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Clinical Cancer Research : An Official... Mar 2018Treatment options are limited for patients with high-risk myelodysplastic syndrome (MDS). The azanucleosides, azacitidine and decitabine, are first-line therapy for MDS...
Treatment options are limited for patients with high-risk myelodysplastic syndrome (MDS). The azanucleosides, azacitidine and decitabine, are first-line therapy for MDS that induce promoter demethylation and gene expression of the highly immunogenic tumor antigen NY-ESO-1. We demonstrated that patients with acute myeloid leukemia (AML) receiving decitabine exhibit induction of NY-ESO-1 expression in circulating blasts. We hypothesized that vaccinating against NY-ESO-1 in patients with MDS receiving decitabine would capitalize upon induced NY-ESO-1 expression in malignant myeloid cells to provoke an NY-ESO-1-specific MDS-directed cytotoxic T-cell immune response. In a phase I study, 9 patients with MDS received an HLA-unrestricted NY-ESO-1 vaccine (CDX-1401 + poly-ICLC) in a nonoverlapping schedule every four weeks with standard-dose decitabine. Analysis of samples serially obtained from the 7 patients who reached the end of the study demonstrated induction of expression in 7 of 7 patients and NY-ESO-1-specific CD4 and CD8 T-lymphocyte responses in 6 of 7 and 4 of 7 of the vaccinated patients, respectively. Myeloid cells expressing NY-ESO-1, isolated from a patient at different time points during decitabine therapy, were capable of activating a cytotoxic response from autologous NY-ESO-1-specific T lymphocytes. Vaccine responses were associated with a detectable population of CD141 conventional dendritic cells, which are critical for the uptake of NY-ESO-1 vaccine and have a recognized role in antitumor immune responses. These data indicate that vaccination against induced NY-ESO-1 expression can produce an antigen-specific immune response in a relatively nonimmunogenic myeloid cancer and highlight the potential for induced antigen-directed immunotherapy in a group of patients with limited options. .
Topics: Aged; Antigens, Neoplasm; Antimetabolites, Antineoplastic; Cancer Vaccines; Carboxymethylcellulose Sodium; Combined Modality Therapy; Decitabine; Dose-Response Relationship, Drug; Drug Administration Schedule; Feasibility Studies; Humans; Immunotherapy; Interferon Inducers; Leukemia, Myeloid, Acute; Membrane Proteins; Middle Aged; Myelodysplastic Syndromes; Myeloid Cells; Poly I-C; Polylysine; T-Lymphocytes, Cytotoxic; Treatment Outcome
PubMed: 28947565
DOI: 10.1158/1078-0432.CCR-17-1792 -
Journal of Hepatocellular Carcinoma 2017To determine the safety of an approach to immunologically enhance local treatment of hepatocellular cancer (HCC) by combining nonlethal radiation, local regional therapy...
A Phase I trial using local regional treatment, nonlethal irradiation, intratumoral and systemic polyinosinic-polycytidylic acid polylysine carboxymethylcellulose to treat liver cancer: in search of the abscopal effect.
PURPOSE
To determine the safety of an approach to immunologically enhance local treatment of hepatocellular cancer (HCC) by combining nonlethal radiation, local regional therapy with intratumoral injection, and systemic administration of a potent Toll-like receptor (TLR) immune adjuvant.
METHODS
Patients with HCC not eligible for liver transplant or surgery were subject to: 1) 3 fractions of 2-Gy focal nonlethal radiation to increase tumor antigen expression, 2) intra-/peri-tumoral (IT) injection of the TLR3 agonist, polyinosinic-polycytidylic acid polylysine carboxymethylcellulose (poly-ICLC), to induce an immunologic "danger" response in the tumor microenvironment with local regional therapy, and 3) systemic boosting of immunity with intramuscular poly-ICLC. Primary end points were safety and tolerability; secondary end points were progression-free survival (PFS) and overall survival (OS) at 6 months, 1 year, and 2 years.
