Peptide Vaccine Research Articles

Frequencies of an Immunogenic HER-2/neu Epitope of CD8+ T Lymphocytes Predict Favorable Clinical Outcomes in Prostate Cancer

HER-2/neu is the human epidermal growth factor receptor 2, which is associated with the progression of prostate cancer (PCa). HER-2/neu-specific T cell immunity has been shown to predict immunologic and clinical responses in PCa patients treated with HER-2/neu peptide vaccines. However, its prognostic role in PCa patients receiving conventional treatment is unknown, and this was addressed in this study. The densities of CD8+ T cells specific for the HER-2/neu(780-788) peptide in the peripheral blood of PCa patients under standard treatments were correlated with TGF-β/IL-8 levels and clinical outcomes. We demonstrated that PCa patients with high frequencies of HER-2/neu(780-788)-specific CD8+ T lymphocytes had better progression-free survival (PFS) as compared with PCa patients with low frequencies. Increased frequencies of HER-2/neu(780-788)-specific CD8+ T lymphocytes were also associated with lower levels of TGF-β and IL-8. Our data provide the first evidence of the predictive role of HER-2/neu-specific T cell immunity in PCa.

A New Strategy for Mapping Epitopes of LACK and PEPCK Proteins of Leishmania amazonensis Specific for Major Histocompatibility Complex Class I.

Leishmaniasis represents a complex of diseases with a broad clinical spectrum and epidemiological diversity, considered a major public health problem. Although there is treatment, there are still no vaccines for cutaneous leishmaniasis. Because Leishmania spp. is an intracellular protozoan with several escape mechanisms, a vaccine must provoke cellular and humoral immune responses. Previously, we identified the Leishmania homolog of receptors for activated C kinase (LACK) and phosphoenolpyruvate carboxykinase (PEPCK) proteins as strong immunogens and candidates for the development of a vaccine strategy. The present work focuses on the in silico prediction and characterization of antigenic epitopes that might interact with mice or human major histocompatibility complex class I. After immunogenicity prediction on the Immune Epitope Database (IEDB) and the Database of MHC Ligands and Peptide Motifs (SYFPEITHI), 26 peptides were selected for interaction assays with infected mouse lymphocytes by flow cytometry and ELISpot. This strategy identified nine antigenic peptides (pL1-H2, pPL3-H2, pL10-HLA, pP13-H2, pP14-H2, pP15-H2, pP16-H2, pP17-H2, pP18-H2, pP26-HLA), which are strong candidates for developing a peptide vaccine against leishmaniasis.

Development of novel self-assembled vaccines based on tumour-specific antigenic peptide and TLR2 agonist for effective breast cancer immunotherapy via activating CD8+ T cells and enhancing their function.

Vaccines based on tumour-specific antigens are a promising approach for immunotherapy. However, the clinical efficacy of tumour-specific antigens is still challenging. Twelve conjugates with self-assembly properties were designed and synthesized using MAGE-A1 peptide and TLR2 agonist, combined with different covalent bonds. All the developed conjugates formed spherical nanoparticles with a diameter of approximately 150 nm, and enhanced the efficacy of the peptide vaccines with the better targeting of lymph nodes. All the conjugates could well bind to serum albumin and improve the plasma stability of the individual antigenic peptides. In particular, conjugate 6 (N-Ac PamCS-M-6) had a more significant ability to promote dendritic cell maturation, CD8+ T cell activation, and subsequent killing of tumour cells, with an in vivo tumour inhibition rate of 70 ± 2.9%. The interaction between specific response and the different conjugation modes was further explored, thereby providing a fundamental basis for novel immune anti-tumour molecular platforms.

