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Journal of Internal Medicine Feb 2012Current vaccines primarily work by inducing protective antibodies. However, in many infections like HIV, malaria and tuberculosis as well as cancers, there remains a... (Review)
Review
Current vaccines primarily work by inducing protective antibodies. However, in many infections like HIV, malaria and tuberculosis as well as cancers, there remains a need for durable and protective T-cell immunity. Here, we summarize our efforts to develop a safe T-cell-based protein vaccine that exploits the pivotal role of dendritic cells (DC) in initiating adaptive immunity. Focusing on HIV, gag-p24 protein antigen is introduced into a monoclonal antibody (mAb) that efficiently and specifically targets the DEC-205 antigen uptake receptor on DC. When administered together with synthetic double-stranded RNA, polyriboinosinic:polyribocytidylic acid (poly IC) or its analogue poly IC stabilized with carboxymethylcellulose and poly-L-lysine (poly ICLC), as adjuvant, HIV gag-p24 within anti-DEC-205 mAb is highly immunogenic in mice, rhesus macaques, and in ongoing research, healthy human volunteers. Human subjects form both T- and B-cell responses to DC-targeted protein. Thus, DC-targeted protein vaccines are a potential new vaccine platform, either alone or in combination with highly attenuated viral vectors, to induce integrated immune responses against microbial or cancer antigens, with improved ease of manufacturing and clinical use.
Topics: Adjuvants, Immunologic; Animals; Antigens, CD; CD8-Positive T-Lymphocytes; Carboxymethylcellulose Sodium; Dendritic Cells; Gene Products, gag; Humans; Immunity, Cellular; Interferon Inducers; Lectins, C-Type; Mice; Minor Histocompatibility Antigens; Poly I-C; Polylysine; Receptors, Cell Surface; Signal Transduction; T-Lymphocytes; Toll-Like Receptors; Vaccines
PubMed: 22126373
DOI: 10.1111/j.1365-2796.2011.02496.x -
Clinical Cancer Research : An Official... Oct 2018Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 and...
Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 and MDA-5 that can activate immune cells, such as dendritic cells, and trigger natural killer cells to kill tumor cells. In this pilot study, eligible patients included those with recurrent metastatic disease in whom prior systemic therapy (head and neck squamous cell cancer and melanoma) failed. Patients received 2 treatment cycles, each cycle consisting of 1 mg poly-ICLC 3× weekly intratumorally (IT) for 2 weeks followed by intramuscular (IM) boosters biweekly for 7 weeks, with a 1-week rest period. Immune response was evaluated by immunohistochemistry (IHC) and RNA sequencing (RNA-seq) in tumor and blood. Two patients completed 2 cycles of IT treatments, and 1 achieved clinical benefit (stable disease, progression-free survival 6 months), whereas the remainder had progressive disease. Poly-ICLC was well tolerated, with principal side effects of fatigue and inflammation at injection site (
poly-ICLC treatment, including upregulation of genes associated with chemokine activity, T-cell activation, and antigen presentation. Poly-ICLC was well tolerated in patients with solid cancer and generated local and systemic immune responses, as evident in the patient achieving clinical benefit. These results warrant further investigation and are currently being explored in a multicenter phase II clinical trial (NCT02423863). . Topics: Aged; Biopsy; Carboxymethylcellulose Sodium; Drug Administration Schedule; Female; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Immunologic Factors; Immunomodulation; Injections, Intralesional; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Pilot Projects; Poly I-C; Polylysine; Prognosis; Tomography, X-Ray Computed; Treatment Outcome
PubMed: 29950349
DOI: 10.1158/1078-0432.CCR-17-1866 -
Frontiers in Immunology 2019Toll-like receptor-3 agonist Poly-ICLC has been known to activate immune cells and induce HIV replication in pre-clinical experiments. In this study we investigated if... (Randomized Controlled Trial)
Randomized Controlled Trial
Toll-like receptor-3 agonist Poly-ICLC has been known to activate immune cells and induce HIV replication in pre-clinical experiments. In this study we investigated if Poly-ICLC could be used for disrupting HIV latency while simultaneously enhancing innate immune responses. This was a randomized, placebo-controlled, double-blinded trial in aviremic, cART-treated HIV-infected subjects. Participants ( = 15) were randomized 3:1 to receive two consecutive daily doses of Poly-ICLC (1.4 mg subcutaneously) vs. placebo. Subjects were observed for adverse events, immune activation, and viral replication. Besides primary outcomes of safety and tolerability, several longitudinal immune parameters were evaluated including immune cell phenotype and function via flowcytometry, ELISA, and transcriptional profiling. PCR assays for plasma HIV-1 RNA, CD4 T cell-associated HIV-1 RNA, and proviral DNA were performed to measure HIV reservoirs and latency. Poly-ICLC was overall safe and well-tolerated. Poly-ICLC-related adverse events were Grade 1/2, with the exception of one Grade 3 neutropenia which was short-lived. Mild Injection site reactions were observed in nearly all participants in the Poly-ICLC arm. Transcriptional analyses revealed upregulation of innate immune pathways in PBMCs following Poly-ICLC treatment, including strong interferon signaling accompanied by transient increases in circulating IP-10 (CXCL10) levels. These responses generally peaked by 24-48 h after the first injection and returned to baseline by day 8. CD4 T cell number and phenotype were unchanged, plasma viral control was maintained and no significant effect on HIV reservoirs was observed. These finding suggest that Poly-ICLC could be safely used for inducing transient innate immune responses in treated HIV subjects indicating promise as an adjuvant for HIV therapeutic vaccines. www.ClinicalTrials.gov, identifier: NCT02071095.
