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Journal For Immunotherapy of Cancer Jun 2019Cancer vaccines require adjuvants to induce effective immune responses; however, there is no consensus on optimal adjuvants. We hypothesized that toll-like receptor... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Cancer vaccines require adjuvants to induce effective immune responses; however, there is no consensus on optimal adjuvants. We hypothesized that toll-like receptor (TLR)3 agonist polyICLC or TLR4 agonist lipopolysaccharide (LPS), combined with CD4 T cell activation, would support strong and durable CD8 T cell responses, whereas addition of an incomplete Freund's adjuvant (IFA) would reduce magnitude and persistence of immune responses.
PATIENTS AND METHODS
Participants with resected stage IIB-IV melanoma received a vaccine comprised of 12 melanoma peptides restricted by Class I MHC (12MP), plus a tetanus helper peptide (Tet). Participants were randomly assigned 2:1 to cohort 1 (LPS dose-escalation) or cohort 2 (polyICLC). Each cohort included 3 subgroups (a-c), receiving 12MP + Tet + TLR agonist without IFA (0), or with IFA in vaccine one (V1), or all six vaccines (V6). Toxicities were recorded (CTCAE v4). T cell responses were measured with IFNγ ELIspot assay ex vivo or after one in vitro stimulation (IVS).
RESULTS
Fifty-three eligible patients were enrolled, of which fifty-one were treated. Treatment-related dose-limiting toxicities (DLTs) were observed in 0/33 patients in cohort 1 and in 2/18 patients in cohort 2 (11%). CD8 T cell responses to 12MP were detected ex vivo in cohort 1 (42%) and in cohort 2 (56%) and in 18, 50, and 72% for subgroups V0, V1, and V6, respectively. T cell responses to melanoma peptides were more durable and of highest magnitude for IFA V6.
CONCLUSIONS
LPS and polyICLC are safe and effective vaccine adjuvants when combined with IFA. Contrary to the central hypothesis, IFA enhanced T cell responses to peptide vaccines when added to TLR agonists. Future studies will aim to understand mechanisms underlying the favorable effects with IFA.
TRIAL REGISTRATION
The clinical trial Mel58 was performed with IRB (#15781) and FDA approval and is registered with Clinicaltrials.gov on April 25, 2012 (NCT01585350). Patients provided written informed consent to participate. Enrollment started on June 24, 2012.
Topics: Adjuvants, Immunologic; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cancer Vaccines; Carboxymethylcellulose Sodium; Female; Freund's Adjuvant; Humans; Lipids; Lipopolysaccharides; Male; Melanoma; Poly I-C; Polylysine; Toll-Like Receptors; Vaccines, Subunit
PubMed: 31248461
DOI: 10.1186/s40425-019-0625-x -
Future Virology Sep 2014Toll-like receptors (TLRs) are sentinel receptors of the host innate immune system that recognize conserved 'pathogen-associated molecular patterns' of invading...
Toll-like receptors (TLRs) are sentinel receptors of the host innate immune system that recognize conserved 'pathogen-associated molecular patterns' of invading microbes, including viruses. The activation of TLRs establishes antiviral innate immune responses and coordinates the development of long-lasting adaptive immunity in order to control viral pathogenesis. However, microbe-induced damage to host tissues may release 'danger-associated molecular patterns' that also activate TLRs, leading to an overexuberant inflammatory response and, ultimately, to tissue damage. Thus, TLRs have proven to be promising targets as therapeutics for the treatment of viral infections that result in inflammatory damage or as adjuvants in order to enhance the efficacy of vaccines. Here, we explore recent advances in TLR biology with a focus on novel drugs that target TLRs (agonists and antagonists) for antiviral therapy.
PubMed: 25620999
DOI: 10.2217/fvl.14.70 -
Mucosal Immunology Sep 2016Despite significant therapeutic advances for HIV-1 infected individuals, a preventative HIV-1 vaccine remains elusive. Studies focusing on early transmission events,...