The emerging role of vaccines in cancer therapies

Globally, there is a severe public health issue with cancer. Comprehensive funding has been provided for the creation of medicinal vaccines against cancer. The efficiency of vaccines in preventing bacterial and viral illnesses has been demonstrated. Over the past 200 years, they have averted many fatal diseases and saved countless lives. Vaccines protect against diseases brought on by viruses and bacteria by exposing recipients to attenuated or inactivated pathogens. Thereby, the individual's immune system can identify the antigen and behave. DNA vaccines, mRNA vaccines, and synthetic peptide vaccines are just a few of the innovative vaccinations created in recent years using modern biotechnology. Immune adjuvants or drug delivery systems are utilized to enhance immunogenicity through extensive immune system research, tests on animal models, and clinical trials of vaccines. This review paper will discuss therapeutic cancer vaccine mechanisms and cancer vaccine delivery methods.

In silico designing of a novel polyvalent multi-subunit peptide vaccine leveraging cross-immunity against human visceral and cutaneous leishmaniasis: an immunoinformatics-based approach

Leishmaniasis is a group of vector-borne infectious diseases caused by over 20 pathogenic Leishmania species that are endemic in many tropical and subtropical countries. The emergence of drug-resistant strains, the adverse side effects of anti-Leishmania drugs, and the absence of a preventative vaccination strategy threaten the sensitive population. Recently, many groups of researchers have exploited the field of reverse vaccinology to develop vaccines, focusing chiefly on inducing immunity against either visceral or cutaneous leishmaniasis. This present work involves retrieving twelve experimentally validated leishmanial antigenic protein sequences from the UniProt database, followed by their antigenicity profiling employing ANTIGENpro and Vaxijen 2.0 servers. MHC-binding epitopes for the same were predicted using both NetCTL 1.2 and SYFPEITHI servers, while epitopes for B cell were computed using ABCpred and BepiPred 2.0 servers. The screened epitopes with significantly higher scores were utilized for designing the vaccine construct with appropriate linkers and natural adjuvant. The secondary and tertiary structures of the synthetic peptide were determined by conditional random fields, shallow neural networks, and profile-profile threading alignment with iterative structure assembly simulations, respectively. The 3-D vaccine model was validated through CASP10-tested refinement and the MolProbity web server. Molecular docking and multi-scale normal mode analysis simulation were performed to analyze the best vaccine-TLR complex. Finally, computational immune simulation findings revealed promising cellular and humoral immune responses, suggesting that the engineered chimeric peptide is a potential broad-spectrum vaccine against visceral and cutaneous leishmaniasis.

Design of a multi-epitopic vaccine against Epstein-Barr virus via computer-based methods.

Scientific findings have shown that Epstein-Barr virus (EBV) plays a key role in the development of some tumor diseases. Therefore, this study intends to take a practical step in controlling the pathogenicity of this virus by designing an effective vaccine based on the virus Capsid Envelope and Epstein-Barr nuclear immunogen (EBNA) Proteins Epitopes. Currently, there are no effective drugs or vaccines to treat or prevent EBV infection. So, we applied a computer-based strategy to design an epitope vaccine. We designed a powerful multi-epitope peptide vaccine against EBV using in silico analysis. The vaccine is made up of 844 amino acids derived from three different types of proteins (Envelope, Capsid, EBNA) found in two different viral strains. responses. These epitopes have a high immunogenic capacity and are not likely to cause allergies. To enhance the vaccine immunogenicity, we used rOv-ASP-1, a recombinant Onchocerca volvulus activation associated protein-1, as an adjuvant and linked it to the vaccine's N and C terminus. The physicochemical and immunological properties of the vaccine structure were evaluated. The proposed vaccine was stable, with a stability index of 33.57 and a pI of 10.10, according to bioinformatic predictions. Docking analysis revealed that the vaccine protein binds correctly with immunological receptors. Our results demonstrated that the multi-epitope vaccine might be potentially immunogenic and induce humoral and cellular immune responses against EBV. This vaccine can interact appropriately with immunological receptors Also, it has a high-quality structure and suitable characteristics such as high stability.

A Synthetic SARS-CoV-2-Derived T-Cell and B-Cell Peptide Cocktail Elicits Full Protection against Lethal Omicron BA.1 Infection in H11-K18-hACE2 Mice.

Emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developing the capacity for immune evasion and resistance to existing vaccines and drugs. To address this, development of vaccines against coronavirus disease 2019 (COVID-19) has focused on universality, strong T cell immunity, and rapid production. Synthetic peptide vaccines, which are inexpensive and quick to produce, show low toxicity, and can be selected from the conserved SARS-CoV-2 proteome, are promising candidates. In this study, we evaluated the effectiveness of a synthetic peptide cocktail containing three murine CD4+ T-cell epitopes from the SARS-CoV-2 nonspike proteome and one B-cell epitope from the Omicron BA.1 receptor-binding domain (RBD), along with aluminum phosphate (Al) adjuvant and 5' cytosine-phosphate-guanine 3' oligodeoxynucleotide (CpG-ODN) adjuvant in mice. The peptide cocktail induced good Th1-biased T-cell responses and effective neutralizing-antibody titers against the Omicron BA.1 variant. Additionally, H11-K18-hACE2 transgenic mice were fully protected against lethal challenge with the BA.1 strain, with a 100% survival rate and reduced pulmonary viral load and pathological lesions. Subcutaneous administration was found to be the superior route for synthetic peptide vaccine delivery. Our findings demonstrate the effectiveness of the peptide cocktail in mice, suggesting the feasibility of synthetic peptide vaccines for humans. IMPORTANCE Current vaccines based on production of neutralizing antibodies fail to prevent the infection and transmission of SARS-CoV-2 Omicron and its subvariants. Understanding the critical factors and avoiding the disadvantages of vaccine strategies are essential for developing a safe and effective COVID-19 vaccine, which would include a more effective and durable cellular response, minimal effects of viral mutations, rapid production against emerging variants, and good safety. Peptide-based vaccines are an excellent alternative because they are inexpensive, quick to produce, and very safe. In addition, human leukocyte antigen T-cell epitopes could be targeted at robust T-cell immunity and selected in the conserved region of the SARS-CoV-2 variants. Our study showed that a synthetic SARS-CoV-2-derived peptide cocktail induced full protection against lethal infection with Omicron BA.1 in H11-K18-hACE2 mice for the first time. This could have implications for the development of effective COVID-19 peptide vaccines for humans.

Whole genome analysis of Neisseria meningitidis isolates from invasive meningococcal disease collected in the Czech Republic over 28 years (1993-2020).

Invasive meningococcal disease belongs among the most dangerous infectious diseases in the world. Several polysaccharide conjugate vaccines against serogroups A, C, W and Y are available and two recombinant peptide vaccines against serogroup B (MenB vaccines) have been developed: MenB-4C (Bexsero) and MenB-fHbp (Trumenba). The aim of this study was to define the clonal composition of the Neisseria meningitidis population in the Czech Republic, to determine changes in this population over time and to estimate the theoretical coverage of isolates by MenB vaccines. This study presents the analysis of whole genome sequencing data of 369 Czech N. meningitidis isolates from invasive meningococcal disease covering 28 years. Serogroup B isolates (MenB) showed high heterogeneity and the most common clonal complexes were cc18, cc32, cc35, cc41/44, and cc269. Isolates of clonal complex cc11 were predominately serogroup C (MenC). The highest number of serogroup W isolates (MenW) belonged to clonal complex cc865, which we described as exclusive to the Czech Republic. Our study supports the theory that this cc865 subpopulation originated in the Czech Republic from MenB isolates by a capsule switching mechanism. A dominant clonal complex of serogroup Y isolates (MenY) was cc23, which formed two genetically quite distant subpopulations and which showed constant representation throughout the observed period. The theoretical coverage of isolates by two MenB vaccines was determined using the Meningococcal Deduced Vaccine Antigen Reactivity Index (MenDeVAR). Estimated Bexsero vaccine coverage was 70.6% (for MenB) and 62.2% (for MenC, W, Y). For Trumenba vaccine, estimated coverage was 74.6% (for MenB) and 65.7% (for MenC, W, Y). Our results demonstrated sufficient coverage of Czech heterogeneous population of N. meningitidis with MenB vaccines and, together with surveillance data on invasive meningococcal disease in the Czech Republic, were the basis for updating recommendations for vaccination against invasive meningococcal disease.

