scholarly journals Nanovaccine impact on dendritic cells: transcriptome analysis enables new insights into antigen and adjuvant effects

Nanomedicine ◽  
2020 ◽  
Vol 15 (21) ◽  
pp. 2053-2069
Author(s):  
David Paßlick ◽  
Jonas Reinholz ◽  
Johanna Simon ◽  
Keti Piradashvili ◽  
Shuai Jiang ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Transcriptome Analysis ◽  
Soluble Form ◽  
Antitumor Effects ◽  
Form Versus ◽  
Interferon Stimulated Genes ◽  
Effective Immune Response ◽  
Adjuvant Effects ◽  
Proteome Expression

Aim: For vaccines the combination between an antigen and adjuvants are both crucially important to trigger an effective immune response in dendritic cells. Innovative adjuvants like resiquimod or muramyldipeptide have their target protein inside the cell. Materials & methods: Up/downregulation and proteome expression was investigated for the adjuvant combination resiquimod and muramyldipeptide in a soluble form versus encapsulated into a nanocarrier. Results: We found that 1225 genes were upregulated after nanocarrier treatment while 478 genes were downregulated. Most prominent were interferon-stimulated genes with more than 25-times higher expression after nanocarrier treatment, for example RSAD2 and ISG15, which were recently found to have antiviral or antitumor effects. Conclusion: Encapsulation gives a more effective upregulation of vaccine-related genes.

A Novel Non-Cleavable Cell Surface Mutant of CD40-Ligand Induces Anti-Leukemic Immune Response and Prevent Systemic Inflammatory Reaction.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3174-3174
Author(s):  
Kazunori Kato ◽  
Yukari Masuta ◽  
Kei Tomihara ◽  
Katsunori Sasaki ◽  
Hirofumi Hamada
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Dendritic Cells ◽  
Tumor Cells ◽  
Side Effect ◽  
Mononuclear Cells ◽  
Cd40 Ligand ◽  
Soluble Form ◽  
Human Leukemia ◽  
Toxic Molecule

Abstract CD40-ligand (CD40L), a member of the TNF family, is expressed transiently on activated CD4-positive T cells and mediates cognate interaction between T cell and antigen-presenting cell (APC) such as dendritic cells. We and other investigators have reported previously that transduction of human leukemia cells with adenovirus encoding full-length CD40-ligand resulted in upregulation of immune costimulatory molecules, enhance APC activity and generation of CTL to leukemia B cells. However, CD40L is cleaved to a soluble form (sCD40L) by metalloproteases and high levels of sCD40L may contribute to the systemic inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis, suggesting a potentially deleterious side effect of CD40L gene therapy. In this study we generated a non-cleavable mutant of CD40L to develop a potentially less toxic molecule for CD40L gene therapy. Four mutants of human CD40L (termed CD40Lm1, m2, m3 and m4) with point mutation of amino acids from E112 to P120 (suggested cleavage site) were created by RT-PCR and cloned into retrovirus and adenovirus vectors. These four mutants of CD40L were transduced into tumor cells and assessed sCD40L production by ELISA, demonstrating that all four mutants resulted in a fully non-cleavable mutant of CD40L. We also confirmed that CD40L mutants could stimulate CD40-positive B and dendritic cells and induce phenotypic alterations and IL-12 production. In order to examine systemic side effect of CD40L, we transplanted tumor cells expressing wild-type (CD40Lwt) or non-cleavable mutant of CD40L (CD40Lm3) in nude mice and have observed for one month period. Two weeks after transplantation, mice with tumors expressing CD40Lwt exhibited arthritis, systemic edema and slight diarrhea, but CD40Lm3 did not induce any systemic inflammatory effect. We also found increased plasma levels of sCD40L (>800 pg/ml) in mice transplanted with CD40Lwt transfectant but not in CD40Lm3 transplanted mice. Additionally, mice with CD40Lwt resulted in increased number of infiltrating mononuclear cells in the liver and kidney, whereas no inflammatory cells were observed in the liver of mice with CD40Lm3. Overall, non-cleavable mutant of CD40L is fully capable of inducing immune response with less toxic molecule and useful tool for CD40L gene therapy of leukemia and lymphoma.