Topics: Adult; CD4-Positive T-Lymphocytes; Carboxymethylcellulose Sodium; Double-Blind Method; Female; HIV; HIV Infections; Humans; Immunity, Innate; Male; Middle Aged; Poly I-C; Polylysine; Toll-Like Receptor 3
PubMed: 31024557
DOI: 10.3389/fimmu.2019.00725 -
Research Square Sep 2023Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been...
UNLABELLED
Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been demonstrated in all patients. To determine the most effective combination of autologous tumor lysate-pulsed DC vaccination, with or without the adjuvant toll-like receptor (TLR) agonists poly-ICLC or resiquimod, we conducted a Phase 2 clinical trial in 23 patients with newly diagnosed or recurrent WHO Grade III-IV malignant gliomas. We then performed deep, high-dimensional immune profiling of these patients to better understand how TLR agonists may influence the systemic immune responses induced by ATL-DC vaccination. Bulk RNAseq data demonstrated highly significant upregulation of type 1 and type 2 interferon gene expression selectively in patients who received adjuvant a TLR agonist together with ATL-DC. CyTOF analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased expression of PD-1 on CD4+ T-cells, decreases in CD38 and CD39 on CD8+ T cells and elevated proportion of monocytes after ATL-DC + TLR agonist administration. In addition, scRNA-seq demonstrated a higher expression fold change of IFN-induced genes with poly-ICLC treatment in both peripheral blood monocytes and T lymphocytes. Patients who had higher expression of interferon response genes lived significantly longer and had longer time to progression compared to those with lower expression. The results suggest that ATL-DC in conjunction with adjuvant poly-ICLC induces a polarized interferon response in circulating monocytes and specific activation of a CD8+ T cell population, which may represent an important blood biomarker for immunotherapy in this patient population.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01204684.
PubMed: 37790490
DOI: 10.21203/rs.3.rs-3287211/v1 -
Cancer Immunology, Immunotherapy : CII Feb 2017The design of efficacious and cost-effective therapeutic vaccines against cancer remains both a research priority and a challenge. For more than a decade, our laboratory... (Review)
Review
The design of efficacious and cost-effective therapeutic vaccines against cancer remains both a research priority and a challenge. For more than a decade, our laboratory has been involved in the development of synthetic peptide-based anti-cancer therapeutic vaccines. We first dedicated our efforts in the identification and validation of peptide epitopes for both CD8 and CD4 T cells from tumor-associated antigens (TAAs). Because of suboptimal immune responses and lack of therapeutic benefit of peptide vaccines containing these epitopes, we have focused our recent efforts in optimizing peptide vaccinations in mouse tumor models using numerous TAA epitopes. In this focused research review, we describe how after taking lessons from the immune system's way of dealing with acute viral infections, we have designed peptide vaccination strategies capable of generating very high numbers of therapeutically effective CD8 T cells. We also discuss some of the remaining challenges to translate these findings into the clinical setting.