Progress in phase III clinical trials of molecular targeted therapy and immunotherapy for glioblastoma.

Glioblastoma (GBM) is the most common primary central nervous system tumor, whose prognosis remains poor under the sequential standard of care, such as neurosurgery followed by concurrent temozolomide radiochemotherapy and adjuvant temozolomide chemotherapy in the presence or absence of tumor treating fields. Accordingly, the advent of molecular targeted therapy and immunotherapy has opened a new era of tumor management. A diverse range of targeted drugs have been tested in patients with GBM in phase III clinical trials. However, these drugs are ineffective for all patients, as evidenced by the fact that only a minority of patients in these trials showed prolonged survival. Furthermore, there are several published phase III clinical trials that involve immune checkpoint inhibitors, peptide vaccines, dendritic cell vaccines, and virotherapy. Accordingly, this review comprehensively overviews existing studies of targeted drugs and immunotherapy for glioma and discusses the challenge and perspective of targeted drugs and immunotherapy for glioma to clarify future directions.

Characterization of immunomodulatory B-cells and T-cells to generate extremely targeted immunoassays and vaccines

Introduction: The Rubella virus has worldwide occurrence and congenital Rubella syndrome are widely recognized as emerging infection in several parts of the world. Methodology: We investigated for peptide vaccine with specific T and B-cell epitopes was identified through bioinformatics-based approaches. These were identified utilizing available Rubella virus E1 glycoprotein sequence databases. The outer-membrane glycoprotein, E1 is a target protein for the prediction of best antigens. Results: The bioinformatics online software Bepipred 2 was used for prediction of potential B-cell epitope (pfcntphgqlevqvppdpgd) was identified and it has shown high conversation against E1 glycoprotein and few other bioinformatics online software NetMHCpan, IEDB and NetCTL was used to identify maximum surface-exposed residues. T-Cell epitope (rpvalpral) was identified and shown to be conserved to E1 Glycoprotein. Predicted epitopes were found to had promiscuous class-I major histocompatibility complex binding affinity to major histocompatibility complex super types, antigenicity scores and high proteasomal cleavage. The three-dimensional modelled structures was created using I-TASSER online server for highlighting the predicted T- and B- cell epitopes. Conclusion: The predicted T and B cell epitope could be used for development of immunoglobulin assay and vaccines.

Abstract P2-20-04: Vaccination against HIF1α/c-MET peptides overcome lapatinib resistance and inhibits tumor growth by immunomodulating in HER2 positive breast cancer