RESULTS
Eighteen patients with HCC not eligible for surgery or liver transplant were treated. Aside from 1 embolization-related severe adverse event, all events were ≤grade II. PFS was 66% at 6 months, 39% at 12 months, and 28% at 24 months. Overall 1-year survival was 69%, and 2-year survival 38%. In patients <60 years old, 2-year survival was 62.5% vs. 11.1% in patients aged >60 years (<0.05). Several patients had prolonged PFS and OS.
CONCLUSION
Intra-tumoral injection of the TLR3 agonist poly-ICLC in patients with HCC is safe and tolerable when combined with local nonlethal radiation and local regional treatment. Further work is in progress to evaluate if this approach improves survival compared to local regional treatment alone and characterize changes in anticancer immunity.
PubMed: 28848723
DOI: 10.2147/JHC.S136652 -
Emerging Microbes & Infections Jun 2017Humoral responses are essential for the protective efficacy of most Ebola virus (EBOV) candidate vaccines; however, the in vivo development of protective anti-EBOV...
Humoral responses are essential for the protective efficacy of most Ebola virus (EBOV) candidate vaccines; however, the in vivo development of protective anti-EBOV B-cell responses is poorly defined. Here, by using the virus-like particle (VLP) as a model antigen, we demonstrate that humoral responses are generated through follicular B-cell and T-cell-dependent mechanisms in a mouse model of EBOV infection. In addition, we show that the inclusion of the clinical-grade dsRNA adjuvant known as poly-ICLC in VLP vaccinations both augments and sustains germinal center B-cell reactions, antigen-specific B-cell frequencies and anti-EBOV serum titers. Finally, we used mice that were deficient in either B-cells or T-cell-dependent antibody production to distinguish the contributing roles of EBOV humoral responses. We demonstrate that while anti-EBOV antibody responses promote protection, VLP-vaccinated mice can survive EBOV infection in the absence of detectable anti-EBOV antibodies. Moreover, we found that adjuvant signaling could circumvent the complete requirement for B-cell immunity in protection against EBOV. Collectively, these studies may prove valuable for the characterization and future development of additional EBOV vaccine candidates.
Topics: Adjuvants, Immunologic; Animals; Antibodies, Viral; B-Lymphocytes; Disease Models, Animal; Ebola Vaccines; Ebolavirus; Germinal Center; Hemorrhagic Fever, Ebola; Mice; RNA, Double-Stranded; T-Lymphocytes; Vaccines, Virus-Like Particle
PubMed: 28588288
DOI: 10.1038/emi.2017.31 -
Journal of Hematology & Oncology Apr 2017Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with... (Clinical Trial)
Clinical Trial
BACKGROUND
Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC).
METHODS
We generated autologous DCs from the peripheral blood of HLA-A2 patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV.A2). Patients received four intradermal injections of 1 × 10 peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28, and 42). Concurrently, patients received intramuscular administration of Poly-ICLC at 30 μg/Kg on vaccination days (i.e., day 0, 14, 28, and 42), as well as on days 3, 17, 21, 31, 37, and 45. Our key objective was to assess safety and feasibility. The effect of DC vaccination on immune response was measured at each DC injection time point by enumerating the phenotype and function of patient T cells.
RESULTS
Twelve patients underwent apheresis: nine patients with metastatic disease, and three patients with locally advanced unresectable disease. Vaccines were successfully manufactured from all individuals. We found that this treatment was well-tolerated, with the most common symptoms being fatigue and/or self-limiting flu-like symptoms. Among the eight patients who underwent imaging on day 56, four patients experienced stable disease while four patients had disease progression. The median overall survival was 7.7 months. One patient survived for 28 months post leukapheresis. MHC class I -tetramer analysis before and after vaccination revealed effective generation of antigen-specific T cells in three patients with stable disease.
CONCLUSION
Vaccination with peptide-pulsed DCs in combination with poly-ICLC is safe and induces a measurable tumor specific T cell population in patients with advanced PC.
