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Translational Andrology and Urology Apr 2020Debate continues as to the superiority of robotic versus open radical prostatectomy for the surgical treatment of localized prostate cancer. Despite this controversy,... (Review)
Review
Debate continues as to the superiority of robotic versus open radical prostatectomy for the surgical treatment of localized prostate cancer. Despite this controversy, retrospective data from high volume centres has demonstrated RARP is associated with improved pentafecta outcomes with lower transfusion rates, less incontinence, lower positive surgical margins and improved potency. Advocates of robotic assisted radical prostatectomy (RARP) believe an enhanced visual field, the precision afforded by robotic technology as well as lack of bleeding, sharp dissection and delicate tissue handling lead to improved outcomes. Prostate Cancer is the second most common cancer diagnosed in men, and as the number of post-surgical patients increases, the complications of urinary incontinence and erectile dysfunction not only have a significant negative impact on patients' quality of life, but have become an expanding part of clinical practice. This article outlines what are believed to be the most important strategies based on anatomical knowledge and technical expertise, that allow robotic prostatectomists to achieve superb outcomes in urinary and erectile function.
PubMed: 32420204
DOI: 10.21037/tau.2020.01.15 -
PLoS Pathogens Aug 2015Cryptococcus neoformans is the most common cause of fungal meningoencephalitis in AIDS patients. Depletion of CD4 cells, such as occurs during advanced AIDS, is known to...
Cryptococcus neoformans is the most common cause of fungal meningoencephalitis in AIDS patients. Depletion of CD4 cells, such as occurs during advanced AIDS, is known to be a critical risk factor for developing cryptococcosis. However, the role of HIV-induced innate inflammation in susceptibility to cryptococcosis has not been evaluated. Thus, we sought to determine the role of Type I IFN induction in host defense against cryptococci by treatment of C. neoformans (H99) infected mice with poly-ICLC (pICLC), a dsRNA virus mimic. Unexpectedly, pICLC treatment greatly extended survival of infected mice and reduced fungal burdens in the brain. Protection from cryptococcosis by pICLC-induced Type I IFN was mediated by MDA5 rather than TLR3. PICLC treatment induced a large, rapid and sustained influx of neutrophils and Ly6Chigh monocytes into the lung while suppressing the development of eosinophilia. The pICLC-mediated protection against H99 was CD4 T cell dependent and analysis of CD4 T cell polyfunctionality showed a reduction in IL-5 producing CD4 T cells, marginal increases in Th1 cells and dramatic increases in RORγt+ Th17 cells in pICLC treated mice. Moreover, the protective effect of pICLC against H99 was diminished in IFNγ KO mice and by IL-17A neutralization with blocking mAbs. Furthermore, pICLC treatment also significantly extended survival of C. gattii infected mice with reduced fungal loads in the lungs. These data demonstrate that induction of type I IFN dramatically improves host resistance against the etiologic agents of cryptococcosis by beneficial alterations in both innate and adaptive immune responses.
Topics: Animals; CD4-Positive T-Lymphocytes; Carboxymethylcellulose Sodium; Cryptococcus neoformans; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Interferon Inducers; Interferon Type I; Meningitis, Cryptococcal; Mice; Mice, Inbred C57BL; Mice, Knockout; Poly I-C; Polylysine
PubMed: 26252005
DOI: 10.1371/journal.ppat.1005040 -
Asian Pacific Journal of Tropical... May 2016To investigate the correlation between activation of toll-like receptors 3 (TLR3) signaling pathway and tumor-associated macrophage and its effect on the tumor growth.
OBJECTIVE
To investigate the correlation between activation of toll-like receptors 3 (TLR3) signaling pathway and tumor-associated macrophage and its effect on the tumor growth.
METHODS
The mice Lewis lung cancer cell lines 3LL and melanoma B16H10 were used to construct the subcutaneous transplantation tumor models and then they were treated with Poly-ICLC. The curative effect was observed and then the T cell and macrophage phenotypes infiltrated in local tumor were detected by flow cytometry. After the in vitro culture of mouse bone marrow-derived macrophage, the real-time PCR and western blot were applied to detect the expression of macrophage activation markers and the activation of intracellular signaling pathways.