Abstract Human Epidermal growth factor Receptor 2 (HER2) is overexpressed in 20% to 30% of breast cancers and is associated with poor prognosis. Patients with advanced HER2-type breast cancer are treated with HER2-directed tyrosine kinase inhibitors as well as antibodies, but many patients finally acquire therapeutic resistance. Therefore, it is important to develop new treatment strategies that circumvent HER2 positive resistant breast cancer. Among the suggested mechanisms of resistance to HER2-targeted therapeutics, tumor hypoxia and relevant biological factors are known as important players. In this study, we aimed to explore the role of tumor hypoxia in the development of resistance to HER2-targeted therapeutics, and whether the role of an immunological therapy targeting this could contribute to overcoming resistance. To this end, we established lapatinib-resistant HER2 positive breast cancer cells in vitro (SKBR3, BT-474 for human and MMC for murine cells). First, we examined if lapatinib-sensitivity is different according to oxygen concentration using lapatinib-resistant cell lines (LR-SKBT3, LR-BT-474, LR-MMC) compared with parent cell lines. Resistant cells were resistant both in normoxic and hypoxic conditions, but parent cells were highly sensitive in both of the oxygen concentration. In the Western blot analysis, HIF1α and c-MET were overexpressed in the resistant cells compared with parent cell lines in both normoxic and hypoxic condition. Interestingly, treatment with lapatinib had reduced HIF1α and c-MET expression at normoxia in parent cell lines but not in resistant cell lines. Under the hypoxic conditions, the difference in expression of HIF1α and c-MET was more pronounced between parent cell lines and resistant cell lines treated with lapatinib. These results indicate that the expression of HIF1α and c-MET was involved in lapatinib-resistant. In a previous study, we have identified epitopes from HIF1α/c-MET and demonstrated effect of delayed bone metastasis in triple negative breast cancer model when used as peptide vaccine. Herein, we evaluated whether the immunization using HIF1α/c-MET peptide vaccine is effective in inhibition of lapatinib-resistant HER2 positive breast cancer growth in vivo. MMTVneu-transgenic mouse model was used and 6- 8 weeks old mice were injected with LR-MMC subcutaneously. Immunization using the HIF1α/c-MET peptide vaccine significantly inhibited growth of LR-MMC cells in MMTVneu-transgenic mice compared with controls. HIF1α/c-MET specific IFN-γ-secreting T cell responses in the splenocytes were significantly higher in the immunized group than controls. Immunohistochemical staining of T cells revealed that expression of tumor HIF1α and c-MET was significantly decreased, while the number of CD8+ T cell was increased in the tumors from immunized animals compared with control tumors. In conclusion, our study demonstrated that the vaccine targeting HIF1α/c-MET might be a promising cancer immunotherapy in lapatinib-resistant HER2 positive breast cancer. In vivo study to evaluate efficacy of combination therapy (lapatinib and HIF1α/c-MET vaccine) is ongoing. Citation Format: Ji Min Lee, Jin Hwa Hong, Soon Young Lim, Ju Won Kim, Ah Reum Lim, Myung Han Hyun, Kyong Hwa Park. Vaccination against HIF1α/c-MET peptides overcome lapatinib resistance and inhibits tumor growth by immunomodulating in HER2 positive breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-20-04.

Nanovaccine: A Hope to Triumph the Battle Against Novel Coronavirus Disease 2019 (COVID-19).

The novel coronavirus 2019 (COVID-19) infection has caused the global emergence of coronavirus in humans during the last 12 months. Till May 11, 2021, the confirmed global COVID-19 cases and deaths reached 158551526 and 3296855, respectively. Goblet cells and ciliated cells in the nose act as the initial infection site of SARS-CoV-2. Thus, mucus immunity is important to protect from infection. The outburst of SARS-CoV-2 infection can be halted only when an effective vaccine will be developed. Globally, over 100 different vaccines are under investigation, including DNA vaccines, RNA vaccines, inactivated virus vaccines, adenovirus-based vaccines, recombinant/subunit protein vaccines, peptide vaccines, virus-like particles, etc. Inactivated virus vaccines and mRNA, and adenovirus-based vaccines have moved fast into patent clinical trials. Vaccines containing spike protein of SARS-CoV as subunit could effectively prevent binding of coronavirus to the host cell and membrane fusion. Thus, spike protein can be used as a major target for subunit vaccine preparation.

Abstract P4-07-23: Results of a Phase 2 Trial of Combination Immunotherapy with Concurrent Nelipepimut-S + GM-CSF and Trastuzumab in High-risk HER2+ Breast Cancer Patients