A phase I, open label, dose escalation and cohort expansion study to evaluate the safety and immune response to autologous dendritic cells (DC) transduced with AdGMCA9 (DC-AdGMCAIX) in patients with mRCC.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 490-490 ◽  
Author(s):  
Fairooz F. Kabbinavar ◽  
Nazy Zomorodian ◽  
Arie S. Belldegrun ◽  
Steven G. Wong ◽  
Adrian Bot ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Dose Escalation ◽  
Clear Cell ◽  
Fusion Gene ◽  
Recombinant Adenovirus ◽  
Ex Vivo ◽  
Open Label ◽  
Antitumor Effects ◽  
Expansion Cohort

490 Background: Carbonic anhydrase IX (CAIX) is an attractive target for the development of a RCC specific vaccine. We developed a fusion gene construct, GM-CSF + CAIX, transduced by a replication deficient adenovirus into autologous dendritic cells (DC) that are injected in patients with mRCC. This is a ph1 study of cancer vaccine against CAIX gene expressed on RCC tumors. Methods: A recombinant adenovirus encoding the GMCSF-CAIX fusion gene (AdGMCAIX) was produced per GMP in collaboration with the NCI RAID program. The final product is produced in an in-house GMP cell processing facility using DCs cultured ex vivo from patients’ PBMC's and engineered with AdGMCAIX prior to intradermal injection. The transduced DCs are expected to stimulate an antigen specific immune response against CAIX expressing RCC, leading to a potential anti-tumor effect. Dose escalation in 3 dose cohorts (5 X 106, 15 X 106, and 50 X 106 cells/administration) follows the std 3+3 ph1 design with an expansion cohort. DC-AdGMCAIX is given intradermally Q 2 weeks X 3 doses. The primary aim is safety of DC-AdGMCAIX injections. Secondary aims are to evaluate immune responses & the antitumor effects per RECIST 1.1. Pts with clear cell mRCC with ECOG 0-1 & measurable disease & adequate organ function were enrolled. Results: Six pts with clear cell mRCC are enrolled. Four pts received all 3 planned vaccine doses and the fifth pt only the 1st dose. No SAE’s were seen to date. One pt had chills that lasted several minutes and transient Gr1 leucopenia. One pt has worsening of pre-existing proteinuria, though unclear if related to the vaccine. One pt has PD & the other two have SD on D85 scans. Tumor bx shows intra-tumoral infiltration by T cells. Conclusions: These early data show that autologous DC transduced by Ad-GMCAIX vector can be safely given to mRCC patients without any acute SAE’s noted at the doses tested so far. The study will complete its 3rd cohort & expansion cohort enrollment. This data support the further development of Ad-GMCAIX vaccine strategies either alone or in combination with approved therapies. Funding: Supported by NCI RAID Initiative NSC 740833 and Kite Pharma.

A phase I, open-label, dose-escalation and cohort expansion study evaluating the safety and immune response to autologous dendritic cells transduced with AdGMCA9 in patients with metastatic renal cell carcinoma.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 653-653
Author(s):  
Izak Faiena ◽  
Nazy Zomorodian ◽  
Begonya Comin-Anduix ◽  
Ankush Sachadeva ◽  
Adrian Bot ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Clear Cell ◽  
Fusion Gene ◽  
Recombinant Adenovirus ◽  
Antitumor Effects ◽  
Gm Csf

653 Background: We developed a fusion gene construct, GM-CSF + CAIX, transduced by a replication deficient adenovirus into autologous dendritic cells (DC) that are injected in patients with metastatic RCC (mRCC) in this phase 1 study targeting CAIX overexpressed on RCC tumors. Methods: A recombinant adenovirus encoding the GMCSF-CAIX fusion gene (AdGMCAIX) manufactured per GMP in collaboration with the NCI Rapid Access to Intervention Development (RAID) program. The final product was produced using DCs produced ex-vivo from patients’ peripheral blood mononuclear cells (PBMC), by culturing with GM-CSF & IL-4, then engineered with AdGMCAIX prior to intradermal injection. The injected transduced DCs were expected to stimulate an antigen specific immune response against CAIX expressing RCC. Three dose escalation cohorts (5, 15, and 50 X 106 cells/administration) were injected based on 3+3 design. DC-AdGMCAIX was given intradermally q2wkX3 doses. The primary aim is safety. Secondary aims are to evaluate immune responses & antitumor effects per RECIST 1.1. Eligibility criteria included patients with clear cell mRCC with ECOG 0-1, measurable disease, and adequate organ function. Results: Fifteen patients with clear cell mRCC were enrolled. Nine patients received all 3 planned vaccine doses, comprising DC expressing CAIX, CD11c and other relevant markers. No serious adverse events (SAEs) were seen. Grade 1/2 AEs include fatigue (3/1), leukopenia (1/1) and flu-like symptoms (0/1). Of the 9 patients who received treatment, 1 expired of progressive disease (PD), 2 patients were lost to follow-up and 6 patients are alive. Of the 6 patients, 5 have PD and are currently receiving standard-of-care therapies, and 1 has completed treatment with stable disease at 6 mon follow up and is being evaluated for retreatment. Conclusions: These early data show that autologous DC transduced by Ad-GMCAIX vector can be safely given to mRCC patients without any SAEs noted at the doses tested. These data support further development of Ad-GMCAIX vaccine strategies, either alone, or in combination with approved therapies. Clinical trial information: NCT01826877.

