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Vaccine Oct 2010Development of a fully effective vaccine against the pre-erythrocytic stage of malaria infection will likely require induction of both humoral and cellular immune...
Poly(I:C) is an effective adjuvant for antibody and multi-functional CD4+ T cell responses to Plasmodium falciparum circumsporozoite protein (CSP) and αDEC-CSP in non human primates.
Development of a fully effective vaccine against the pre-erythrocytic stage of malaria infection will likely require induction of both humoral and cellular immune responses. Protein based vaccines can elicit such broad-based immunity depending on the adjuvant and how the protein is formulated. Here to assess these variables, non human primates (NHP) were immunized three times with Plasmodium falciparum (Pf) circumsporozoite protein (CSP) or CSP cloned into MG38, a monoclonal antibody that targets DEC-205 (αDEC-CSP), an endocytic receptor on dendritic cells (DCs). Both vaccines were administered with or without poly(I:C) as adjuvant. Following three immunizations, the magnitude and quality of cytokine secreting CD4+ T cells were comparable between CSP+poly(I:C) and αDEC-CSP+poly(I:C) groups with both regimens eliciting multi-functional cytokine responses. However, NHP immunized with CSP+poly(I:C) had significantly higher serum titers of CSP-specific IgG antibodies and indirect immunofluorescent antibody (IFA) titers against Pf sporozoites. Furthermore, sera from both CSP or αDEC-CSP+poly(I:C) immunized animals limited sporozoite invasion of a hepatocyte cell line (HC04) in vitro. To determine whether CSP-specific responses could be enhanced, all NHP primed with CSP or αDEC-CSP+poly(I:C) were boosted with a single dose of 150,000 irradiated Pf sporozoites (PfSPZ) intravenously. Remarkably, boosting had no effect on the CSP-specific immunity. Finally, immunization with CSP+poly-ICLC reduced malaria parasite burden in the liver in an experimental mouse model. Taken together, these data showing that poly(I:C) is an effective adjuvant for inducing potent antibody and Th1 immunity with CSP based vaccines offers a potential alternative to the existing protein based pre-erythrocytic vaccines.
Topics: Adjuvants, Immunologic; Animals; Antibodies, Protozoan; CD4-Positive T-Lymphocytes; Cell Line; Disease Models, Animal; Female; Interferon-gamma; Macaca mulatta; Malaria Vaccines; Malaria, Falciparum; Mice; Mice, Inbred C57BL; Plasmodium falciparum; Poly I-C; Protozoan Proteins; Recombinant Proteins; Sporozoites
PubMed: 20846528
DOI: 10.1016/j.vaccine.2010.08.098 -
Infection and Immunity Nov 1981Two series of interferon-inducing complexes containing polyriboinosinic and polyribocytidylic acids, poly-L-lysine, and carboxymethyl cellulose were prepared. One series...
Two series of interferon-inducing complexes containing polyriboinosinic and polyribocytidylic acids, poly-L-lysine, and carboxymethyl cellulose were prepared. One series contained carboxymethyl cellulose, 27,000-molecular-weight poly-L-lysine, and either 4S, 6S, or 9S polyriboinosinic and polyribocytidylic acids. The other series contained carboxymethyl cellulose, 9S polyriboinosinic and polyribocytidylic acids, and poly-L-lysine, whose molecular weights ranged from 2,000 to 27,000. The homogeneity of these double-stranded polynucleotide complexes was confirmed by single-step thermal denaturation profiles and by single peaks in sucrose gradient velocity sedimentation. The complexes have a greater resistance to hydrolysis by ribonuclease than does polyriboinosinic-polyribocytidylic acid. The resistance to ribonuclease increased with the increasing size of polynucleotide homopolymers and poly-L-lysine. In monkeys and, to a lesser extent, in mice, serum interferon levels induced by the different complexes were related to the degree of resistance of the complexes to hydrolysis by ribonuclease. In mice, 4S, 6S, and 9S complexes of polyriboinosinic-polyribocytidylic acid, poly-L-lysine, and carboxymethyl cellulose had a higher level of toxicity than did polyriboinosinic-polyribocytidylic acid as measured by 50% lethal dose. The toxicity was parallel to the ribonuclease resistance of the complexes. It was concluded that an increase in the size of the polynucleotides and the polyamino acids in these complexes leads to higher resistance to hydrolysis by ribonuclease and to greater interferon responses in mice and rhesus monkeys.