RESULTS
The survival time of mice with brown tumor treated with Poly-ICLC significantly increased and the tumor growth was inhibited. The ratio of local tumor-infiltrated Treg decreased, while the ratio of CD8(+) T cell increased significantly. The macrophages surface CD206 expression was down-regulated while the expression of iNOS increased. The Poly-ICLC could promote the expression of M1 markers (IL-1β, TNF-α and iNOS) in bone marrow-derived macrophage and inhibited the expression of M2 molecules (Arg-1, YM-1 and CD206). The phosphorylation level of downstream p65, TBK1 and IRF3 increased significantly.
CONCLUSIONS
The Poly-ICLC can activate the TLR3 downstream signaling pathway to induce a M1 polarization of tumor associated macrophage, thereby inhibiting the tumor growth.
PubMed: 27261859
DOI: 10.1016/j.apjtm.2016.03.019 -
Neuro-oncology Feb 2024Central nervous system (CNS) WHO grade 2 low-grade glioma (LGG) patients are at high risk for recurrence and with unfavorable long-term prognosis due to the treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Central nervous system (CNS) WHO grade 2 low-grade glioma (LGG) patients are at high risk for recurrence and with unfavorable long-term prognosis due to the treatment resistance and malignant transformation to high-grade glioma. Considering the relatively intact systemic immunity and slow-growing nature, immunotherapy may offer an effective treatment option for LGG patients.
METHODS
We conducted a prospective, randomized pilot study to evaluate the safety and immunological response of the multipeptide IMA950 vaccine with agonistic anti-CD27 antibody, varlilumab, in CNS WHO grade 2 LGG patients. Patients were randomized to receive combination therapy with IMA950 + poly-ICLC and varlilumab (Arm 1) or IMA950 + poly-ICLC (Arm 2) before surgery, followed by adjuvant vaccines.
RESULTS
A total of 14 eligible patients were enrolled in the study. Four patients received pre-surgery vaccines but were excluded from postsurgery vaccines due to the high-grade diagnosis of the resected tumor. No regimen-limiting toxicity was observed. All patients demonstrated a significant increase of anti-IMA950 CD8+ T-cell response postvaccine in the peripheral blood, but no IMA950-reactive CD8+ T cells were detected in the resected tumor. Mass cytometry analyses revealed that adding varlilumab promoted T helper type 1 effector memory CD4+ and effector memory CD8+ T-cell differentiation in the PBMC but not in the tumor microenvironment.
CONCLUSION
The combinational immunotherapy, including varlilumab, was well-tolerated and induced vaccine-reactive T-cell expansion in the peripheral blood but without a detectable response in the tumor. Further developments of strategies to overcome the blood-tumor barrier are warranted to improve the efficacy of immunotherapy for LGG patients.
Topics: Humans; Pilot Projects; Leukocytes, Mononuclear; Prospective Studies; Glioma; Cancer Vaccines; Cell Differentiation; Tumor Microenvironment; Peptides; Antibodies, Monoclonal, Humanized
PubMed: 37758193
DOI: 10.1093/neuonc/noad185 -
Oncoimmunology 2018Cetuximab immunotherapy targeting the epidermal growth factor receptor (EGFR) has been used to treat nasopharyngeal cancer (NPC) with some success. Therefore, combining...
Cetuximab immunotherapy targeting the epidermal growth factor receptor (EGFR) has been used to treat nasopharyngeal cancer (NPC) with some success. Therefore, combining an immune adjuvant to boost the immune microenvironment may improve its clinical efficacy. Herein, we investigate the immune-stimulatory effects of Poly-ICLC (a TLR3 agonist) in enhancing cetuximab-based immunotherapy and correlate these responses with FcɣRIIIa (V158F) or TLR3 single nucleotide polymorphisms (SNPs- L412F and C829T) expressed on immune effector cells. We observed high levels of TLR3 mRNA in NPC cells; and both TLR3 and EGFR expression were unaffected by Poly-ICLC treatment. Cetuximab plus Poly-ICLC significantly enhanced NK-mediated ADCC through up-regulation of CD107a and Granzyme B expression. This effect was independent of FcɣRIIIa-V158F and TLR3-L412F or TLR3-C829T polymorphisms expressed on NK cells. Additionally, IFN-ɣ expression and secretion were doubled following cetuximab plus poly-ICLC treatment; compared to either treatment alone. This effect was independent of TLR3 polymorphisms. Consequentially, adaptive immune responses were also seen with increased DC maturation (CD83), co-stimulatory molecules expression (CD80 and CD86) and increased frequency of EGFR-specific CD8 + T cells following Poly-ICLC treatment. The percentage of CD80+ CD83+ and CD83+ CD86+ DC was highest in the Poly-ICLC plus cetuximab group, compared to either treatment alone. These results demonstrate the effectiveness of Poly-ICLC in enhancing both cetuximab-mediated innate and adaptive anti-tumor immunity against NPC, which is independent of FcɣRIIIa-158, TLR3-L412F or TLR3-C829T polymorphisms. Additionally, Poly-ICLC does not downregulate EGFR expression on NPC cells and hence, will not dampen cetuximab anti-tumor activity.