Despite significant therapeutic advances for HIV-1 infected individuals, a preventative HIV-1 vaccine remains elusive. Studies focusing on early transmission events, including the observation that there is a profound loss of gastrointestinal (GI) CD4(+) T cells during acute HIV-1 infection, highlight the importance of inducing HIV-specific immunity within the gut. Here we report on the generation of cellular and humoral immune responses in the intestines by a mucosally administered, dendritic cell (DC) targeted vaccine. Our results show that nasally delivered α-CD205-p24 vaccine in combination with polyICLC, induced polyfunctional immune responses within naso-pulmonary lymphoid sites that disseminated widely to systemic and mucosal (GI tract and the vaginal epithelium) sites. Qualitatively, while α-CD205-p24 prime-boost immunization generated CD4(+) T-cell responses, heterologous prime-boost immunization with α-CD205-p24 and NYVAC gag-p24 generated high levels of HIV-specific CD4(+) and CD8(+) T cells within the GI tract. Finally, DC-targeting enhanced the amplitude and longevity of vaccine-induced immune responses in the GI tract. This is the first report of a nasally delivered, DC-targeted vaccine to generate HIV-specific immune responses in the GI tract and will potentially inform the design of preventative approaches against HIV-1 and other mucosal infections.
Topics: AIDS Vaccines; Administration, Intranasal; Animals; Antigens, CD; Antigens, Viral; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Carboxymethylcellulose Sodium; Dendritic Cells; Female; Gastrointestinal Tract; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Immunity, Cellular; Immunity, Humoral; Immunization, Secondary; Interferon Inducers; Lectins, C-Type; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Minor Histocompatibility Antigens; Poly I-C; Polylysine; Receptors, Cell Surface; Vaccination; Viral Vaccines; gag Gene Products, Human Immunodeficiency Virus
PubMed: 26732678
DOI: 10.1038/mi.2015.133 -
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 -
PloS One 2018HIV-1 infection can be controlled by anti-retroviral drug therapy, but this is a lifetime treatment and the virus remains latent and rapidly rebounds if therapy is... (Comparative Study)
Comparative Study
HIV-1 infection can be controlled by anti-retroviral drug therapy, but this is a lifetime treatment and the virus remains latent and rapidly rebounds if therapy is stopped. HIV-1-infected individuals under this drug regimen have increased rates of cancers, cardiovascular diseases, and autoimmunity due to compromised immunity. A therapeutic vaccine boosting cellular immunity against HIV-1 is therefore desirable and, possibly combined with other immune modulating agents, could obviate the need for long-term drug therapies. An approach to elicit strong T cell-based immunity is to direct virus protein antigens specifically to dendritic cells (DCs), which are the key cell type for controlling immune responses. For eliciting therapeutic cellular immunity in HIV-1-infected individuals, we developed vaccines comprised of five T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol (HIV5pep) fused to monoclonal antibodies that bind either, the antigen presenting cell activating receptor CD40, or the endocytic dendritic cell immunoreceptor DCIR. The study aimed to demonstrate vaccine safety, establish efficacy for broad T cell responses in both primed and naïve settings, and identify one candidate vaccine for human therapeutic development. The vaccines were administered to Rhesus macaques by intradermal injection with poly-ICLC adjuvant. The animals were either i) naïve or, ii) previously primed with modified vaccinia Ankara vector (MVA) encoding HIV-1 Gag, Pol, and Nef (MVA GagPolNef). In the MVA-primed groups, both DC-targeting vaccinations boosted HIV5pep-specific blood CD4+ T cells producing multiple cytokines, but did not affect the MVA-elicited CD8+ T cell responses. In the naive groups, both DC-targeting vaccines elicited antigen-specific polyfunctional CD4+ and CD8+ T cell responses to multiple epitopes and these responses were unchanged by a subsequent MVA GagPolNef boost. In both settings, the T cell responses elicited via the CD40-targeting vaccine were more robust and were detectable in all the animals, favoring further development of the CD40-targeting vaccine for therapeutic vaccination of HIV-1-infected individuals.