Topics: Animals; Carboxymethylcellulose Sodium; Centrifugation, Density Gradient; Female; Interferons; Macaca mulatta; Male; Methylcellulose; Mice; Molecular Weight; Peptides; Poly I-C; Polylysine; Ribonucleases; Temperature
PubMed: 6171519
DOI: 10.1128/iai.34.2.416-421.1981 -
Experimental Hematology & Oncology 2018The optimal strategy for vaccination to induce CD8 T cell responses against WT1 is not known.
BACKGROUND
The optimal strategy for vaccination to induce CD8 T cell responses against WT1 is not known.
METHODS
A pilot randomized study in HLA-A02 patients to receive vaccination with WT1 in Montanide or in poly ICLC, a TLR3 agonist, to explore the novel immune adjuvant was conducted. Seven patients were randomized. Four patients received WT1 in Montanide, and three with WT1 in poly ICLC. Five patients were in morphologic remission and two had residual morphologic disease at the study entry.
RESULTS
All patients finished the induction phase without any major toxicity except mild transient local injection reaction. One patient on the Montanide arm developed aseptic ulceration at two vaccine sites which healed without antibiotics. Three of 4 patients on the Montanide arm had a decreased expression of WT1 after WT1 vaccination, and two of them demonstrated generation of WT1-specific cytotoxic CD8 T cell responses with biased TCR beta chain enrichment. In contrast, no obvious WT1-specific immune responses were detected in two patients on the poly ICLC arm, nor was there clonal enrichment by TCR alpha/beta sequencing; however, these patients did also have decreased WT1 expression and remained in remission several years after the initiation of treatment.
CONCLUSIONS
WT1 peptide vaccine with Montanide as an adjuvant induces detectable WT1-specific CD8 T cell responses with clonal TCR enrichment, which may be capable of controlling leukemia recurrence in the setting of minimal residual disease. Poly ICLC may induce anti-leukemic activity in the absence of detectable WT1 specific CD8 T cell responses. NCT01842139, 7/3/2012 retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT01842139.
PubMed: 29344432
DOI: 10.1186/s40164-018-0093-x -
Journal For Immunotherapy of Cancer Jun 2020In vivo targeting of human papillomavirus (HPV) derived antigens to dendritic cells might constitute an efficient immunotherapeutic strategy against cervical cancer. In...
BACKGROUND
In vivo targeting of human papillomavirus (HPV) derived antigens to dendritic cells might constitute an efficient immunotherapeutic strategy against cervical cancer. In previous works, we have shown that the extra domain A from murine fibronectin (mEDA) can be used to target antigens to toll-like receptor 4 (TLR4) expressing dendritic cells and induce strong antigen-specific immune responses. In the present study, we have produced a bivalent therapeutic vaccine candidate consisting of the human EDA (hEDA) fused to E7 proteins from HPV16 and HPV18 (hEDA-HPVE7-16/18) and evaluate its potential as a therapeutic vaccine against cervical cancer.
MATERIALS AND METHODS
Recombinant fusion proteins containing HPV E7 proteins from HPV16 and HPV18 virus subtypes fused to hEDA were produced and tested in vitro on their capacity to bind TLR4 and induce the production of tumor necrosis factor-α or interleukin (IL)-12 by human monocytes and dendritic cells. The immunogenicity and potential therapeutic activity of the vaccine in combination with cisplatin or with the TLR3 agonist molecules polyinosinic-polycytidylic acid (Poly IC) or Poly ICLC was evaluated in mice bearing subcutaneous or genital orthotopic HPV16 TC-1 tumors.
RESULTS
hEDA-HPVE7-16/18 prototype vaccine binds human TLR4 and stimulate TLR4-dependent signaling pathways and IL-12 production by human monocyte-derived dendritic cell. Vaccination with hEDA-HPVE7-16/18 induced strong HPVE7-specific Cytotoxic T lymphocyte (CTL) responses and eliminated established tumors in the TC-1-based tumor model. The antitumor efficacy was significantly improved by combining the fusion protein with cisplatin or with the TLR-3 ligand Poly IC and especially with the stabilized analog Poly ICLC. Moreover, hEDA-HPVE7-16/18+Poly ICLC induced full tumor regression in 100% of mice bearing orthotopic genital HPV tumors.
CONCLUSION
Our results suggest that this therapeutic vaccine formulation may be an effective treatment for cervical tumors that do not respond to current therapies.
