Research

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Open AccessArticle

Anti-Tumor Effects of Peptide Therapeutic and Peptide Vaccine Antibody Co-targeting HER-1 and HER-2 in Esophageal Cancer (EC) and HER-1 and IGF-1R in Triple-Negative Breast Cancer (TNBC)

by Jay Overholser, Kristen Henkins Ambegaokar, Siobhan M. Eze, Eduardo Sanabria-Figueroa, Rita Nahta, Tanios Bekaii-Saab and Pravin T.P. Kaumaya

Vaccines 2015, 3(3), 519-543; https://doi.org/10.3390/vaccines3030519 - 06 Jul 2015

Cited by 16 | Viewed by 7322

Abstract

Despite the promise of targeted therapies, there remains an urgent need for effective treatment for esophageal cancer (EC) and triple-negative breast cancer (TNBC). Current FDA-approved drugs have significant problems of toxicity, safety, selectivity, efficacy and development of resistance. In this manuscript, we demonstrate [...] Read more.

Despite the promise of targeted therapies, there remains an urgent need for effective treatment for esophageal cancer (EC) and triple-negative breast cancer (TNBC). Current FDA-approved drugs have significant problems of toxicity, safety, selectivity, efficacy and development of resistance. In this manuscript, we demonstrate that rationally designed peptide vaccines/mimics are a viable therapeutic strategy for blocking aberrant molecular signaling pathways with high affinity, specificity, potency and safety. Specifically, we postulate that novel combination treatments targeting members of the EGFR family and IGF-1R will yield significant anti-tumor effects in in vitro models of EC and TNBC possibly overcoming mechanisms of resistance. We show that the combination of HER-1 and HER-2 or HER-1 and IGF-1R peptide mimics/vaccine antibodies exhibited enhanced antitumor properties with significant inhibition of tumorigenesis in OE19 EC and MDA-MB-231 TNBC cell lines. Our work elucidates the mechanisms of HER-1/IGF-1R and HER-1/HER-2 signaling in these cancer cell lines, and the promising results support the rationale for dual targeting with HER-1 and HER-2 or IGF-1R as an improved treatment regimen for advanced therapy tailored to difference types of cancer. Full article

(This article belongs to the Special Issue Cancer Vaccines)

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Open AccessArticle

Epitope Prediction Assays Combined with Validation Assays Strongly Narrows down Putative Cytotoxic T Lymphocyte Epitopes

by Peng Peng Ip, Hans W. Nijman and Toos Daemen

Vaccines 2015, 3(2), 203-220; https://doi.org/10.3390/vaccines3020203 - 24 Mar 2015

Cited by 19 | Viewed by 7189

Abstract

Tumor vaccine design requires prediction and validation of immunogenic MHC class I epitopes expressed by target cells as well as MHC class II epitopes expressed by antigen-presenting cells essential for the induction of optimal immune responses. Epitope prediction methods are based on different [...] Read more.

Tumor vaccine design requires prediction and validation of immunogenic MHC class I epitopes expressed by target cells as well as MHC class II epitopes expressed by antigen-presenting cells essential for the induction of optimal immune responses. Epitope prediction methods are based on different algorithms and are instrumental for a first screening of possible epitopes. However, their results do not reflect a one-to-one correlation with experimental data. We combined several in silico prediction methods to unravel the most promising C57BL/6 mouse-restricted Hepatitis C virus (HCV) MHC class I epitopes and validated these epitopes in vitro and in vivo. Cytotoxic T lymphocyte (CTL) epitopes within the HCV non-structural proteins were identified, and proteasomal cleavage sites and helper T cell (Th) epitopes at close proximity to these CTL epitopes were analyzed using multiple prediction algorithms. This combined in silico analysis enhances the precision of identification of functional HCV-specific CTL epitopes. This approach will be applicable to the design of human vaccines not only for HCV, but also for other antigens in which T-cell responses play a crucial role. Full article

(This article belongs to the Special Issue Cancer Vaccines)

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Open AccessArticle

EBV-Associated Cancer and Autoimmunity: Searching for Therapies

by Giovanni Capone, Candida Fasano, Guglielmo Lucchese, Michele Calabrò and Darja Kanduc

Vaccines 2015, 3(1), 74-89; https://doi.org/10.3390/vaccines3010074 - 05 Feb 2015

Cited by 16 | Viewed by 6527

Abstract

Epstein-Barr virus (EBV) infects B-, T-, and NK cells and has been associated not only with a wide range of lymphoid malignancies but also with autoimmune diseases such as lupus erythematosus, rheumatoid arthritis and, in particular, multiple sclerosis. Hence, effective immunotherapeutic approaches to [...] Read more.