Topics: AIDS Vaccines; Animals; CD40 Antigens; Dendritic Cells; Epitopes, T-Lymphocyte; HIV Antibodies; HIV-1; Macaca mulatta; Male; Molecular Targeted Therapy; Receptors, Immunologic
PubMed: 30500852
DOI: 10.1371/journal.pone.0207794 -
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 -
Frontiers in Immunology 2018Devil facial tumor disease (DFTD) is renowned for its successful evasion of the host immune system. Down regulation of the major histocompatabilty complex class I...
Devil facial tumor disease (DFTD) is renowned for its successful evasion of the host immune system. Down regulation of the major histocompatabilty complex class I molecule (MHC-I) on the DFTD cells is a primary mechanism of immune escape. Immunization trials on captive Tasmanian devils have previously demonstrated that an immune response against DFTD can be induced, and that immune-mediated tumor regression can occur. However, these trials were limited by their small sample sizes. Here, we describe the results of two DFTD immunization trials on cohorts of devils prior to their wild release as part of the Tasmanian Government's Wild Devil Recovery project. 95% of the devils developed anti-DFTD antibody responses. Given the relatively large sample sizes of the trials ( = 19 and = 33), these responses are likely to reflect those of the general devil population. DFTD cells manipulated to express MHC-I were used as the antigenic basis of the immunizations in both trials. Although the adjuvant composition and number of immunizations differed between trials, similar anti-DFTD antibody levels were obtained. The first trial comprised DFTD cells and the adjuvant combination of ISCOMATRIX™, polyIC, and CpG with up to four immunizations given at monthly intervals. This compared to the second trial whereby two immunizations comprising DFTD cells and the adjuvant combination ISCOMATRIX™, polyICLC (Hiltonol) and imiquimod were given a month apart, providing a shorter and, therefore, more practical protocol. Both trials incorporated a booster immunization given up to 5 months after the primary course. A key finding was that devils in the second trial responded more quickly and maintained their antibody levels for longer compared to devils in the first trial. The different adjuvant combination incorporating the RNAase resistant polyICLC and imiquimod used in the second trial is likely to be responsible. The seroconversion in the majority of devils in these anti-DFTD immunization trials was remarkable, especially as DFTD is hallmarked by its immune evasion mechanisms. Microsatellite analyzes of MHC revealed that some MHC-I microsatellites correlated to stronger immune responses. These trials signify the first step in the long-term objective of releasing devils with immunity to DFTD into the wild.
Topics: Adjuvants, Immunologic; Animals; Cancer Vaccines; Carboxymethylcellulose Sodium; Facial Neoplasms; Female; Histocompatibility Antigens Class I; Imiquimod; Immunity, Humoral; Immunization, Secondary; Immunoglobulin G; Immunotherapy; Male; Marsupialia; Poly I-C; Polylysine; Tumor Escape
PubMed: 29515577
DOI: 10.3389/fimmu.2018.00259 -
Minerva Medica Feb 2021The world is now entering its 9 month of combat against a pandemic of deadly pneumonia. Started out from China in December 2019, the disease has been declared as caused...
The world is now entering its 9 month of combat against a pandemic of deadly pneumonia. Started out from China in December 2019, the disease has been declared as caused by infection with a so far unknown RNA Coronavirus of the respiratory family, then named severe acute respiratory syndrome coronavirus SARS-CoV-2. In the absence of a vaccine, and with scientists still struggling for an effective therapy, COVID-19 (the SARS-dependent syndrome) carries up to now, a death toll of more than 590,000 (July 18,2020) undermining jobs and finance of contemporary society in all continents. Social distancing, the only measure hitherto shown to restrain virus spread, has been progressively loosened from May 2020 in some countries, leaving us in the fear of repeat attacks from the unchecked virus. We discuss the problem and propose to tentatively boost the antivirus cell machinery by using lab-made viral mimics to engage cell receptors.
Topics: COVID-19; Carboxymethylcellulose Sodium; Cytokine Release Syndrome; Humans; Immunization, Passive; Interferon Inducers; Mucocutaneous Lymph Node Syndrome; Physical Distancing; Poly I-C; Polylysine; Practice Guidelines as Topic; RNA, Double-Stranded; RNA, Viral; Recurrence; SARS-CoV-2; Secondary Prevention; COVID-19 Drug Treatment; COVID-19 Serotherapy
PubMed: 33104300
DOI: 10.23736/S0026-4806.20.07054-8 -
Journal of Clinical Medicine Aug 2020Treatment decisions for both early and advanced genitourinary (GU) malignancies take into account the risk of dying from the malignancy as well as the risk of death due...