Topics: Animals; Cancer Vaccines; DNA-Binding Proteins; Dendritic Cells; Female; Fibronectins; Human papillomavirus 16; Human papillomavirus 18; Humans; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Oncogene Proteins, Viral; Papillomavirus E7 Proteins; Papillomavirus Infections; T-Lymphocytes, Cytotoxic
PubMed: 32581060
DOI: 10.1136/jitc-2020-000704 -
Neurologia Medico-chirurgica Nov 1983
Topics: Adjuvants, Immunologic; Animals; Brain Neoplasms; Carboxymethylcellulose Sodium; Glioma; Interferon Inducers; Methylcellulose; Methylcholanthrene; Mice; Mice, Inbred C57BL; Peptides; Poly I-C; Polylysine; Propionibacterium acnes
PubMed: 6201759
DOI: 10.2176/nmc.23.841 -
Cancers Apr 2019Immunotherapy, including therapeutic vaccines, is increasingly being developed for patients with high-grade glioma, and combinations of immunotherapies and synergy with...
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, = 0.50) nor in median OS (7.8 vs. 10.0 months for vaccinated and control patients, respectively, = 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.
PubMed: 30986995
DOI: 10.3390/cancers11040464 -
Cancer Immunology, Immunotherapy : CII Jul 2018Cytotoxic T lymphocytes (CTLs) are effective components of the immune system capable of destroying tumor cells. Generation of CTLs using peptide vaccines is a practical...
Cytotoxic T lymphocytes (CTLs) are effective components of the immune system capable of destroying tumor cells. Generation of CTLs using peptide vaccines is a practical approach to treat cancer. We have previously described a peptide vaccination strategy that generates vast numbers of endogenous tumor-reactive CTLs after two sequential immunizations (prime-boost) using poly-ICLC adjuvant, which stimulates endosomal toll-like receptor 3 (TLR3) and cytoplasmic melanoma differentiation antigen 5 (MDA5). Dendritic cells (DCs) play an important role not only in antigen presentation but are critical in generating costimulatory cytokines that promote CTL expansion. Poly-ICLC was shown to be more effective than poly-IC in generating type-I interferon (IFN-I) in various DC subsets, through its enhanced ability to escape the endosomal compartment and stimulate MDA5. In our system, IFN-I did not directly function as a T cell costimulatory cytokine, but enhanced CTL expansion through the induction of IL15. With palmitoylated peptide vaccines, CD8α+ DCs were essential for peptide crosspresentation. For vaccine boosts, non-professional antigen-presenting cells were able to present minimal epitope peptides, but DCs were still required for CTL expansions through the production of IFN-I mediated by poly-ICLC. Overall, these results clarify the roles of DCs, TLR3, MDA5, IFN-I and IL15 in the generation of vast and effective antitumor CTL responses using peptide and poly-IC vaccines.
Topics: Animals; Cancer Vaccines; Carboxymethylcellulose Sodium; Dendritic Cells; Interferon Inducers; Interferon Type I; Interferon-Induced Helicase, IFIH1; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Knockout; Poly I-C; Polylysine; T-Lymphocytes, Cytotoxic; Toll-Like Receptor 3; Tumor Cells, Cultured; Vaccination; Vaccines, Subunit
PubMed: 29696308
DOI: 10.1007/s00262-018-2164-6 -
Journal of Virology Aug 2005Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) cause a similar spectrum of respiratory infections in humans. Classified within the Paramyxoviridae...
Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) cause a similar spectrum of respiratory infections in humans. Classified within the Paramyxoviridae family, Pneumovirinae subfamily, RSV and hMPV present a significant degree of divergence in genome constellation, organization, and protein sequences. RSV has been reported to be a poor inducer of alpha/beta interferons (IFN-alpha/beta) and partially resistant to its antiviral activity. The nature of the innate immune response to hMPV is currently unknown. Herein, an experimental mouse model was used to investigate the interplay between RSV and hMPV infections and IFN-alpha in the airways. RSV-infected BALB/c mice treated intranasally with either poly-ICLC, a potent inducer of IFN-alpha, or directly with recombinant IFN-alpha showed significantly reduced lung viral titers, inflammation, and clinical disease than untreated controls. However, RSV was significantly less sensitive to the antiviral activity of IFN-alpha than hMPV. Similarly, when the ability to directly induce IFN-alpha production was assessed, RSV was clearly a weaker inducer of IFN-alpha than hMPV, as shown by both kinetics and the absolute amount of IFN-alpha secreted into the bronchoalveolar lavage. To further investigate the putative inhibitory effect of these viruses on IFN-alpha production, mice were infected for 48 h prior to treatment with poly-ICLC or a specific Toll-like receptor 9 ligand, CpG oligodeoxynucleotides. Strikingly, both poly-ICLC- and CpG-mediated IFN-alpha production was abrogated by either RSV or MPV infection. These results suggest that a complex interplay between virus-specific and host-mediated responses regulates IFN-alpha in the lung during infection by members of the Pneumovirinae family.