Abstract INTRODUCTION: The HER2-targeted peptide vaccine nelipepimut-S + GM-CSF (NeuVax) has been shown to be safe, immunogenic, and potentially synergistic with trastuzumab. Here we present the results of a randomized phase 2 trial assessing the ability of nelipepimut-S/GM-CSF versus GM-CSF alone, added to the standard adjuvant Trastuzumab, to prevent recurrences in high-risk HER2-positive breast cancer patients. METHODS: The study was a multi-center, prospective, randomized, controlled, single-blinded, phase 2 trial. Enrolled patients had high risk HER2+ breast cancer defined by the presence of residual disease post neoadjuvant therapy or by the presence of positive lymph nodes after upfront surgery. Eligible patients had completed an approved trastuzumab-chemotherapy containing regimen and they were receiving adjuvant Trastuzumab monotherapy. Enrollment was limited to patients with HLA-A2, A3, A24, and/or A26 alleles. Patients received intradermal injections of nelipepimut-S + GM-CSF or placebo + GM-CSF every three weeks for six total vaccinations with concurrent, standard monotherapy with iv trastuzumab. After completion of the primary vaccine series, booster inoculations were administered every six months for four doses. The primary outcome measure was invasive disease-free survival (iDFS) at 36 months. Secondary outcome measures were distant recurrence-free survival (DRFS), toxicity assessment, and evaluation of immune response. RESULTS: 100 patients were enrolled and randomized 1:1 to nelipepimut-S/GM-CSF or GM-CSF alone. There were no significant clinicopathologic differences between the groups. There was no difference in related local (p=0.49) or systemic toxicities (p=0.41). Kaplan-Meier estimates of iDFS at 36 months were 79% in the nelipepimut-S arm and 92% in the placebo arm (log rank, p=0.11). DRFS at 36 months was estimated to be 90% in the nelipepimut-S arm and 95% in the placebo arm (log rank, p=0.40). Delayed type hypersensitivity (DTH) response to nelipepimut-S was measured and considered positive if there was more than 5 mm induration after 48 hours. DTH response converted from negative to positive in 11% of patients in the vaccine group versus 5% of patients in the placebo group (p=0.36). In both groups, iDFS at 36 months was 100% for those with a positive DTH response post-inoculation and 88% for those with a negative DTH response post-inoculation (log rank, p=0.29). CONCLUSION: Combination immunotherapy with concurrent nelipepimut-S + GM-CSF and trastuzumab is safe, however there was no difference in iDFS or DRFS among high-risk HER2+ breast cancer patients who received nelipepimut-S + GM-CSF compared to GM-CSF alone. We observed a trend towards improved iDFS in patients with a positive DTH response to nelipepimut-S, though it was not statistically significant. Citation Format: Ankur Tiwari, Guy Clifton, Carmen Calfa, Gheath Alatrash, Jarrod Holmes, Isabelle Bedrosian, George Peoples, Elizabeth A. Mittendorf. Results of a Phase 2 Trial of Combination Immunotherapy with Concurrent Nelipepimut-S + GM-CSF and Trastuzumab in High-risk HER2+ Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-23.

Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy

BackgroundCirculating transforming growth factor-β (TGF-β)-specific T cells that recognize TGF-β-expressing immune regulatory cells have been described in patients with cancer. TGF-β-derived peptide vaccination modulates the tumor microenvironment and has shown...

Abstract P2-20-05: Personalized tumor vaccine can suppress tumor growth and metastasis in the syngeneic mouse breast cancer model