TRIAL REGISTRATION
NCT01410968 ; Name of registry: clinicaltrials.gov; Date of registration: 08/04/2011).
Topics: Aged; Antigens, Neoplasm; Cancer Vaccines; Carboxymethylcellulose Sodium; Dendritic Cells; Female; Humans; Immunotherapy, Active; Lymphocyte Activation; Lymphocyte Count; Male; Middle Aged; Pancreatic Neoplasms; Peptides; Pilot Projects; Poly I-C; Polylysine; Transplantation, Autologous; Vaccination
PubMed: 28388966
DOI: 10.1186/s13045-017-0459-2 -
Journal of Virology May 2017We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic...
Superiority in Rhesus Macaques of Targeting HIV-1 Env gp140 to CD40 versus LOX-1 in Combination with Replication-Competent NYVAC-KC for Induction of Env-Specific Antibody and T Cell Responses.
We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic cells (DCs), in rhesus macaques primed with a poxvirus vector (NYVAC-KC) expressing Env gp140. The DC-targeting vaccines, humanized recombinant monoclonal antibodies fused to Env gp140, were administered as a boost with poly-ICLC adjuvant either alone or coadministered with the NYVAC-KC vector. All the DC-targeting vaccine administrations with poly-ICLC increased the low-level serum anti-Env IgG responses elicited by NYVAC-KC priming significantly more (up to a value of 0.01) than in a group without poly-ICLC. The responses were robust and cross-reactive and contained antibodies specific to multiple epitopes within gp140, including the C1, C2, V1, V2, and V3, C4, C5, and gp41 immunodominant regions. The DC-targeting vaccines also elicited modest serum Env-specific IgA responses. All groups gave serum neutralization activity limited to tier 1 viruses and antibody-dependent cytotoxicity responses (ADCC) after DC-targeting boosts. Furthermore, CD4 and CD8 T cell responses specific to multiple Env epitopes were strongly boosted by the DC-targeting vaccines plus poly-ICLC. Together, these results indicate that prime-boost immunization via NYVAC-KC and either anti-CD40.Env gp140/poly-ICLC or anti-LOX-1.Env gp140/poly-ICLC induced balanced antibody and T cell responses against HIV-1 Env. Coadministration of NYVAC-KC with the DC-targeting vaccines increased T cell responses but had minimal effects on antibody responses except for suppressing serum IgA responses. Overall, targeting Env to CD40 gave more robust T cell and serum antibody responses with broader epitope representation and greater durability than with LOX-1. An effective vaccine to prevent HIV-1 infection does not yet exist. An approach to elicit strong protective antibody development is to direct virus protein antigens specifically to dendritic cells, which are now known to be the key cell type for controlling immunity. In this study, we have tested in nonhuman primates two prototype vaccines engineered to direct the HIV-1 coat protein Env to dendritic cells. These vaccines bind to either CD40 or LOX-1, two dendritic cell surface receptors with different functions and tissue distributions. We tested the vaccines described above in combination with attenuated virus vectors that express Env. Both vaccines, but especially that delivered via CD40, raised robust immunity against HIV-1 as measured by monitoring potentially protective antibody and T cell responses in the blood. The safety and efficacy of the CD40-targeted vaccine justify further development for future human clinical trials.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; CD4-Positive T-Lymphocytes; CD40 Antigens; CD8-Positive T-Lymphocytes; CHO Cells; Carboxymethylcellulose Sodium; Cricetulus; Dendritic Cells; HIV Antibodies; HIV-1; Immunoglobulin A; Immunoglobulin G; Macaca mulatta; Male; Poly I-C; Polylysine; Scavenger Receptors, Class E; Vaccination; env Gene Products, Human Immunodeficiency Virus
PubMed: 28202751
DOI: 10.1128/JVI.01596-16 -
Antiviral Research Mar 2017Hiltonol, (Poly IC:LC), a potent immunomodulator, is a synthetic, double-stranded polyriboinosinic-polyribocytidylic acid (poly IC) stabilized with Poly-L-lysine and...