Epstein-Barr virus (EBV) infects B-, T-, and NK cells and has been associated not only with a wide range of lymphoid malignancies but also with autoimmune diseases such as lupus erythematosus, rheumatoid arthritis and, in particular, multiple sclerosis. Hence, effective immunotherapeutic approaches to eradicate EBV infection might overthrow cancer and autoimmunity incidence. However, currently no effective anti-EBV immunotherapy is available. Here we use the concept that protein immunogenicity is allocated in rare peptide sequences and search the Epstein-Barr nuclear antigen 1 (EBNA1) sequence for peptides unique to the viral protein and absent in the human host. We report on a set of unique EBV EBNA1 peptides that might be used in designing peptide-based therapies able to specifically hitting the virus or neutralizing pathogenic autoantibodies. Full article

(This article belongs to the Special Issue Cancer Vaccines)

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Review

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Open AccessReview

Targeting Transcriptional Regulators of CD8+ T Cell Dysfunction to Boost Anti-Tumor Immunity

by Katherine A. Waugh, Sonia M. Leach and Jill E. Slansky

Vaccines 2015, 3(3), 771-802; https://doi.org/10.3390/vaccines3030771 - 17 Sep 2015

Cited by 10 | Viewed by 7631

Abstract

Transcription is a dynamic process influenced by the cellular environment: healthy, transformed, and otherwise. Genome-wide mRNA expression profiles reflect the collective impact of pathways modulating cell function under different conditions. In this review we focus on the transcriptional pathways that control tumor infiltrating [...] Read more.

Transcription is a dynamic process influenced by the cellular environment: healthy, transformed, and otherwise. Genome-wide mRNA expression profiles reflect the collective impact of pathways modulating cell function under different conditions. In this review we focus on the transcriptional pathways that control tumor infiltrating CD8+ T cell (TIL) function. Simultaneous restraint of overlapping inhibitory pathways may confer TIL resistance to multiple mechanisms of suppression traditionally referred to as exhaustion, tolerance, or anergy. Although decades of work have laid a solid foundation of altered transcriptional networks underlying various subsets of hypofunctional or “dysfunctional” CD8+ T cells, an understanding of the relevance in TIL has just begun. With recent technological advances, it is now feasible to further elucidate and utilize these pathways in immunotherapy platforms that seek to increase TIL function. Full article

(This article belongs to the Special Issue Cancer Vaccines)

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Open AccessReview

Cancer Dormancy: A Regulatory Role for Endogenous Immunity in Establishing and Maintaining the Tumor Dormant State

by Constantin N. Baxevanis and Sonia A. Perez

Vaccines 2015, 3(3), 597-619; https://doi.org/10.3390/vaccines3030597 - 30 Jul 2015

Cited by 46 | Viewed by 8450

Abstract

The significant contribution of host immunity in early tumorigenesis has been recently recognized as a result of our better understanding of the molecular pathways regulating tumor cell biology and tumor-lymphocyte interactions. Emerging evidence suggests that disseminated dormant tumor cells derived from primary tumors [...] Read more.

The significant contribution of host immunity in early tumorigenesis has been recently recognized as a result of our better understanding of the molecular pathways regulating tumor cell biology and tumor-lymphocyte interactions. Emerging evidence suggests that disseminated dormant tumor cells derived from primary tumors before or after immune surveillance, are responsible for subsequent metastases. Recent trends from the field of onco-immunology suggest that efficiently stimulating endogenous anticancer immunity is a prerequisite for the successful outcome of conventional cancer therapies. Harnessing the immune system to achieve clinical efficacy is realistic in the context of conventional therapies resulting in immunogenic cell death and/or immunostimulatory side effects. Targeted therapies designed to target oncogenic pathways in tumor cells can also positively regulate the endogenous immune response and tumor microenvironment. Identification of T cell inhibitory signals has prompted the development of immune checkpoint inhibitors, which specifically hinder immune effector inhibition, reinvigorating and potentially expanding the preexisting anticancer immune response. This anticancer immunity can be amplified in the setting of immunotherapies, mostly in the form of vaccines, which boost naturally occurring T cell clones specifically recognizing tumor antigens. Thus, a promising anticancer therapy will aim to activate patients’ naturally occurring anticancer immunity either to eliminate residual tumor cells or to prolong dormancy in disseminated tumor cells. Such an endogenous anticancer immunity plays a significant role for controlling the balance between dormant tumor cells and tumor escape, and restraining metastases. In this review, we mean to suggest that anticancer therapies aiming to stimulate the endogenous antitumor responses provide the concept of the therapeutic management of cancer. Full article

