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Oncoimmunology Mar 2021Ipilimumab (IPI) can enhance immunity to the cancer-testis antigen NY-ESO-1. A clinical trial was designed to assess safety, immunogenicity, and clinical responses with...
Ipilimumab (IPI) can enhance immunity to the cancer-testis antigen NY-ESO-1. A clinical trial was designed to assess safety, immunogenicity, and clinical responses with IPI + NY-ESO-1 vaccines and effects on the tumor microenvironment (TME). Patients with measurable NY-ESO-1 tumors were enrolled among three arms: A) IPI + NY-ESO-1 protein + poly-ICLC (pICLC) + incomplete Freund's adjuvant (IFA); B) IPI + NY-ESO-1 overlapping long peptides (OLP) + pICLC + IFA; and C) IPI + NY-ESO-1 OLP + pICLC. Clinical responses were assessed by irRC. T cell and Ab responses were assessed by IFN-gamma ELIspot and ELISA. Tumor biopsies pre- and post-treatment were evaluated for immune infiltrates. Eight patients were enrolled: 5, 2, and 1 in Arms A-C, respectively. There were no DLTs. Best clinical responses were SD (4) and PD (4). T-cell and antibody (Ab) responses to NY-ESO-1 were detected in 6 (75%) and 7 (88%) patients, respectively, and were associated with SD. The breadth of Ab responses was greater for patients with SD than PD ( = .036). For five patients evaluable in the TME, treatment was associated with increases in proliferating (Ki67) CD8 T cells and decreases in RORγt CD4 T cells. T cell densities increased for those with SD. Detection of T cell responses to NY-ESO-1 ex vivo in most patients suggests that IPI may have enhanced those responses. Proliferating intratumoral CD8 T cells increased after vaccination plus IPI suggesting favorable impact of IPI plus NY-ESO-1 vaccines on the TME. : Ab = antibody; CTCAE = NCI Common Terminology Criteria for Adverse Events; DHFR/DHRP = dihydrofolate reductase; DLT = Dose-limiting toxicity; ELISA = enzyme-linked immunosorbent assay; IFA = incomplete Freund's adjuvant (Montanide ISA-51); IFNγ = Interferon gamma; IPI = Ipilimumab; irRC = immune-related response criteria; mIFH = multispectral immunofluorescence histology; OLP = NY-ESO-1 overlapping long peptides; PBMC = peripheral blood mononuclear cells; PD = Progressive disease; pICLC = poly-ICLC (Hiltonol), a TLR3/MDA-5 agonist; RLT = Regimen-limiting Toxicity; ROI = regions of interest; RT = room temperature; SAE = serious adverse event; SD = stable disease; TEAE = treatment-emergent adverse events; TLR = toll-like receptor; TME = tumor microenvironment; TRAE = treatment-related adverse events.
Topics: Antigens, Neoplasm; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cancer Vaccines; Humans; Ipilimumab; Leukocytes, Mononuclear; Male; Melanoma; Tumor Microenvironment
PubMed: 33796406
DOI: 10.1080/2162402X.2021.1898105 -
Cancer Immunology, Immunotherapy : CII Nov 2021The nanoparticle complex of cholesteryl pullulan (CHP) and NY-ESO-1 antigen protein (CHP-NY-ESO-1) presents multiple epitope peptides to MHC class I and II pathways,...
The nanoparticle complex of cholesteryl pullulan (CHP) and NY-ESO-1 antigen protein (CHP-NY-ESO-1) presents multiple epitope peptides to MHC class I and II pathways, leading to CD8 and CD4 T cell responses. Poly-ICLC is a synthetic, double-stranded RNA, an agonist of toll-like receptor (TLR)-3, and a cytoplasmic receptor of melanoma differentiation-associated gene (MDA)-5. It should be a suitable immune adjuvant of cancer vaccine to overcome the inhibitory tumor microenvironment. We conducted a phase 1 clinical trial of CHP-NY-ESO-1 with poly-ICLC in patients with advanced or recurrent esophageal cancer. CHP-NY-ESO-1/poly-ICLC (μg/mg) was administered at a dose of 200/0.5 or 200/1.0 (cohorts 1 and 2, respectively) every 2 weeks for a total of six doses. The primary endpoints were safety and immune response. The secondary endpoint was tumor response. In total, 16 patients were enrolled, and six patients in each cohort completed the trial. The most common adverse event (AE) was injection site skin reaction (86.7%). No grade 3 or higher drug-related AEs were observed. No tumor responses were observed, and three patients (30%) had stable disease. The immune response was comparable between the two cohorts, and all patients (100%) achieved antibody responses with a median of 2.5 vaccinations. Comparing CHP-NY-ESO-1 alone to the poly-ICLC combination, all patients in both groups exhibited antibody responses, but the titers were higher in the combination group. In a mouse model, adding anti-PD-1 antibody to the combination of CHP-NY-ESO-1/poly-ICLC suppressed the growth of NY-ESO-1-expressing tumors. Combining the vaccine with PD-1 blockade holds promise in human trials.
