct 2018
Cited by 14 | Viewed by 4221
Abstract
Cancer vaccines based on plasmid DNA represent a good therapeutic perspective, despite their low potency. Animal-derived hyaluronidases (Hyals) are employed in oncological clinical practice. Hyal has been also demonstrated to be a good enhancer of intramuscular Gene Electro-Transfer (GET) efficiency in anti-cancer preclinical [...] Read more.
Cancer vaccines based on plasmid DNA represent a good therapeutic perspective, despite their low potency. Animal-derived hyaluronidases (Hyals) are employed in oncological clinical practice. Hyal has been also demonstrated to be a good enhancer of intramuscular Gene Electro-Transfer (GET) efficiency in anti-cancer preclinical protocols, with increased transfected cells and higher expression of the encoded genes. Nevertheless, the use of animal-derived Hyals results limited respect to their potentialities, since such preparations could be affected by low purity, variable potency and uncertain safety. To improve the delivery of intramuscular GET-based protocols in mouse, we investigated a new recombinant Hyal, the rHyal-sk, to assess in vivo safety and activity of this treatment at cellular and biochemical levels. We evaluated the cellular events and the inflammation chemical mediators involved at different time points after rHyal-sk administration plus GET. Our results demonstrated the in vivo safety and efficacy of rHyal-sk when injected once intramuscularly in association with GET, with no toxicity, good plasmid in-take ability, useful inflammatory response activation, and low immunogenicity. Following these findings, we would recommend the use of the new rHyal-sk for the delivery of DNA-based vaccines and immunotherapy, as well as into clinical practice, for tumor disease treatments. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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15 pages, 2051 KiB  
Article
Sperm Protein 17 Expression by Murine Epithelial Ovarian Cancer Cells and Its Impact on Tumor Progression
by Qian Gao, Sue D. Xiang, Kirsty Wilson, Mutsa Madondo, Andrew N. Stephens and Magdalena Plebanski
Cancers 2018, 10(8), 276; https://doi.org/10.3390/cancers10080276 - 20 Aug 2018
Cited by 11 | Viewed by 4457
Abstract
The cancer testis antigen sperm protein 17 (Sp17) is a promising antigenic target in epithelial ovarian cancer (EOC) vaccine development. However, its role in ovarian cancer is unclear. We isolated and expanded Sp17+ and Sp17− clones from the murine EOC cell [...] Read more.
The cancer testis antigen sperm protein 17 (Sp17) is a promising antigenic target in epithelial ovarian cancer (EOC) vaccine development. However, its role in ovarian cancer is unclear. We isolated and expanded Sp17+ and Sp17− clones from the murine EOC cell line ID8, and compared their in-vitro cell growth characteristics and in-vivo tumorigenicity. We also examined the potential co-expression of molecules that may influence cancer cell survival and interaction with immune cells. These include stimulatory and immunosuppressive molecules, such as major histocompatibility class I molecules (MHC I), MHC II, cytotoxic T lymphocyte associated antigen-4 (CTLA-4), CD73, CD39, tumor necrosis factor receptor II (TNFRII), signal transducer and activator of transcription 3 (STAT3) and programmed death-ligand 1 (PD-L1). Whilst the presence of Sp17 was not correlated with the ID8 cell proliferation/growth capacity in vitro, it was critical to enable progressive tumor formation in vivo. Flow cytometry revealed that Sp17+ ID8 cells displayed higher expression of both STAT3 and PD-L1, whilst MHC II expression was lower. Moreover, Sp17high (PD-L1+MHCII−) cell populations showed significantly enhanced resistance to Paclitaxel-induced cell death in vitro compared to Sp17low (PD-L1−MHCII+) cells, which was associated in turn with increased STAT3 expression. Together, the data support Sp17 as a factor associated with in-vivo tumor progression and chemo-resistance, validating it as a suitable target for vaccine development. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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Review

Jump to: Editorial, Research

23 pages, 1940 KiB  
Review
Releasing the Immune System Brakes Using siRNAs Enhances Cancer Immunotherapy
by Mouldy Sioud
Cancers 2019, 11(2), 176; https://doi.org/10.3390/cancers11020176 - 03 Feb 2019
Cited by 19 | Viewed by 4825
Abstract
Therapeutic dendritic cell (DC) cancer vaccines rely on the immune system to eradicate tumour cells. Although tumour antigen-specific T cell responses have been observed in most studies, clinical responses are fairly low, arguing for the need to improve the design of DC-based vaccines. [...] Read more.