scholarly journals Immunotherapy Using Oxygenated Water and Tumor-Derived Exosomes Potentiates Antitumor Immune Response and Attenuates Malignancy Tendency in Mice Model of Breast Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Nafiseh Pakravan ◽  
Ardeshir Abbasi ◽  
Zuhair Mohammad Hassan
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Tumor Size ◽  
Tumor Antigens ◽  
The Body ◽  
Mice Model ◽  
Antitumor Effects ◽  
Female Population ◽  
Effective Immune Response ◽  
Oxygenated Water

Breast cancer is one of the most common type of tumor and the leading cause of death in the world’s female population. Various therapeutic approaches have been used to treat tumors but have not led to complete recovery and have even damaged normal cells in the body. Moreover, metastatic tumors such as breast cancer are much more resistant to treatment, and current treatments have not been very successful in treating them and remain a challenge. Therefore, new approaches should be applied to overcome this problem. Given the importance of hypoxia in tumor survival, we aimed to test the antitumor effects of oxygenated water to decrease hypoxia along with tumor-derived exosomes to target tumor. The purpose of administering oxygenated water and tumor exosomes was to reduce hypoxia and establish an effective immune response against tumor antigens, respectively. For this purpose, the breast cancer mice model was induced using the 4T1 cell line in Balb/c mice and treated with oxygenated water via an intratumoral (IT) and/or intraperitoneal (IP) route and/or exosome (TEX). Oxygenation via the IT+IP route was more efficient than oxygenation via the IT or IP route. The efficiency of oxygenation via the two routes along with TEX led to the best therapeutic outcome. Antitumor immune responses directed by TEX became optimized when systemic (IP) and local (IT) oxygenation was applied compared to administration of TEX alone. Results demonstrated a significant reduction in tumor size and the highest levels of IFN-γ and IL-17 and the lowest levels of IL-4 FoxP3, HIF-1α, VEGF, MMP-2, and MMP-9 in the IT+IP+TEX-treated group. Oxygenated water on the one hand could reduce tumor size, hypoxia, angiogenesis, and metastasis in the tumor microenvironment and on the other hand increases the effective immune response against the tumor systemically. This therapeutic approach is proposed as a new strategy for devising vaccines in a personalized approach.

scholarly journals A New Bioassay Platform Design for the Discovery of Small Molecules with Anticancer Immunotherapeutic Activity

Marine Drugs ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. 604
Author(s):  
Carmela Gallo ◽  
Giusi Barra ◽  
Marisa Saponaro ◽  
Emiliano Manzo ◽  
Laura Fioretto ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Small Molecules ◽  
Adaptive Immune Response ◽  
Human Monocyte ◽  
Antitumor Effects ◽  
Immature Mouse ◽  
New Bioassay ◽  
Selection Of

Immunotherapy takes advantage of the immune system to prevent, control, and eliminate neoplastic cells. The research in the field has already led to major breakthroughs to treat cancer. In this work, we describe a platform that integrates in vitro bioassays to test the immune response and direct antitumor effects for the preclinical discovery of anticancer candidates. The platform relies on the use of dendritic cells that are professional antigen-presenting cells (APC) able to activate T cells and trigger a primary adaptive immune response. The experimental procedure is based on two phenotypic assays for the selection of chemical leads by both a panel of nine tumor cell lines and growth factor-dependent immature mouse dendritic cells (D1). The positive hits are then validated by a secondary test on human monocyte-derived dendritic cells (MoDCs). The aim of this approach is the selection of potential immunotherapeutic small molecules from natural extracts or chemical libraries.

The Inducing Roles of the New Isolated Bursal Hexapeptide and Pentapeptide on the Immune Response of AIV Vaccine in Mice

2019 ◽  
Vol 26 (7) ◽  
pp. 542-549 ◽  
Author(s):  
Shan Shan Hao ◽  
Man Man Zong ◽  
Ze Zhang ◽  
Jia Xi Cai ◽  
Yang Zheng ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Amino Acid ◽  
T Cell ◽  
Antigen Presentation ◽  
Amino Acid Sequences ◽  
Cell Subpopulation ◽  
Igg Antibody ◽  
Antibody Titers ◽  
Specific Igg