Topics: Adjuvants, Immunologic; Aged; Aged, 80 and over; Animals; Antigens, Neoplasm; Cancer Vaccines; Carboxymethylcellulose Sodium; Esophageal Neoplasms; Female; Glucans; Humans; Interferon Inducers; Male; Membrane Proteins; Mice; Middle Aged; Nanoparticles; Poly I-C; Polylysine
PubMed: 33751208
DOI: 10.1007/s00262-021-02892-w -
International Journal of Molecular... Feb 2021NSCLC (non-small cell lung cancer) is a leading cause of cancer-related deaths worldwide. Clinical trials showed that Hiltonol, a stable dsRNA representing an advanced...
NSCLC (non-small cell lung cancer) is a leading cause of cancer-related deaths worldwide. Clinical trials showed that Hiltonol, a stable dsRNA representing an advanced form of polyI:C (polyinosinic-polycytidilic acid), is an adjuvant cancer-immunomodulator. However, its mechanisms of action and effect on lung cancer have not been explored pre-clinically. Here, we examined, for the first time, how a novel Hiltonol cocktail kills NSCLC cells. By retrospective analysis of NSCLC patient tissues obtained from the tumor biobank; pre-clinical studies with Hiltonol alone or Hiltonol cocktail [Hiltonol+anti-IL6+AG490 (JAK2 inhibitor)+Stattic (STAT3 inhibitor)]; cytokine analysis; gene knockdown and gain/loss-of-function studies, we uncovered the mechanisms of action of Hiltonol. We demonstrated that Hiltonol kills the cancer cells and suppresses the metastatic potential of NSCLC through: (i) upregulation of pro-apoptotic Caspase-9 and Caspase-3, (ii) induction of cytosolic cytochrome , (iii) modulation of pro-inflammatory cytokines (GRO, MCP-1, IL-8, and IL-6) and anticancer IL-24 in NSCLC subtypes, and (iv) upregulation of tumor suppressors, PKR (protein kinase R) and OAS (2'5' oligoadenylate synthetase). In silico analysis showed that Lys296 of PKR and Lys66 of OAS interact with Hiltonol. These Lys residues are purportedly involved in the catalytic/signaling activity of the tumor suppressors. Furthermore, knockdown of PKR/OAS abrogated the anticancer action of Hiltonol, provoking survival of cancer cells. Ex vivo analysis of NSCLC patient tissues corroborated that loss of PKR and OAS is associated with cancer advancement. Altogether, our findings unraveled the significance of studying tumor biobank tissues, which suggests PKR and OAS as precision oncological suppressor candidates to be targeted by this novel Hiltonol cocktail which represents a prospective drug for development into a potent and tailored therapy for NSCLC subtypes.
Topics: 2',5'-Oligoadenylate Synthetase; A549 Cells; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Binding Sites; Carboxymethylcellulose Sodium; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cyclic S-Oxides; Gene Expression Regulation, Neoplastic; Humans; Interleukin-6; Lung Neoplasms; Models, Molecular; Poly I-C; Polylysine; Tumor Microenvironment; Tyrphostins; eIF-2 Kinase
PubMed: 33562773
DOI: 10.3390/ijms22041626 -
Cancer Discovery Mar 2021Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique...
Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in , pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4 and CD8 T-cell responses, with immune responses to 99% of the vaccinated peptide antigens. SIGNIFICANCE: Predicting neoantigens has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design..
Topics: Animals; Antigens, Neoplasm; Biomarkers, Tumor; Cancer Vaccines; Cell Line, Tumor; Clinical Trials as Topic; DNA Mutational Analysis; Disease Models, Animal; Disease Progression; Genomics; Humans; Immunity, Cellular; Immunogenicity, Vaccine; Melanoma, Experimental; Mice; Mutation; Neoplasms; T-Lymphocytes; Treatment Outcome; Vaccination
PubMed: 33504579
DOI: 10.1158/2159-8290.CD-20-0377 -
Frontiers in Immunology 2020Photochemical internalization (PCI) is a technology for inducing release of endocytosed antigens into the cell cytosol a light-induced process. Preclinical experiments...
Photochemical Internalization Enhanced Vaccination Is Safe, and Gives Promising Cellular Immune Responses to an HPV Peptide-Based Vaccine in a Phase I Clinical Study in Healthy Volunteers.