Topics: Animals; Cancer Vaccines; Disease Models, Animal; Humans; Melanoma, Experimental; Vaccines, Subunit; Virus Diseases
PubMed: 27052572
DOI: 10.1007/s00262-016-1834-5 -
Annals of Translational Medicine Jun 2021Prognosis of metastatic melanoma has undergone substantial improvement with the discovery of checkpoint inhibitors. Immunotherapies and targeted therapies have improved... (Review)
Review
Prognosis of metastatic melanoma has undergone substantial improvement with the discovery of checkpoint inhibitors. Immunotherapies and targeted therapies have improved the median overall survival (OS) of metastatic melanoma from 6 months to more than 3 years. However, still about half of the patients die due to uncontrolled disease. Therefore, multiple strategies are currently being investigated to improve outcomes. One such strategy is intralesional/intratumoral (IT) therapies which can either directly kill the tumor cells or make the tumor more immunogenic to be recognized by the immune system. Talimogene laherparepvec (T-VEC), an oncolytic virus, is the first FDA approved IT therapy. This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid interleukin-12 electroporation (pIL-12 EP), IT ipilimumab, INT230-6 (cisplatin and vinblastine with an amphiphilic penetration enhancer), TTI-621 (SIRPαFc), CD-40 agonistic antibodies (ABBV-927 and APX005M), antimicrobial peptide LL37 and other miscellaneous agents.
PubMed: 34277838
DOI: 10.21037/atm-21-491 -
Neuro-oncology Aug 2016Low-grade gliomas (LGGs) are the most common brain tumors of childhood. Although surgical resection is curative for well-circumscribed superficial lesions, tumors that...
BACKGROUND
Low-grade gliomas (LGGs) are the most common brain tumors of childhood. Although surgical resection is curative for well-circumscribed superficial lesions, tumors that are infiltrative or arise from deep structures are therapeutically challenging, and new treatment approaches are needed. Having identified a panel of glioma-associated antigens (GAAs) overexpressed in these tumors, we initiated a pilot trial of vaccinations with peptides for GAA epitopes in human leukocyte antigen-A2+ children with recurrent LGG that had progressed after at least 2 prior regimens.
METHODS
Peptide epitopes for 3 GAAs (EphA2, IL-13Rα2, and survivin) were emulsified in Montanide-ISA-51 and administered subcutaneously adjacent to intramuscular injections of polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose every 3 weeks for 8 courses, followed by booster vaccines every 6 weeks. Primary endpoints were safety and T-lymphocyte responses against GAA epitopes. Treatment response was evaluated clinically and by MRI.
RESULTS
Fourteen children were enrolled. Other than grade 3 urticaria in one child, no regimen-limiting toxicity was encountered. Vaccination induced immunoreactivity to at least one vaccine-targeted GAA in all 12 evaluable patients: to IL-13Rα2 in 3, EphA2 in 11, and survivin in 3. One child with a metastatic LGG had asymptomatic pseudoprogression noted 6 weeks after starting vaccination, followed by dramatic disease regression with >75% shrinkage of primary tumor and regression of metastatic disease, persisting >57 months. Three other children had sustained partial responses, lasting >10, >31, and >45 months, and one had a transient response.
CONCLUSIONS
GAA peptide vaccination in children with recurrent LGGs is generally well tolerated, with preliminary evidence of immunological and clinical activity.
Topics: Adolescent; Antigens, Neoplasm; Brain Neoplasms; Carboxymethylcellulose Sodium; Child; Child, Preschool; Disease-Free Survival; Epitopes; Female; Glioma; Humans; Infant; Inhibitor of Apoptosis Proteins; Interferon Inducers; Interleukin-13 Receptor alpha2 Subunit; Male; Neoplasm Grading; Pilot Projects; Poly I-C; Polylysine; Receptor, EphA2; Survivin; Treatment Outcome; Vaccination
PubMed: 26984745
DOI: 10.1093/neuonc/now026 -
Journal of Neurochemistry Nov 2012Preconditioning with a low dose of harmful stimulus prior to injury induces tolerance to a subsequent ischemic challenge resulting in neuroprotection against stroke....
Preconditioning with a low dose of harmful stimulus prior to injury induces tolerance to a subsequent ischemic challenge resulting in neuroprotection against stroke. Experimental models of preconditioning primarily focus on neurons as the cellular target of cerebral protection, while less attention has been paid to the cerebrovascular compartment, whose role in the pathogenesis of ischemic brain injury is crucial. We have shown that preconditioning with polyinosinic polycytidylic acid (poly-ICLC) protects against cerebral ischemic damage. To delineate the mechanism of poly-ICLC protection, we investigated whether poly-ICLC preconditioning preserves the function of the blood-brain barrier (BBB) in response to ischemic injury. Using an in vitro BBB model, we found that poly-ICLC treatment prior to exposure to oxygen-glucose deprivation maintained the paracellular and transcellular transport across the endothelium and attenuated the drop in transendothelial electric resistance. We found that poly-ICLC treatment induced interferon (IFN) β mRNA expression in astrocytes and microglia and that type I IFN signaling in brain microvascular endothelial cells was required for protection. Importantly, this implicates a potential mechanism underlying neuroprotection in our in vivo experimental stroke model, where type I IFN signaling is required for poly-ICLC-induced neuroprotection against ischemic injury. In conclusion, we are the first to show that preconditioning with poly-ICLC attenuates ischemia-induced BBB dysfunction. This mechanism is likely an important feature of poly-ICLC-mediated neuroprotection and highlights the therapeutic potential of targeting BBB signaling pathways to protect the brain against stroke.