Hiltonol, (Poly IC:LC), a potent immunomodulator, is a synthetic, double-stranded polyriboinosinic-polyribocytidylic acid (poly IC) stabilized with Poly-L-lysine and carboxymethyl cellulose (LC). Hiltonol was tested for efficacy in a lethal SARS-CoV-infected BALB/c mouse model. Hiltonol at 5, 1, 0.5 or 0.25 mg/kg/day by intranasal (i.n.) route resulted in significant survival benefit when administered at selected times 24 h prior to challenge with a lethal dose of mouse-adapted severe acute respiratory syndrome coronavirus (SARS-CoV). The infected BALB/c mice receiving the Hiltonol treatments were also significantly effective in protecting mice against weight loss due to infection (p < 0.001). Groups of 20 mice were dosed with Hiltonol at 2.5 or 0.75 mg/kg by intranasal instillation 7, 14, and 21 days before virus exposure and a second dose was given 24 h later, prophylactic Hiltonol treatments (2.5 mg/kg/day) were completely protective in preventing death, and in causing significant reduction in lung hemorrhage scores, lung weights and lung virus titers. Hiltonol was also effective as a therapeutic when give up to 8 h post virus exposure; 100% of the-infected mice were protected against death when Hiltonol was administered at 5 mg/kg/day 8 h after infection. Our data suggest that Hiltonol treatment of SARS-CoV infection in mice leads to substantial prophylactic and therapeutic effects and could be used for treatment of other virus disease such as those caused by MERS-CoV a related coronavirus. These properties might be therapeutically advantageous if Hiltonol is considered for possible clinical use.
Topics: Adjuvants, Immunologic; Administration, Intranasal; Animals; Carboxymethylcellulose Sodium; Disease Models, Animal; Immunomodulation; Interferon Inducers; Lung; Mice; Mice, Inbred BALB C; Poly I-C; Polylysine; Severe acute respiratory syndrome-related coronavirus; Severe Acute Respiratory Syndrome; Survival Analysis
PubMed: 27956136
DOI: 10.1016/j.antiviral.2016.12.007 -
Journal of Neuro-oncology Dec 2016Recurrent high-grade gliomas (HGGs) of childhood have an exceedingly poor prognosis with current therapies. Accordingly, new treatment approaches are needed. We...
Antigen-specific immunoreactivity and clinical outcome following vaccination with glioma-associated antigen peptides in children with recurrent high-grade gliomas: results of a pilot study.
Recurrent high-grade gliomas (HGGs) of childhood have an exceedingly poor prognosis with current therapies. Accordingly, new treatment approaches are needed. We initiated a pilot trial of vaccinations with peptide epitopes derived from glioma-associated antigens (GAAs) overexpressed in these tumors in HLA-A2+ children with recurrent HGG that had progressed after prior treatments. Peptide epitopes for three GAAs (EphA2, IL13Rα2, survivin), emulsified in Montanide-ISA-51, were administered subcutaneously adjacent to intramuscular injections of poly-ICLC every 3 weeks for 8 courses, followed by booster vaccines every 6 weeks. Primary endpoints were safety and T-cell responses against the GAA epitopes, assessed by enzyme-linked immunosorbent spot (ELISPOT) analysis. Treatment response was evaluated clinically and by magnetic resonance imaging. Twelve children were enrolled, 6 with glioblastoma, 5 with anaplastic astrocytoma, and one with malignant gliomatosis cerebri. No dose-limiting non-CNS toxicity was encountered. ELISPOT analysis, in ten children, showed GAA responses in 9: to IL13Rα2 in 4, EphA2 in 9, and survivin in 3. One child had presumed symptomatic pseudoprogression, discontinued vaccine therapy, and responded to subsequent treatment. One other child had a partial response that persisted throughout 2 years of vaccine therapy, and continues at >39 months. Median progression-free survival (PFS) from the start of vaccination was 4.1 months and median overall survival (OS) was 12.9 months. 6-month PFS and OS were 33 and 73 %, respectively. GAA peptide vaccination in children with recurrent malignant gliomas is generally well tolerated, and has preliminary evidence of immunological and modest clinical activity.