BACKGROUND AND AIMS
Photochemical internalization (PCI) is a technology for inducing release of endocytosed antigens into the cell cytosol a light-induced process. Preclinical experiments have shown that PCI improves MHC class I antigen presentation, resulting in strongly enhanced CD8+ T-cell responses to polypeptide antigens. In PCI vaccination a mixture of the photosensitizing compound fimaporfin, vaccine antigens, and an adjuvant is administered intradermally followed by illumination of the vaccination site. This work describes an open label, phase I study in healthy volunteers, to assess the safety, tolerability, and immune response to PCI vaccination in combination with the adjuvant poly-ICLC (Hiltonol) (ClinicalTrials.gov Identifier: NCT02947854).
METHODS
The primary objective of the study was to assess the safety and local tolerance of PCI mediated vaccination, and to identify a safe fimaporfin dose for later clinical studies. A secondary objective was to analyze the immunological responses to the vaccination. Each subject received 3 doses of HPV16 E7 peptide antigens and two doses of Keyhole Limpet Hemocyanin (KLH) protein. A control group received Hiltonol and vaccine antigens only, whereas the PCI groups in addition received fimaporfin + light. Local and systemic adverse effects were assessed by standard criteria, and cellular and humoral immune responses were analyzed by ELISpot, flow cytometry, and ELISA assays.
RESULTS
96 healthy volunteers were vaccinated with fimaporfin doses of 0.75-50 µg. Doses below 17.5 µg were safe and tolerable, higher doses exhibited local tolerability issues in some study subjects, mainly erythema, and pain during illumination. There were few, and only mild and expected systemic adverse events. The employment of PCI increased the number of subjects exhibiting a T-cell response to the HPV peptide vaccine about 10-fold over what was achieved with the antigen/Hiltonol combination without PCI. Moreover, the use of PCI seemed to result in a more consistent and multifunctional CD8+ T-cell response. An enhancement of the humoral immune response to KLH vaccination was also observed.
CONCLUSIONS
Using PCI in combination with Hiltonol for intradermal vaccination is safe at fimaporfin doses below 17.5 µg, and gives encouraging immune responses to peptide and protein based vaccination.
Topics: Adult; Cells, Cultured; Female; Healthy Volunteers; Human papillomavirus 16; Humans; Immunity, Cellular; Lighting; Male; Middle Aged; Papillomavirus E7 Proteins; Papillomavirus Infections; Papillomavirus Vaccines; Peptides; Photochemical Processes; Photosensitizing Agents; T-Lymphocytes; Vaccination; Vaccines, Subunit; Young Adult
PubMed: 33488576
DOI: 10.3389/fimmu.2020.576756 -
Journal For Immunotherapy of Cancer Jan 2021Peptide vaccines designed to stimulate melanoma-reactive CD4 T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We... (Clinical Trial)
Clinical Trial
BACKGROUND
Peptide vaccines designed to stimulate melanoma-reactive CD4 T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund's adjuvant (IFA) would be safe and would support strong, durable CD4 T cell and Ab responses. We also hypothesized that oral low-dose metronomic cyclophosphamide (mCy) would be safe, would reduce circulating regulatory T cells (T-regs) and would further enhance immunogenicity.
PARTICIPANTS AND METHODS
An adaptive design based on toxicity and durable CD4+ T cell immune response (dRsp) was used to assign participants with resected stage IIA-IV melanoma to one of four study regimens. The regimens included a vaccine comprising six melanoma peptides restricted by Class II MHC (6MHP) in an emulsion with IFA alone (Arm A), with IFA plus systemic mCy (Arm B), with IFA+ local polyICLC (Arm C), or with IFA+ polyICLC+ mCy (Arm D). Toxicities were recorded (CTCAE V.4.03). T cell responses were measured by interferon γ ELIspot assay ex vivo. Serum Ab responses to 6MHP were measured by ELISA. Circulating T-regs were assessed by flow cytometry.
RESULTS
Forty-eight eligible participants were enrolled and treated. Early data on safety and dRsp favored enrollment on arm D. Total enrollment on Arms A-D were 3, 7, 6, and 32, respectively. Treatment-related dose-limiting toxicities (DLTs) were observed in 1/7 (14%) participants on arm B and 2/32 (6%) on arm D. None exceeded the 25% DLT threshold for early closure to enrollment for any arm. Strong durable T cell responses to 6MHP were detected ex vivo in 0%, 29%, 67%, and 47% of participants on arms A-D, respectively. IgG Ab responses were greatest for arms C and D. Circulating T-regs frequencies were not altered by mCy.
CONCLUSIONS
6MHP vaccines administered with IFA, polyICLC, and mCy were well tolerated. The dRsp rate for arm D of 47% (90% CI 32 to 63) exceeded the 18% (90% CI 11 to 26) rate previously observed with 6MHP in IFA alone. Vaccination with IFA+ polyICLC (arm C) also showed promise for enhancing T cell and Ab responses.