Abstract Objective Immunotherapy using the tumor-specific antigens (TSAs) is a promising strategy in breast cancer. Studies have suggested that the in vivo exposures to certain tumors can induce adaptive anti-tumor immunity in syngeneic tumor models. In this study, we show the efficacy of the tumor lysate vaccine and peptide-based vaccine against tumor neoantigen in suppressing tumor growth and metastasis in 4T1 syngeneic tumor models. Method We used BALB/c mice and its syngeneic tumor cell lines to evaluate the anti-tumor effect induced by the transient exposure to the tumor cells. For tumor vaccines, we synthesized the tumor lysate vaccine by the freeze-thaw method or synthetic peptide against the selected tumor neoantigens identified by exome sequencing. We systemic and local immune remodeling was investigated by using immunohistochemistry, flow cytometry, and single cell RNA sequencing. Results We observed a significant reduction of tumor growth and metastasis in 4T1 syngeneic tumors when the mice were previously exposed to the same cells (pre-exposure group). This anti-tumor effect induced by the exposures to the tumor was cell line-specific. The 4T1 tumor lysate vaccines administered prior to the tumor cell injection also showed significant inhibitory effect on tumor growth and metastasis. T lymphocytes, isolated from the tumor tissues of the 4T1 pre-exposure mice and lysate vaccine-treated mice, showed higher levels of TNF-ɑ and IFN-ɣ when compared to the control those from the control tumors. The lysate vaccine treatment resulted in a substantial remodeling of tumor microenvironment including reduction of myeloid-derived suppressor cells and M2 tumor-associated macrophages. On the other hand, the numbers of M1 tumor-associated macrophages and effector memory CD8+ T cells were increased by the lysate vaccine. While the peptide vaccine showed no inhibitory effect on the primary tumor growth, it also suppressed spontaneous lung metastasis. Finally, we administered lysate tumor vaccine after the tumor establishment to determine the therapeutic effect. The lysate vaccine significantly suppressed the tumor growth and lung metastasis of the syngeneic 4T1 tumors. Conclusion Tumor lysate vaccine can suppress the tumor growth and metastasis in the 4T1 syngeneic mouse models by inducing substantial remodeling of tumor immune microenvironment. Additionally, tumor lysate vaccine can elicit similar anti-tumor immune response when administered after the establishment of the primary tumor suggesting a potential therapeutic value. Citation Format: Hyeong-Gon Moon, Hye Youn Son, Woo Hang Heo, Mingji Quan, SONGBIN LI, Haritonova Valentina, Hamin Jeong, Wonshik Han, Han-Byoel Lee, YUJEONG HER, Ju Hee Kim. Personalized tumor vaccine can suppress tumor growth and metastasis in the syngeneic mouse breast cancer model [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-20-05.

Design and construction of multi epitope- peptide vaccine candidate for rabies virus.

Rabies virus is a zoonotic pathogen that causes lethal encephalitis with a case fatality rate of almost 100% in unvaccinated individuals. The currently available vaccines against rabies are composed of inactivated viral particles that only confer a short-term immune response. It is well-known that the entry of rabies virus into host cells is mediated by a trimeric glycoprotein presents on the surface of viral envelope. As the sole viral surface protein, this trimeric glycoprotein represents a promising molecular target to design new vaccines and neutralizing antibodies against rabies virus. Epitope mapping studies had identified several antigenic sites on the surface of trimeric pre-fusion glycoprotein of rabies virus. Therefore, it is of interest to screen the rabies virus glycoprotein by different web-based immuno-informatics tools to identify potential B-cells and T-cells linear epitopes. Here, we present a construct of peptide vaccine that consists of these predicted linear epitopes of rabies virus glycoprotein together with appropriate linkers and adjuvant. Various online prediction tools, molecular docking and dynamics simulation assume that the vaccine construct may be stable, safe and effective. However, validation of these in-silico results is necessary both in vitro and in vivo setting.

Altered HLA-A2-restricted TP53 epitope induces specific CTL cytotoxicity against hepatocellular carcinoma.

High-frequency mutation of the TP53 tumor suppressor gene is observed in multiple human cancers, which promotes cancer progression. However, the mutated gene-encoded protein may serve as a tumor antigen to elicit tumor-specific immune responses. In this study, we detected widespread expression of shared TP53-Y220C neoantigen in hepatocellular carcinoma with low affinity and low stability of binding to HLA-A0201 molecules. We substituted the amino acid sequences VVPCEPPEV with VLPCEPPEV in the TP53-Y220C neoantigen to yield a TP53-Y220C (L2) neoantigen. This altered neoantigen was found to increase affinity and stability and induce more cytotoxic T lymphocytes (CTLs), indicating improvements in immunogenicity. In vitro assays showed the cytotoxicity of CTLs stimulated by both TP53-Y220C and TP53-Y220C (L2) neoantigens against multiple HLA-A0201-positive cancer cells expressing TP53-Y220C neoantigens; however, the TP53-Y220C (L2) neoantigen showed higher cytotoxicity than the TP53-Y220C neoantigen against cancer cells. More importantly, in vivo assays demonstrated greater inhibition of hepatocellular carcinoma cell proliferation by TP53-Y220C (L2) neoantigen-specific CTLs relative to TP53-Y220C neoantigen in zebrafish and nonobese diabetic/severe combined immune deficiency mouse models. The results of this study demonstrate enhanced immunogenicity of the shared TP53-Y220C (L2) neoantigen, which has the potential as dendritic cells or peptide vaccines for multiple cancers.