Therapeutic dendritic cell (DC) cancer vaccines rely on the immune system to eradicate tumour cells. Although tumour antigen-specific T cell responses have been observed in most studies, clinical responses are fairly low, arguing for the need to improve the design of DC-based vaccines. The incorporation of small interfering RNAs (siRNAs) against immunosuppressive factors in the manufacturing process of DCs can turn the vaccine into potent immune stimulators. Additionally, siRNA modification of ex vivo-expanded T cells for adoptive immunotherapy enhanced their killing potency. Most of the siRNA-targeted immune inhibitory factors have been successful in that their blockade produced the strongest cytotoxic T cell responses in preclinical and clinical studies. Cancer patients treated with the siRNA-modified DC vaccines showed promising clinical benefits providing a strong rationale for further development of these immunogenic vaccine formulations. This review covers the progress in combining siRNAs with DC vaccines or T cell therapy to boost anti-tumour immunity. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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15 pages, 690 KiB  
Review
Anti-Cancer Vaccine for HPV-Associated Neoplasms: Focus on a Therapeutic HPV Vaccine Based on a Novel Tumor Antigen Delivery Method Using Endogenously Engineered Exosomes
by Paola Di Bonito, Luisa Accardi, Luisa Galati, Flavia Ferrantelli and Maurizio Federico
Cancers 2019, 11(2), 138; https://doi.org/10.3390/cancers11020138 - 24 Jan 2019
Cited by 25 | Viewed by 5340
Abstract
Some human papillomavirus (HPV) genotypes are universally recognized as major etiological agents not only of ano-genital tumors but also of head and neck cancers, which show increasing incidence. The evaluation of current and future therapeutic approaches against HPV-induced tumors is a global health [...] Read more.
Some human papillomavirus (HPV) genotypes are universally recognized as major etiological agents not only of ano-genital tumors but also of head and neck cancers, which show increasing incidence. The evaluation of current and future therapeutic approaches against HPV-induced tumors is a global health priority, despite an effective prophylactic vaccine against 7 of the 12 genotypes involved in the etiology of tumors being currently available. In this review, we present the main anti-HPV therapeutic approaches in clinical experimentation, with a focus on a novel tumor antigen delivery method using engineered exosomes, that we recently developed. Our system allows the induction of an efficient unrestricted cytotoxic T lymphocyte (CTL) immune response against the HPV16-E7 tumor-associated antigen, with the formation of endogenously engineered exosomes, i.e., nanovesicles spontaneously released by all cell types. Immunogenic exosomes are uploaded with HPV16-E7 due to the fusion with a unique exosome-anchoring protein referred to as Nefmut. Intramuscular injection of a DNA vector expressing the fusion protein generates exosomes sufficiently immunogenic to elicit a potent anti-16E7 CTL immune response. The approach is described here and the advantages over other existing methodologies are reported. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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12 pages, 932 KiB  
Review
Cancer Immunotherapy: Silencing Intracellular Negative Immune Regulators of Dendritic Cells
by Yao-Hua Liu, I-Jeng Yeh, Ming-Derg Lai, Kuan-Ting Liu, Po-Lin Kuo and Meng-Chi Yen
Cancers 2019, 11(1), 108; https://doi.org/10.3390/cancers11010108 - 17 Jan 2019
Cited by 4 | Viewed by 4541
Abstract
Dendritic cells (DCs) are capable of activating adaptive immune responses, or inducing immune suppression or tolerance. In the tumor microenvironment, the function of DCs is polarized into immune suppression that attenuates the effect of T cells, promoting differentiation of regulatory T cells and [...] Read more.