(This article belongs to the Special Issue Cancer Vaccines)

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Open AccessReview

Systems Biology Approach for Cancer Vaccine Development and Evaluation

by Luisa Circelli, Annacarmen Petrizzo, Maria Tagliamonte, Maria Lina Tornesello, Franco M. Buonaguro and Luigi Buonaguro

Vaccines 2015, 3(3), 544-555; https://doi.org/10.3390/vaccines3030544 - 14 Jul 2015

Cited by 11 | Viewed by 6804

Abstract

Therapeutic cancer vaccines do not hold promise yet as an effective anti-cancer treatment. Lack of efficacy or poor clinical outcomes are due to several antigenic and immunological aspects that need to be addressed in order to reverse such trends and significantly improve cancer [...] Read more.

Therapeutic cancer vaccines do not hold promise yet as an effective anti-cancer treatment. Lack of efficacy or poor clinical outcomes are due to several antigenic and immunological aspects that need to be addressed in order to reverse such trends and significantly improve cancer vaccines’ efficacy. The newly developed high throughput technologies and computational tools are instrumental to this aim allowing the identification of more specific antigens and the comprehensive analysis of the innate and adaptive immunities. Here, we review the potentiality of systems biology in providing novel insights in the mechanisms of the action of vaccines to improve their design and effectiveness. Full article

(This article belongs to the Special Issue Cancer Vaccines)

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Open AccessReview

Interest of Tumor-Specific CD4 T Helper 1 Cells for Therapeutic Anticancer Vaccine

by Jeanne Galaine, Christophe Borg, Yann Godet and Olivier Adotévi

Vaccines 2015, 3(3), 490-502; https://doi.org/10.3390/vaccines3030490 - 30 Jun 2015

Cited by 40 | Viewed by 6477

Abstract

Nowadays, immunotherapy represents one promising approach for cancer treatment. Recently, spectacular results of cancer immunotherapy clinical trials have confirmed the crucial role of immune system in cancer regression. Therapeutic cancer vaccine represents one widely used immunotherapy strategy to stimulate tumor specific T cell [...] Read more.

Nowadays, immunotherapy represents one promising approach for cancer treatment. Recently, spectacular results of cancer immunotherapy clinical trials have confirmed the crucial role of immune system in cancer regression. Therapeutic cancer vaccine represents one widely used immunotherapy strategy to stimulate tumor specific T cell responses but clinical impact remains disappointing in targeting CD8 T cells. Although CD8 T cells have been initially considered to be the main protagonists, it is now clear that CD4 T cells also play a critical role in antitumor response. In this article, we discuss the role of tumor antigen-specific CD4 T cell responses and how we can target these cells to improve cancer vaccines. Full article

(This article belongs to the Special Issue Cancer Vaccines)

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Open AccessReview

The Promise of Preventive Cancer Vaccines

by Pier-Luigi Lollini, Federica Cavallo, Patrizia Nanni and Elena Quaglino

Vaccines 2015, 3(2), 467-489; https://doi.org/10.3390/vaccines3020467 - 17 Jun 2015

Cited by 35 | Viewed by 10927

Abstract

Years of unsuccessful attempts at fighting established tumors with vaccines have taught us all that they are only able to truly impact patient survival when used in a preventive setting, as would normally be the case for traditional vaccines against infectious diseases. While [...] Read more.

Years of unsuccessful attempts at fighting established tumors with vaccines have taught us all that they are only able to truly impact patient survival when used in a preventive setting, as would normally be the case for traditional vaccines against infectious diseases. While true primary cancer prevention is still but a long-term goal, secondary and tertiary prevention are already in the clinic and providing encouraging results. A combination of immunopreventive cancer strategies and recently approved checkpoint inhibitors is a further promise of forthcoming successful cancer disease control, but prevention will require a considerable reduction of currently reported toxicities. These considerations summed with the increased understanding of tumor antigens allow space for an optimistic view of the future. Full article

(This article belongs to the Special Issue Cancer Vaccines)

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Open AccessReview

Signaling Circuits and Regulation of Immune Suppression by Ovarian Tumor-Associated Macrophages

by Martin J. Cannon, Debopam Ghosh and Swetha Gujja

Vaccines 2015, 3(2), 448-466; https://doi.org/10.3390/vaccines3020448 - 29 May 2015

Cited by 18 | Viewed by 8144

Abstract

The barriers presented by immune suppression in the ovarian tumor microenvironment present one of the biggest challenges to development of successful tumor vaccine strategies for prevention of disease recurrence and progression following primary surgery and chemotherapy. New insights gained over the last decade [...] Read more.