Immunogenicity of peptide-based vaccine composed of epitopes from Echinococcus granulosusrEg.P29.

Echinococcus granulosus is one of the main causes of economic loss in the livestock industry because of its food-borne transmission. Cutting off the transmission route is a valid prevention method, and vaccines are the most effective means of controlling and eliminating infectious diseases. However, no human-related vaccine has been yet marketed. As a genetic engineering vaccine, recombinant protein P29 of E. granulosus (rEg.P29) could provide protection against deadly challenges. In this study, we generated peptide vaccines (rEg.P29T , rEg.P29B , and rEg.P29T+B ) based on rEg.P29 and an immunized model was established by subcutaneous immunization. Further evaluation showed that peptide vaccine immunization in mice induced T helper type 1 (Th1)-mediated cellular immune responses, leading to high levels of rEg.P29 or rEg.P29B -specific antibodies. In addition, rEg.P29T+B immunization can induce a higher antibody and cytokine production level than single-epitope vaccines, and immune memory is also longer. Collectively, these results suggest that rEg.P29T+B has the potential to be developed as an efficient subunit vaccine for use in areas where E. granulosus is endemic.

Cancer vaccines based on whole-tumor lysate or neoepitopes with validated HLA binding outperform those with predicted HLA-binding affinity

Antigen selection and prioritization represent crucial determinants of vaccines' efficacy. Here, we compare two personalized dendritic cell-based vaccination strategies using whole-tumor lysate or neoantigens. Data in mouse and in cancer patients demonstrate that peptide vaccines using neoantigens predicted on the sole basis of in silico peptide-major histocompatibility complex (MHC) binding affinity underperform relative to whole-tumor-lysate vaccines. In contrast, effective invitro peptide-MHC binding affinity and peptide immunogenicity significantly improve the prioritization of tumor-rejecting neoepitopes and result in more efficacious vaccines.

Phase I Study of a Multivalent WT1 Peptide Vaccine (Galinpepimut-S) in Combination with Nivolumab in Patients with WT1-Expressing Ovarian Cancer in Second or Third Remission.

We examined the safety and immunogenicity of sequential administration of a tetravalent, non-HLA (human leukocyte antigen) restricted, heteroclitic Wilms' Tumor 1 (WT1) peptide vaccine (galinpepimut-S) with anti-PD-1 (programmed cell death protein 1) nivolumab. This open-label, non-randomized phase I study enrolled patients with WT1-expressing ovarian cancer in second or third remission from June 2016 to July 2017. Therapy included six (every two weeks) subcutaneous inoculations of galinpepimut-S vaccine adjuvanted with Montanide, low-dose subcutaneous sargramostim at the injection site, with intravenous nivolumab over 12 weeks, and up to six additional doses until disease progression or toxicity. One-year progression-free survival (PFS) was correlated to T-cell responses and WT1-specific immunoglobulin (Ig)G levels. Eleven patients were enrolled; seven experienced a grade 1 adverse event, and one experienced a grade ≥3 adverse event considered a dose-limiting toxicity. Ten (91%) of eleven patients had T-cell responses to WT1 peptides. Seven (88%) of eight evaluable patients had IgG against WT1 antigen and full-length protein. In evaluable patients who received >2 treatments of galinpepimut-S and nivolumab, the 1-year PFS rate was 70%. Coadministration of galinpepimut-S and nivolumab demonstrated a tolerable toxicity profile and induced immune responses, as indicated by immunophenotyping and WT1-specific IgG production. Exploratory analysis for efficacy yielded a promising 1-year PFS rate.