Topics: Adolescent; Antigens, Neoplasm; Brain Neoplasms; Carboxymethylcellulose Sodium; Child; Child, Preschool; Female; Glioma; Humans; Immunotherapy, Active; Infant; Inhibitor of Apoptosis Proteins; Interleukin-13 Receptor alpha1 Subunit; Male; Peptides; Pilot Projects; Poly I-C; Polylysine; Receptor, EphA2; Receptors, Interleukin-13; Survivin; Treatment Outcome; Young Adult
PubMed: 27624914
DOI: 10.1007/s11060-016-2245-3 -
PloS One 2016Ebola virus (EBOV), a member of the Filoviridae that can cause severe hemorrhagic fever in humans and nonhuman primates, poses a significant threat to the public health....
Ebola virus (EBOV), a member of the Filoviridae that can cause severe hemorrhagic fever in humans and nonhuman primates, poses a significant threat to the public health. Currently, there are no licensed vaccines or therapeutics to prevent and treat EBOV infection. Several vaccines based on the EBOV glycoprotein (GP) are under development, including vectored, virus-like particles, and protein-based subunit vaccines. We previously demonstrated that a subunit vaccine containing the extracellular domain of the Ebola ebolavirus (EBOV) GP fused to the Fc fragment of human IgG1 (EBOVgp-Fc) protected mice against EBOV lethal challenge. Here, we show that the EBOVgp-Fc vaccine formulated with QS-21, alum, or polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) adjuvants induced strong humoral immune responses in guinea pigs. The vaccinated animals developed anti-GP total antibody titers of approximately 105-106 and neutralizing antibody titers of approximately 103 as assessed by a BSL-2 neutralization assay based on vesicular stomatitis virus (VSV) pseudotypes. The poly-ICLC formulated EBOVgp-Fc vaccine protected all the guinea pigs against EBOV lethal challenge performed under BSL-4 conditions whereas the same vaccine formulated with QS-21 or alum only induced partial protection. Vaccination with a mucin-deleted EBOVgp-Fc construct formulated with QS-21 adjuvant did not have a significant effect in anti-GP antibody levels and protection against EBOV lethal challenge compared to the full-length GP construct. The bulk of the humoral response induced by the EBOVgp-Fc vaccine was directed against epitopes outside the EBOV mucin region. Our findings indicate that different adjuvants can eliciting varying levels of protection against lethal EBOV challenge in guinea pigs vaccinated with EBOVgp-Fc, and suggest that levels of total anti-GP antibodies elicit by protein-based GP subunit vaccines do not correlate with protection. Our data further support the development of Fc fusions of GP as a candidate vaccine for human use.
Topics: Adjuvants, Immunologic; Alum Compounds; Animals; Antibodies, Neutralizing; Antibodies, Viral; Carboxymethylcellulose Sodium; Ebola Vaccines; Ebolavirus; Female; Guinea Pigs; Hemorrhagic Fever, Ebola; Humans; Immunoglobulin Fc Fragments; Male; Poly I-C; Polylysine; Recombinant Fusion Proteins; Saponins; Vaccines, Synthetic; Viral Envelope Proteins
PubMed: 27622456
DOI: 10.1371/journal.pone.0162446 -
PloS One 2016Myeloid dendritic cells (mDCs) contribute to both HIV pathogenesis and elicitation of antiviral immunity. Understanding how mDC responses to stimuli shape HIV infection...