Background: Bursa of Fabricius is the acknowledged central humoral immune organ. The bursal-derived peptides play the important roles on the immature B cell development and antibody production. Objective: Here we explored the functions of the new isolated bursal hexapeptide and pentapeptide on the humoral, cellular immune response and antigen presentation to Avian Influenza Virus (AIV) vaccine in mice immunization. Methods: The bursa extract samples were purified following RP HPLC method, and were analyzed with MS/MS to identify the amino acid sequences. Mice were twice subcutaneously injected with AIV inactivated vaccine plus with two new isolated bursal peptides at three dosages, respectively. On two weeks after the second immunization, sera samples were collected from the immunized mice to measure AIV-specific IgG antibody levels and HI antibody titers. Also, on 7th day after the second immunization, lymphocytes were isolated from the immunized mice to detect T cell subtype and lymphocyte viabilities, and the expressions of co-stimulatory molecule on dendritic cells in the immunized mice. Results: Two new bursal hexapeptide and pentapeptide with amino acid sequences KGNRVY and MPPTH were isolated, respectively. Our investigation proved the strong regulatory roles of bursal hexapeptide on AIV-specific IgG levels and HI antibody titers, and lymphocyte viabilities, and the significant increased T cells subpopulation and expressions of MHCII molecule on dendritic cells in the immunized mice. Moreover, our findings verified the significantly enhanced AIV-specific IgG antibody and HI titers, and the strong increased T cell subpopulation and expressions of CD40 molecule on dendritic cells in the mice immunized with AIV vaccine and bursal pentapeptide. Conclusion: We isolated and identified two new hexapeptide and pentapeptide from bursa, and proved that these two bursal peptides effectively induced the AIV-specific antibody, T cell and antigen presentation immune responses, which provided an experimental basis for the further clinical application of the bursal derived active peptide on the vaccine improvement.

scholarly journals Tumor cytotoxicity and immunogenicity of a novel V-jet neon plasma source compared to the kINPen

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lea Miebach ◽  
Eric Freund ◽  
Stefan Horn ◽  
Felix Niessner ◽  
Sanjeev Kumar Sagwal ◽  
...  
Keyword(s):  
Cell Death ◽  
Dendritic Cells ◽  
Cancer Cells ◽  
Treatment Time ◽  
Plasma Source ◽  
In Vivo Model ◽  
Antitumor Effects ◽  
Plasma Device

AbstractRecent research indicated the potential of cold physical plasma in cancer therapy. The plethora of plasma-derived reactive oxygen and nitrogen species (ROS/RNS) mediate diverse antitumor effects after eliciting oxidative stress in cancer cells. We aimed at exploiting this principle using a newly designed dual-jet neon plasma source (Vjet) to treat colorectal cancer cells. A treatment time-dependent ROS/RNS generation induced oxidation, growth retardation, and cell death within 3D tumor spheroids were found. In TUM-CAM, a semi in vivo model, the Vjet markedly reduced vascularized tumors' growth, but an increase of tumor cell immunogenicity or uptake by dendritic cells was not observed. By comparison, the argon-driven single jet kINPen, known to mediate anticancer effects in vitro, in vivo, and in patients, generated less ROS/RNS and terminal cell death in spheroids. In the TUM-CAM model, however, the kINPen was equivalently effective and induced a stronger expression of immunogenic cancer cell death (ICD) markers, leading to increased phagocytosis of kINPen but not Vjet plasma-treated tumor cells by dendritic cells. Moreover, the Vjet was characterized according to the requirements of the DIN-SPEC 91315. Our results highlight the plasma device-specific action on cancer cells for evaluating optimal discharges for plasma cancer treatment.

scholarly journals Innate cell profiles during the acute and convalescent phase of SARS-CoV-2 infection in children

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Melanie R. Neeland ◽  
Samantha Bannister ◽  
Vanessa Clifford ◽  
Kate Dohle ◽  
Kim Mulholland ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Acute Phase ◽  
Innate Immune ◽  
Low Density ◽  
Innate Immune Responses ◽  
Immunological Mechanisms ◽  
Activated Neutrophils ◽  
Classical Monocytes

AbstractChildren have mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed disease (COVID-19) compared to adults and the immunological mechanisms underlying this difference remain unclear. Here, we report acute and convalescent innate immune responses in 48 children and 70 adults infected with, or exposed to, SARS-CoV-2. We find clinically mild SARS-CoV-2 infection in children is characterised by reduced circulating subsets of monocytes (classical, intermediate, non-classical), dendritic cells and natural killer cells during the acute phase. In contrast, SARS-CoV-2-infected adults show reduced proportions of non-classical monocytes only. We also observe increased proportions of CD63+ activated neutrophils during the acute phase to SARS-CoV-2 in infected children. Children and adults exposed to SARS-CoV-2 but negative on PCR testing display increased proportions of low-density neutrophils that we observe up to 7 weeks post exposure. This study characterises the innate immune response during SARS-CoV-2 infection and household exposure in children.

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