Topics: Administration, Metronomic; Administration, Oral; Antibodies; CD4-Positive T-Lymphocytes; Cancer Vaccines; Carboxymethylcellulose Sodium; Combined Modality Therapy; Cyclophosphamide; Female; Freund's Adjuvant; Humans; Lipids; Male; Melanoma; Neoplasm Staging; Poly I-C; Polylysine; T-Lymphocytes, Regulatory; Treatment Outcome; Vaccines, Subunit
PubMed: 33479025
DOI: 10.1136/jitc-2020-000934 -
The Urologic Clinics of North America Nov 2020Relatively simple, synthetic, double-stranded RNAs can be powerful viral pathogen-associated molecular pattern (PAMP) mimics, inducing a panoply of antiviral and... (Review)
Review
Relatively simple, synthetic, double-stranded RNAs can be powerful viral pathogen-associated molecular pattern (PAMP) mimics, inducing a panoply of antiviral and antitumor responses that act at multiple stages of host defense. Their mechanisms of action and uses are beginning to be understood, alone, in combination with other therapeutics, or as novel PAMP-adjuvants providing the critical danger signal that has been missing from most cancer and other modern vaccines. Dose, timing, route of administration combinations, and other clinical variables can have a critical impact on immunogenicity. This article reviews advances in the use of polyinosinic-polycytidylic acid and derivatives, in particular poly-ICLC.
Topics: Adjuvants, Immunologic; Cancer Vaccines; Carboxymethylcellulose Sodium; Clinical Trials as Topic; Humans; Immunologic Factors; Male; Pathogen-Associated Molecular Pattern Molecules; Poly I-C; Polylysine; Prostatic Neoplasms; RNA, Double-Stranded
PubMed: 33446322
DOI: 10.1016/j.ucl.2020.10.003 -
Biological Psychiatry May 2021Maternal immune activation (MIA) is a proposed risk factor for multiple neuropsychiatric disorders, including schizophrenia. However, the molecular mechanisms through...
BACKGROUND
Maternal immune activation (MIA) is a proposed risk factor for multiple neuropsychiatric disorders, including schizophrenia. However, the molecular mechanisms through which MIA imparts risk remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for studying underlying molecular correlates.
METHODS
We performed RNA sequencing across psychiatrically relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus) and primary visual cortex for comparison from 3.5- to 4-year-old male MIA-exposed and control offspring-an age comparable to mid adolescence in humans.
RESULTS
We identify 266 unique genes differentially expressed in at least one brain region, with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Although we observed temporal and regional differences, transcriptomic changes were shared across first- and second-trimester exposures, including for the top differentially expressed genes-PIWIL2 and MGARP. In addition to PIWIL2, several other regulators of retrotransposition and endogenous transposable elements were dysregulated following MIA, potentially connecting MIA to retrotransposition.
CONCLUSIONS
Together, these results begin to elucidate the brain-level molecular processes through which MIA may impart risk for psychiatric disease.
Topics: Animals; Argonaute Proteins; Behavior, Animal; Disease Models, Animal; Female; Humans; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; Primates; Transcriptome
PubMed: 33386132
DOI: 10.1016/j.biopsych.2020.10.016 -
Nature Cancer Dec 2020Generating responses to tumor antigens poses a challenge for immunotherapy. This phase II trial (NCT02129075) tested fms-like tyrosine kinase 3 (Flt3) ligand... (Randomized Controlled Trial)
Randomized Controlled Trial
Generating responses to tumor antigens poses a challenge for immunotherapy. This phase II trial (NCT02129075) tested fms-like tyrosine kinase 3 (Flt3) ligand pre-treatment enhancement of responses to dendritic cell (DC)-targeting vaccines. We evaluated a regimen of Flt3L (CDX-301) to increase DCs and other antigen-presenting cells, poly-ICLC (TLR3 agonist that activates DCs) and a vaccine comprising anti-DEC-205-NY-ESO-1, a fusion antibody targeting CD205, linked to NY-ESO-1. High-risk melanoma patients were randomized to vaccine, with and without CDX-301. The end point was immune response to NY-ESO-1. Flt3L increased peripheral monocytes and conventional DCs (cDCs), including cross-presenting cDC1 and cDC2 and plasmacytoid DCs. Significant increases in humoral and T-cell responses and activation of DCs, natural killer cells and T cells were elicited. Transcriptional analyses revealed gene signatures associated with CDX-301 induction of an early, durable immune response. This study reveals in vivo effects of Flt3L on innate immune cells in the setting of vaccination, leading to an immunogenic vaccine regimen.
Topics: Cancer Vaccines; Dendritic Cells; Humans; Immunity; Melanoma; Membrane Proteins; fms-Like Tyrosine Kinase 3
PubMed: 35121932
DOI: 10.1038/s43018-020-00143-y -
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