Treatment decisions for both early and advanced genitourinary (GU) malignancies take into account the risk of dying from the malignancy as well as the risk of death due to other causes such as other co-morbidities. COVID-19 is a new additional and immediate risk to a patient's morbidity and mortality and there is a need for an accurate assessment as to the potential impact on of this syndrome on GU cancer patients. The aim of this work was to develop a risk tool to identify GU cancer patients at risk of diagnosis, hospitalization, intubation, and mortality from COVID-19. A retrospective case showed a series of GU cancer patients screened for COVID-19 across the Mount Sinai Health System (MSHS). Four hundred eighty-four had a GU malignancy and 149 tested positive for SARS-CoV-2. Demographic and clinical variables of >38,000 patients were available in the institutional database and were utilized to develop decision aides to predict a positive SARS-CoV-2 test, as well as COVID-19-related hospitalization, intubation, and death. A risk tool was developed using a combination of machine learning methods and utilized BMI, temperature, heart rate, respiratory rate, blood pressure, and oxygen saturation. The risk tool for predicting a diagnosis of SARS-CoV-2 had an AUC of 0.83, predicting hospitalization for management of COVID-19 had an AUC of 0.95, predicting patients requiring intubation had an AUC of 0.97, and for predicting COVID-19-related death, the risk tool had an AUC of 0.79. The models had an acceptable calibration and provided a superior net benefit over other common strategies across the entire range of threshold probabilities.
PubMed: 32872607
DOI: 10.3390/jcm9092799 -
Cancer Immunology, Immunotherapy : CII Mar 2018A substantial body of evidence suggests the existence of MUC1-specific antibodies and cytotoxic T cell activities in pancreatic cancer patients. However, tumor-induced...
A substantial body of evidence suggests the existence of MUC1-specific antibodies and cytotoxic T cell activities in pancreatic cancer patients. However, tumor-induced immunosuppression renders these responses ineffective. The current study explores a novel therapeutic combination wherein tumor-bearing hosts can be immunologically primed with their own antigen, through opsonization with a tumor antigen-targeted antibody, mAb-AR20.5. We evaluated the efficacy of immunization with this antibody in combination with PolyICLC and anti-PD-L1. The therapeutic combination of mAb-AR20.5 + anti-PD-L1 + PolyICLC induced rejection of human MUC1 expressing tumors and provided a long-lasting, MUC1-specific cellular immune response, which could be adoptively transferred and shown to provide protection against tumor challenge in human MUC1 transgenic (MUC.Tg) mice. Furthermore, antibody depletion studies revealed that CD8 cells were effectors for the MUC1-specific immune response generated by the mAb-AR20.5 + anti-PD-L1 + PolyICLC combination. Multichromatic flow cytometry data analysis demonstrated a significant increase over time in circulating, activated CD8 T cells, CD3CD4CD8(DN) T cells, and mature dendritic cells in mAb-AR20.5 + anti-PD-L1 + PolyICLC combination-treated, tumor-bearing mice, as compared to saline-treated control counterparts. Our study provides a proof of principle that an effective and long-lasting anti-tumor cellular immunity can be achieved in pancreatic tumor-bearing hosts against their own antigen (MUC1), which can be further potentiated using a vaccine adjuvant and an immune checkpoint inhibitor.
Topics: Animals; Antibodies, Monoclonal; Antimetabolites, Antineoplastic; B7-H1 Antigen; Carboxymethylcellulose Sodium; Cytotoxicity, Immunologic; Deoxycytidine; Humans; Immunity, Cellular; Mice; Mice, Transgenic; Mucin-1; Pancreatic Neoplasms; Poly I-C; Polylysine; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Gemcitabine
PubMed: 29204701
DOI: 10.1007/s00262-017-2095-7