Myeloid dendritic cells (mDCs) contribute to both HIV pathogenesis and elicitation of antiviral immunity. Understanding how mDC responses to stimuli shape HIV infection outcomes will inform HIV prevention and treatment strategies. The long double-stranded RNA (dsRNA) viral mimic, polyinosinic polycytidylic acid (polyIC, PIC) potently stimulates DCs to focus Th1 responses, triggers direct antiviral activity in vitro, and boosts anti-HIV responses in vivo. Stabilized polyICLC (PICLC) is being developed for vaccine adjuvant applications in humans, making it critical to understand how mDC sensing of PICLC influences HIV infection. Using the monocyte-derived DC (moDC) model, we sought to describe how PICLC (vs. other dsRNAs) impacts HIV infection within DCs and DC-T cell mixtures. We extended this work to in vivo macaque rectal transmission studies by administering PICLC with or before rectal SIVmac239 (SIVwt) or SIVmac239ΔNef (SIVΔNef) challenge. Like PIC, PICLC activated DCs and T cells, increased expression of α4β7 and CD169, and induced type I IFN responses in vitro. The type of dsRNA and timing of dsRNA exposure differentially impacted in vitro DC-driven HIV infection. Rectal PICLC treatment similarly induced DC and T cell activation and pro- and anti-HIV factors locally and systemically. Importantly, this did not enhance SIV transmission in vivo. Instead, SIV acquisition was marginally reduced after a single high dose challenge. Interestingly, in the PICLC-treated, SIVΔNef-infected animals, SIVΔNef viremia was higher, in line with the importance of DC and T cell activation in SIVΔNef replication. In the right combination anti-HIV strategy, PICLC has the potential to limit HIV infection and boost HIV immunity.
Topics: Animals; Carboxymethylcellulose Sodium; Dendritic Cells; HIV Infections; HIV-1; Humans; Interferon Type I; Lymphocyte Activation; Macaca; Monocytes; Myeloid Cells; Poly I-C; Polylysine; RNA, Double-Stranded; Simian Immunodeficiency Virus; Th1 Cells
PubMed: 27603520
DOI: 10.1371/journal.pone.0161730 -
Cancer Immunology, Immunotherapy : CII Oct 2016A recent report from the Center for Disease Control identified melanoma as being among the highest causes of cancer-related mortalities in the USA. While interventions... (Review)
Review
A recent report from the Center for Disease Control identified melanoma as being among the highest causes of cancer-related mortalities in the USA. While interventions such as checkpoint blockade have made substantial impact in terms of improving response rates and overall survival, a significant number of patients fail to respond to treatment or become resistant to therapy. A better understanding of the tumor microenvironment in these patients becomes imperative for identifying immune suppressive mechanisms that impact the development of effective anti-tumor immune responses. We have investigated innate immune cells (dendritic cells, NK cells) in the tumor microenvironment (TME) in order to devise effective targeted anticancer immune therapies. We find that matrix metalloproteinase-2 (MMP-2), secreted from melanoma cells and stromal cells, cleaves IFNAR1 and stimulates TLR-2 on dendritic cells (DC) within the TME. Both these events independently culminate in programing the DCs to promote pro-tumorigenic TH2 T cell differentiation. In addition, we have shown that NK cells become functionally exhausted in melanoma patients. We identified the expression of Tim-3 as one of the factors responsible for NK cell exhaustion and showed that anti-Tim3 antibodies partially reversed this exhaustion. We have initiated local intervention strategies such as intra-tumoral administration of DC activating Poly-ICLC and compared the efficacy of different TLR agonists and melanoma antigens for use as combination tumor vaccine in clinical trials. Such approaches will provide a unique insight into tumor biology and will facilitate in development of highly effective and cell type-specific immune therapies.
Topics: Animals; Dendritic Cells; Hepatitis A Virus Cellular Receptor 2; Humans; Immunity, Innate; Immunotherapy; Killer Cells, Natural; Matrix Metalloproteinase 2; Melanoma; Receptor, Interferon alpha-beta; Th2 Cells; Toll-Like Receptor 2; Tumor Escape; Tumor Microenvironment
PubMed: 27344341
DOI: 10.1007/s00262-016-1859-9