Dendritic cells (DCs) are capable of activating adaptive immune responses, or inducing immune suppression or tolerance. In the tumor microenvironment, the function of DCs is polarized into immune suppression that attenuates the effect of T cells, promoting differentiation of regulatory T cells and supporting tumor progression. Therefore, blocking negative immune regulators in DCs is considered a strategy of cancer immunotherapy. Antibodies can target molecules on the cell surface, but not intracellular molecules of DCs. The delivery of short-hairpin RNAs (shRNA) and small-interfering RNAs (siRNA) should be a strategy to silence specific intracellular targets in DCs. This review provides an overview of the known negative immune regulators of DCs. Moreover, a combination of shRNA/siRNA and DC vaccines, DNA vaccines in animal models, and clinical trials are also discussed. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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14 pages, 257 KiB  
Review
Optimising Cancer Vaccine Design in Sarcoma
by Alexandra Pender, Robin L. Jones and Seth Pollack
Cancers 2019, 11(1), 1; https://doi.org/10.3390/cancers11010001 - 20 Dec 2018
Cited by 11 | Viewed by 3590
Abstract
Immunotherapeutics are increasingly recognized as a key tool in the armamentarium against malignancy. The success of immune checkpoint-targeting drugs and adoptive cell therapy has refocused attention on the potential anti-cancer effect of eliciting a tumour-specific immunological response. Sarcomas are a rare and diverse [...] Read more.
Immunotherapeutics are increasingly recognized as a key tool in the armamentarium against malignancy. The success of immune checkpoint-targeting drugs and adoptive cell therapy has refocused attention on the potential anti-cancer effect of eliciting a tumour-specific immunological response. Sarcomas are a rare and diverse group of tumours with a limited prognosis in advanced disease despite systemic therapeutics. Various vaccine strategies including peptide vaccines against cancer testis antigens, dendritic cell vaccines, and viral vectors have been trialled in sarcoma with growing evidence of efficacy. Here, we review the principles of successful vaccine development and how these have been applied thus far to the treatment of sarcoma. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
24 pages, 849 KiB  
Review
Oncolytic Viruses for Canine Cancer Treatment
by Diana Sánchez, Gabriela Cesarman-Maus, Alfredo Amador-Molina and Marcela Lizano
Cancers 2018, 10(11), 404; https://doi.org/10.3390/cancers10110404 - 27 Oct 2018
Cited by 29 | Viewed by 10020
Abstract
Oncolytic virotherapy has been investigated for several decades and is emerging as a plausible biological therapy with several ongoing clinical trials and two viruses are now approved for cancer treatment in humans. The direct cytotoxicity and immune-stimulatory effects make oncolytic viruses an interesting [...] Read more.
Oncolytic virotherapy has been investigated for several decades and is emerging as a plausible biological therapy with several ongoing clinical trials and two viruses are now approved for cancer treatment in humans. The direct cytotoxicity and immune-stimulatory effects make oncolytic viruses an interesting strategy for cancer treatment. In this review, we summarize the results of in vitro and in vivo published studies of oncolytic viruses in different phases of evaluation in dogs, using PubMed and Google scholar as search platforms, without time restrictions (to date). Natural and genetically modified oncolytic viruses were evaluated with some encouraging results. The most studied viruses to date are the reovirus, myxoma virus, and vaccinia, tested mostly in solid tumors such as osteosarcomas, mammary gland tumors, soft tissue sarcomas, and mastocytomas. Although the results are promising, there are issues that need addressing such as ensuring tumor specificity, developing optimal dosing, circumventing preexisting antibodies from previous exposure or the development of antibodies during treatment, and assuring a reasonable safety profile, all of which are required in order to make this approach a successful therapy in dogs. Full article
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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