Current methods of epitope identification for cancer vaccine design

Cherryholmes, Gregory; Stanton, Sasha E.; Disis, Mary L.

doi:10.1016/j.vaccine.2015.06.116

Cited by 25 publications

(11 citation statements)

References 57 publications

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“…However, the development of effective multi-epitope vaccines remains challenging due to the difficulties in the selection of appropriate antigen candidates, immunodominant epitopes and an efficient delivery system (L. Zhang 2018). Therefore, the prediction of suitable antigenic epitopes of a target protein by immunoinformatic methods is extremely important for designing a multi-epitope vaccine (Yin et al 2016;Cherryholmes, Stanton, and Disis 2015).…”

Section: Discussionmentioning

confidence: 99%

Structural Basis and Designing of Peptide Vaccine using PE-PGRS Family Protein of Mycobacterium ulcerans – An Integrated Vaccinomics Approach

Nain

Karim

Sen³

et al. 2019

Preprint

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Buruli ulcer is an emerging-necrotizing skin infection, responsible for permanent deformity if untreated, caused by the pathogen Mycobacterium ulcerans (M. ulcerans). Despite this debilitating condition, no specific disease-modifying therapeutics or vaccination is available. Therefore, we aimed to design an effective multi-epitope vaccine against M.ulcerans through an integrated vaccinomics approach. Briefly, the highest antigenic PE-PGRS protein was selected from which the promiscuous T-and B-cell epitopes were predicted. After rigorous assessment, 15 promising CTL, HTL and LBL epitopes were selected. The identified T-cell epitopes showed marked interactions towards the HLA binding alleles and provided 99.8% world population coverage. Consequently, a vaccine chimera was designed by connecting these epitopes with suitable linkers and adjuvant (LprG). The vaccine construct was antigenic and immunogenic as well as non-allergenic; hence, subjected to homology modelling. The molecular docking and dynamic simulation revealed strong and stable binding affinity between the vaccine and TLR2 receptor. The binding energy (∆G) and dissociation constant (Kd) were -15.3 kcal/mol and 5.9×10 -12 M, respectively. Further, disulfide engineering was applied to improve vaccine' stability and higher expression in Escherichia coli K12 system was ensured by codon optimization and cloning in silico.The computer-simulated immune responses were characterized by higher levels of IgM and IgG antibodies,helper T-cells with increased IFN-γ production, and macrophage activity crucial for immunity against M. ulcerans.Therefore, our data suggest that, if the designed vaccine is validated experimentally, it will prevent Buruli ulcer by generating robust immune response against M. ulcerans.

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Section: Discussionmentioning

confidence: 99%

Structural Basis and Designing of Peptide Vaccine using PE-PGRS Family Protein of Mycobacterium ulcerans – An Integrated Vaccinomics Approach

Nain

Karim

Sen³

et al. 2019

Preprint

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“…The incentive for this has been not only to avoid undesired autoimmunity, but also to avoid the self-tolerance mechanisms that would prevent or seriously weaken the response to the vaccine. This effort has yielded and continues to yield a large number of antigens (31), even some on premalignant lesions (32), with a better safety profile in preclinical testing that would be expected to carry a lower risk when applied in the clinic for the first time.…”

Section: Review Of the Recommendations And Discussionmentioning

confidence: 99%

The FDA Guidance on Therapeutic Cancer Vaccines: The Need for Revision to Include Preventive Cancer Vaccines or for a New Guidance Dedicated to Them

Finn

Khleif

Herberman³

2015

Cancer Prevention Research

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Cancer vaccines based on antigens derived from self molecules rather than pathogens, have been under basic and clinical investigations for many years. Up until very recently they had been tested primarily in the setting of metastatic disease with the goal to engage the immune system in slowing down disease progression. Many therapeutic vaccine trials, either investigator-initiated or led by pharmaceutical companies, have been completed and many are currently ongoing, following the FDA Guidance on therapeutic cancer vaccines published in 2011. In recent years the target of cancer vaccines is being shifted to early cancer and even premalignant disease with the goal of preventing cancer. While some issues addressed in the FDA Guidance on therapeutic vaccines apply to preventive vaccines, many do not. Here we discuss a set of recommendations for revising the current Guidance to also cover preventive vaccines, or to include in a new Guidance dedicated specifically to vaccines for cancer prevention.

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“…Immune therapies have been developed to actively and specifically stimulate the host immune system using cytokines including high-dose interleukin (IL)-2 [ 1 ]; molecular vaccines targeting tumor-associated antigen (TAA) [ 2 ]; cellular immunotherapies including dendritic cell (DC) vaccines [ 3 ]; and adoptive T-cell therapy such as tumor-infiltrating lymphocyte (TIL), cytotoxic T lymphocyte (CTL), transgenic T-cell receptors, and chimeric antigen receptors [ 4 ]. Although effective anti-tumor immune responses have been documented in previous clinical trials, several impediments including the reduced or lost molecular expressions of tumor antigen and class I, and the production of immunosuppressive cytokines, immunosuppressive cells including regulatory T cells (Tregs) and immune checkpoint molecules have been found to inhibit anti-tumor immunity [ 3 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

A phase I clinical trial of RNF43 peptide-related immune cell therapy combined with low-dose cyclophosphamide in patients with advanced solid tumors

et al. 2018

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The objective of this study was to investigate the safety and the tolerability of combined cellular immunotherapy with low-dose cyclophosphamide (CPA) in patients with advanced solid tumors. This study targeted a novel tumor-associated antigen, ring finger protein 43 (RNF43). Eligible patients were resistant to standard therapy, HLA-A*24:02- or A*02:01-positive and exhibiting high RNF43 expression in their tumor cells. They were administered 300 mg/m2 CPA followed by autologous lymphocytes, preliminarily cultured with autologous RNF43 peptide-pulsed dendritic cells (DCs), RNF43 peptide-pulsed DCs and systemic low dose interleukin-2. The primary endpoint was safety whereas the secondary endpoint was immunological and clinical response to treatment. Ten patients, in total, were enrolled in this trial. Primarily, no adverse events greater than Grade 3 were observed. Six out of 10 patients showed stable disease (SD) on day 49, while 4 other patients showed progressive disease. In addition, one patient with SD exhibited a partial response after the second trial. The frequency of regulatory T cells (Tregs) in patients with SD significantly decreased after CPA administration. The ratio of interferon-γ-producing, tumor-reactive CD8+ T cells increased with time in patients with SD. We successfully showed that the combination of immune cell therapy and CPA was safe, might induce tumor-specific immune responses and clinical efficacy, and was accompanied by a decreased ratio of Tregs in patients with RNF43-positive advanced solid tumors.

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Current methods of epitope identification for cancer vaccine design

Cited by 25 publications

References 57 publications

Structural Basis and Designing of Peptide Vaccine using PE-PGRS Family Protein of Mycobacterium ulcerans – An Integrated Vaccinomics Approach

Structural Basis and Designing of Peptide Vaccine using PE-PGRS Family Protein of Mycobacterium ulcerans – An Integrated Vaccinomics Approach

The FDA Guidance on Therapeutic Cancer Vaccines: The Need for Revision to Include Preventive Cancer Vaccines or for a New Guidance Dedicated to Them

A phase I clinical trial of RNF43 peptide-related immune cell therapy combined with low-dose cyclophosphamide in patients with advanced solid tumors

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