Topics: Animals; Antiviral Agents; Carboxymethylcellulose Sodium; Female; Interferon-alpha; Interferon-beta; Lung; Metapneumovirus; Mice; Mice, Inbred BALB C; Paramyxoviridae Infections; Poly I-C; Polylysine; Respiratory Syncytial Virus Infections; Virus Replication
PubMed: 16051812
DOI: 10.1128/JVI.79.16.10190-10199.2005 -
Clinical Cancer Research : An Official... Jan 2015WHO grade 2 low-grade gliomas (LGG) with high risk factors for recurrence are mostly lethal despite current treatments. We conducted a phase I study to evaluate the... (Clinical Trial)
Clinical Trial
PURPOSE
WHO grade 2 low-grade gliomas (LGG) with high risk factors for recurrence are mostly lethal despite current treatments. We conducted a phase I study to evaluate the safety and immunogenicity of subcutaneous vaccinations with synthetic peptides for glioma-associated antigen (GAA) epitopes in HLA-A2(+) adults with high-risk LGGs in the following three cohorts: (i) patients without prior progression, chemotherapy, or radiotherapy (RT); (ii) patients without prior progression or chemotherapy but with prior RT; and (iii) recurrent patients.
EXPERIMENTAL DESIGN
GAAs were IL13Rα2, EphA2, WT1, and Survivin. Synthetic peptides were emulsified in Montanide-ISA-51 and given every 3 weeks for eight courses with intramuscular injections of poly-ICLC, followed by q12 week booster vaccines.
RESULTS
Cohorts 1, 2, and 3 enrolled 12, 1, and 10 patients, respectively. No regimen-limiting toxicity was encountered except for one case with grade 3 fever, fatigue, and mood disturbance (cohort 1). ELISPOT assays demonstrated robust IFNγ responses against at least three of the four GAA epitopes in 10 and 4 cases of cohorts 1 and 3, respectively. Cohort 1 patients demonstrated significantly higher IFNγ responses than cohort 3 patients. Median progression-free survival (PFS) periods since the first vaccine are 17 months in cohort 1 (range, 10-47+) and 12 months in cohort 3 (range, 3-41+). The only patient with large astrocytoma in cohort 2 has been progression-free for more than 67 months since diagnosis.
CONCLUSION
The current regimen is well tolerated and induces robust GAA-specific responses in WHO grade 2 glioma patients. These results warrant further evaluations of this approach. Clin Cancer Res; 21(2); 286-94. ©2014 AACR.
Topics: Adult; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; CD8-Positive T-Lymphocytes; Cancer Vaccines; Carboxymethylcellulose Sodium; Disease-Free Survival; Female; Glioma; Humans; Male; Middle Aged; Neoplasm Grading; Pilot Projects; Poly I-C; Polylysine; Treatment Outcome; Vaccines, Subunit
PubMed: 25424847
DOI: 10.1158/1078-0432.CCR-14-1790 -
Antimicrobial Agents and Chemotherapy Mar 1982Polyriboinosinic-polyribocytidylic acid complexed with poly-l-lysine and carboxymethylcellulose [poly(ICLC)] is a potent interferon inducer when given parenterally to... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Polyriboinosinic-polyribocytidylic acid complexed with poly-l-lysine and carboxymethylcellulose [poly(ICLC)] is a potent interferon inducer when given parenterally to humans. Topical application in animal models has shown beneficial antiviral and clinical effects. In a randomized, double-blinded, placebo-controlled trial of topical poly(ICLC) in recurrent genital herpes simplex virus infection, five clinical and two virological parameters were followed. Fifty-seven men and women, with 78 recurrences of genital herpes, were stratified by sex. No clinical or antiviral differences between poly(ICLC) and placebo groups in either stratum were found. Further analysis of male subgroups by age and size of lesions showed no changes in the rapidity of healing or viral shedding.
Topics: Administration, Topical; Adult; Carboxymethylcellulose Sodium; Clinical Trials as Topic; Double-Blind Method; Female; Herpes Genitalis; Humans; Male; Methylcellulose; Peptides; Poly I-C; Polylysine; Recurrence
PubMed: 7049075
DOI: 10.1128/AAC.21.3.481