Topics: Analysis of Variance; Animals; Animals, Newborn; Blood-Brain Barrier; Brain Infarction; Carboxymethylcellulose Sodium; Cells, Cultured; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Glucose; Hypoxia; Infarction, Middle Cerebral Artery; Interferon Regulatory Factor-1; Interferon-beta; Ischemic Preconditioning; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroglia; Neuroprotective Agents; Poly I-C; Polylysine; RNA, Messenger; Signal Transduction; Tight Junctions; Time Factors
PubMed: 23050645
DOI: 10.1111/j.1471-4159.2012.07946.x -
Nature Communications May 2024In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed... (Randomized Controlled Trial)
Randomized Controlled Trial
In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.
Topics: Humans; Dendritic Cells; Glioma; Female; Male; Interferons; Middle Aged; Cancer Vaccines; CD8-Positive T-Lymphocytes; Poly I-C; Adult; Toll-Like Receptors; Imidazoles; Aged; Vaccination; Monocytes; Brain Neoplasms; CD4-Positive T-Lymphocytes; Immunotherapy; Toll-Like Receptor Agonists; Carboxymethylcellulose Sodium; Polylysine
PubMed: 38719809
DOI: 10.1038/s41467-024-48073-y -
Frontiers in Immunology 2020Glioblastoma, the most common aggressive cancer, has a poor prognosis. Among the current standard treatment strategies, radiation therapy is the most commonly...
Glioblastoma, the most common aggressive cancer, has a poor prognosis. Among the current standard treatment strategies, radiation therapy is the most commonly recommended. However, it is often unsuccessful at completely eliminating the cancer from the brain. A combination of radiation with other treatment methods should therefore be considered. It has been reported that radiotherapy in combination with immunotherapy might show a synergistic effect; however, this still needs to be investigated. In the current study, a "branched multipeptide and peptide adjuvants [such as pan DR epitope (PADRE) and polyinosinic-polycytidylic acid-stabilized with polylysine and carboxymethylcellulose-(poly-ICLC)]," namely vaccine and anti-PD1, were used as components of immunotherapy to assist in the anti-tumor effects of radiotherapy against glioblastomas. With regard to experimental design, immunological characterization of GL261 cells was performed and the effects of radiation on this cell line were also evaluated. An intracranial GL261 mouse glioma model was established, and therapeutic effects were observed based on tumor size and survival time. The distribution of effector immune cells in the spleen, based on cytotoxic T lymphocyte (CTL) and natural killer (NK) cell function, was determined. The pro-inflammatory and anti-inflammatory cytokine production from re-stimulated splenocytes and single tumor cells were also evaluated. As GL261 cells demonstrated both immunological characteristics and radiation sensitivity, they were found to be promising candidates for testing this combination treatment. Combinatorial treatment with radiation, vaccine, and anti-PD1 prolonged mouse survival by delaying tumor growth. Although this combination treatment led to an increase in the functional activity of both CTLs and NK cells, as evidenced by the increased percentage of these cells in the spleen, there was a greater shift toward CTL rather than NK cell activity. Moreover, the released cytokines from re-stimulated splenocytes and single tumor cells also showed a shift toward the pro-inflammatory response. This study suggests that immunotherapy comprising a branched multipeptide plus PADRE, poly-ICLC, and anti-PD1 could potentially enhance the anti-tumor effects of radiotherapy in a glioblastoma mouse model.
Topics: Adjuvants, Immunologic; Animals; Brain Neoplasms; Cancer Vaccines; Combined Modality Therapy; Disease Models, Animal; Female; Glioblastoma; Immunotherapy; Mice; Mice, Inbred C57BL; Radiotherapy; Vaccines, Subunit
PubMed: 32733437
DOI: 10.3389/fimmu.2020.01165