PubMed: 30377565
DOI: 10.1080/2162402X.2018.1500109 -
Oncotarget Sep 2015Hepatocellular carcinoma (HCC) is associated with high mortality and the current therapy for advanced HCC, Sorafenib, offers limited survival benefits. Here we assessed...
Hepatocellular carcinoma (HCC) is associated with high mortality and the current therapy for advanced HCC, Sorafenib, offers limited survival benefits. Here we assessed whether combining the TLR3 agonist: lysine-stabilized polyinosinic-polycytidylic-acid (poly-ICLC) with Sorafenib could enhance tumor control in HCC. Combinatorial therapy with poly-ICLC and Sorafenib increased apoptosis and reduced proliferation of HCC cell lines in vitro, in association with impaired phosphorylation of AKT, MEK and ERK. In vivo, the combinatorial treatment enhanced control of tumor growth in two mouse models: one transplanted with Hepa 1-6 cells, and the other with liver tumors induced using the Sleeping beauty transposon. Tumor cell apoptosis and host immune responses in the tumor microenvironment were enhanced. Particularly, the activation of local NK cells, T cells, macrophages and dendritic cells was enhanced. Decreased expression of the inhibitory signaling molecules PD-1 and PD-L1 was observed in tumor-infiltrating CD8+ T cells and tumor cells, respectively. Tumor infiltration by monocytic-myeloid derived suppressor cells (Mo-MDSC) was also reduced indicating the reversion of the immunosuppressive tumor microenvironment. Our data demonstrated that the combinatorial therapy with poly-ICLC and Sorafenib enhances tumor control and local immune response hence providing a rationale for future clinical studies.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; CD8-Positive T-Lymphocytes; Carboxymethylcellulose Sodium; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Progression; Extracellular Signal-Regulated MAP Kinases; Humans; Immune System; Immunosuppressive Agents; Liver Neoplasms; MAP Kinase Kinase Kinases; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Niacinamide; Phenylurea Compounds; Phosphorylation; Poly I-C; Polylysine; Proto-Oncogene Proteins c-akt; Signal Transduction; Sorafenib; Toll-Like Receptor 3
PubMed: 26287667
DOI: 10.18632/oncotarget.4583 -
Stroke Jan 2016Preconditioning with poly-l-lysine and carboxymethylcellulose (ICLC) provides robust neuroprotection from cerebral ischemia in a mouse stroke model. However, the...
BACKGROUND AND PURPOSE
Preconditioning with poly-l-lysine and carboxymethylcellulose (ICLC) provides robust neuroprotection from cerebral ischemia in a mouse stroke model. However, the receptor that mediates neuroprotection is unknown. As a synthetic double-stranded RNA, poly-ICLC may bind endosomal Toll-like receptor 3 or one of the cytosolic retinoic acid-inducible gene-I-like receptor family members, retinoic acid-inducible gene-I, or melanoma differentiation-associated protein 5. Activation of these receptors culminates in type I interferons (IFN-α/β) induction-a response required for poly-ICLC-induced neuroprotection. In this study, we investigate the receptor required for poly-ICLC-induced neuroprotection.
METHODS
Toll-like receptor 3, melanoma differentiation-associated protein 5-, and IFN-promoter stimulator 1-deficient mice were treated with poly-ICLC 24 hours before middle cerebral artery occlusion. Infarct volume was measured 24 hours after stroke to identify the receptor signaling pathways involved in protection. IFN-α/β induction was measured in plasma samples collected 6 hours after poly-ICLC treatment. IFN-β-deficient mice were used to test the requirement of IFN-β for poly-ICLC-induced neuroprotection. Mice were treated with recombinant IFN-α-A to test the role of IFN-α as a potential mediator of neuroprotection.
RESULTS
Poly-ICLC induction of both neuroprotection and systemic IFN-α/β requires the cytosolic receptor melanoma differentiation-associated protein 5 and the adapter molecule IFN-promoter stimulator 1, whereas it is independent of Toll-like receptor 3. IFN-β is not required for poly-ICLC-induced neuroprotection. IFN-α treatment protects against stroke.