The barriers presented by immune suppression in the ovarian tumor microenvironment present one of the biggest challenges to development of successful tumor vaccine strategies for prevention of disease recurrence and progression following primary surgery and chemotherapy. New insights gained over the last decade have revealed multiple mechanisms of immune regulation, with ovarian tumor-associated macrophages/DC likely to fulfill a central role in creating a highly immunosuppressive milieu that supports disease progression and blocks anti-tumor immunity. This review provides an appraisal of some of the key signaling pathways that may contribute to immune suppression in ovarian cancer, with a particular focus on the potential involvement of the c-KIT/PI3K/AKT, wnt/β-catenin, IL-6/STAT3 and AhR signaling pathways in regulation of indoleamine 2,3-dioxygenase expression in tumor-associated macrophages. Knowledge of intercellular and intracellular circuits that shape immune suppression may afford insights for development of adjuvant treatments that alleviate immunosuppression in the tumor microenvironment and enhance the clinical efficacy of ovarian tumor vaccines. Full article

(This article belongs to the Special Issue Cancer Vaccines)

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Open AccessReview

Integrating Immune Checkpoint Blockade with Anti-Neo/Mutated Antigens Reactivity to Increase the Clinical Outcome of Immunotherapy

by Giorgio Parmiani, Cristina Maccalli and Michele Maio

Vaccines 2015, 3(2), 420-428; https://doi.org/10.3390/vaccines3020420 - 21 May 2015

Cited by 16 | Viewed by 5809

Abstract

Antibodies to immune checkpoints have entered the clinical arena and have been shown to provide a clinical benefit for metastatic melanoma and, possibly, for other tumors as well. In this review paper we summarize this therapeutic activity and underline the functional mechanisms that [...] Read more.

Antibodies to immune checkpoints have entered the clinical arena and have been shown to provide a clinical benefit for metastatic melanoma and, possibly, for other tumors as well. In this review paper we summarize this therapeutic activity and underline the functional mechanisms that may be involved. Among them, we discuss the so far neglected role of tumor-associated antigens (TAAs) deriving from tumor somatic mutations and summarize the results of recent trials showing the immunogenic strength of such TAAs which can be specifically targeted by T cells activated by immune checkpoint antibodies. Finally we discuss new immunotherapy approaches that involve the combination of self/shared- or neo-TAAs-based vaccines and immune checkpoint blockade antibodies, to increase the clinical response of metastatic melanoma patients. Full article

(This article belongs to the Special Issue Cancer Vaccines)

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Open AccessReview

CpG Oligonucleotides as Cancer Vaccine Adjuvants

by Hidekazu Shirota, Debra Tross and Dennis M. Klinman

Vaccines 2015, 3(2), 390-407; https://doi.org/10.3390/vaccines3020390 - 08 May 2015

Cited by 101 | Viewed by 10061

Abstract

Adjuvants improve host responsiveness to co-delivered vaccines through a variety of mechanisms. Agents that trigger cells expressing Toll-like receptors (TLR) activate an innate immune response that enhances the induction of vaccine-specific immunity. When administered in combination with vaccines designed to prevent or slow [...] Read more.

Adjuvants improve host responsiveness to co-delivered vaccines through a variety of mechanisms. Agents that trigger cells expressing Toll-like receptors (TLR) activate an innate immune response that enhances the induction of vaccine-specific immunity. When administered in combination with vaccines designed to prevent or slow tumor growth, TLR agonists have significantly improved the generation of cytotoxic T lymphocytes. Unfortunately, vaccines containing TLR agonists have rarely been able to eliminate large established tumors when administered systemically. To improve efficacy, attention has focused on delivering TLR agonists intra-tumorally with the intent of altering the tumor microenvironment. Agonists targeting TLRs 7/8 or 9 can reduce the frequency of Tregs while causing immunosuppressive MDSC in the tumor bed to differentiate into tumoricidal macrophages thereby enhancing tumor elimination. This work reviews pre-clinical and clinical studies concerning the utility of TLR 7/8/9 agonists as adjuvants for tumor vaccines. Full article

(This article belongs to the Special Issue Cancer Vaccines)

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