CONCLUSIONS
Poly-ICLC preconditioning is mediated by melanoma differentiation-associated protein 5 and its adaptor molecule IFN-promoter stimulator 1. This is the first evidence that a cytosolic receptor can mediate neuroprotection, providing a new target for the development of therapeutic agents to protect the brain from ischemic injury.
Topics: Animals; Brain Ischemia; Carboxymethylcellulose Sodium; DEAD-box RNA Helicases; Interferon-Induced Helicase, IFIH1; Ischemic Preconditioning; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Poly I-C; Polylysine; Stroke
PubMed: 26564103
DOI: 10.1161/STROKEAHA.115.010329 -
Journal For Immunotherapy of Cancer Sep 2020Immunotherapies, such as immune checkpoint inhibitors and adoptive cell therapies, have revolutionized cancer treatment and resulted in complete and durable responses in...
BACKGROUND
Immunotherapies, such as immune checkpoint inhibitors and adoptive cell therapies, have revolutionized cancer treatment and resulted in complete and durable responses in some patients. Unfortunately, most immunotherapy treated patients still fail to respond. Absence of T cell infiltration to the tumor site is one of the major obstacles limiting immunotherapy efficacy against solid tumors. Thus, the development of strategies that enhance T cell infiltration and broaden the antitumor efficacy of immunotherapies is greatly needed.
METHODS
We used mouse tumor models, genetically deficient mice and vascular endothelial cells (VECs) to study the requirements for T cell infiltration into tumors.
RESULTS
A specific formulation of poly-IC, containing poly-lysine and carboxymethylcellulose (PICLC) facilitated the traffic and infiltration of effector CD8 T cells into the tumors that reduced tumor growth. Surprisingly, intratumoral injection of PICLC was significantly less effective in inducing tumor T cell infiltration and controlling growth of tumors as compared with systemic (intravenous or intramuscular) administration. Systemically administered PICLC, but not poly-IC stimulated tumor VECs via the double-stranded RNA cytoplasmic sensor MDA5, resulting in enhanced adhesion molecule expression and the production of type I interferon (IFN-I) and T cell recruiting chemokines. Expression of IFNαβ receptor in VECs was necessary to obtain the antitumor effects by PICLC and IFN-I was found to directly stimulate the secretion of T cell recruiting chemokines by VECs indicating that this cytokine-chemokine regulatory axis is crucial for recruiting effector T cells into the tumor parenchyma. Unexpectedly, these effects of PICLC were mostly observed in tumors and not in normal tissues.
CONCLUSIONS
These findings have strong implications for the improvement of all types of T cell-based immunotherapies for solid cancers. We predict that systemic administration of PICLC will improve immune checkpoint inhibitor therapy, adoptive cell therapies and therapeutic cancer vaccines.
Topics: Animals; Disease Models, Animal; Female; Humans; Immunotherapy; Mice; Poly I-C; T-Lymphocytes
PubMed: 32958686
DOI: 10.1136/jitc-2020-001224 -
Journal For Immunotherapy of Cancer May 2020Phosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized by CD8 T-cells. These peptides are...
BACKGROUND
Phosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized by CD8 T-cells. These peptides are promising targets for cancer immunotherapy. Previous work identified an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) as one such target. The purpose of this study was to characterize a second phosphopeptide, from breast cancer antiestrogen resistance 3 (BCAR3), and to evaluate safety and immunogenicity of a novel immunotherapic vaccine comprising either or both of these phosphorylated peptides.
METHODS
Phosphorylated BCAR3 protein was evaluated in melanoma and breast cancer cell lines by Western blot, and recognition by T-cells specific for HLA-A*0201-restricted phosphorylated BCAR3 peptide (pBCAR3) was determined by Cr release assay and intracellular cytokine staining. Human tumor explants were also evaluated by mass spectrometry for presentation of pIRS2 and pBCAR3 peptides. For the clinical trial, participants with resected stage IIA-IV melanoma were vaccinated 6 times over 12 weeks with one or both peptides in incomplete Freund's adjuvant and Hiltonol (poly-ICLC). Adverse events (AEs) were coded based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V.4.03, with provision for early study termination if dose-limiting toxicity (DLT) rates exceeded 33%. The enrollment target was 12 participants evaluable for immune response to each peptide. T-cell responses were assessed by interferon-γ ELISpot assay.
RESULTS
pBCAR3 peptides were immunogenic in vivo in mice, and in vitro in normal human donors, and T-cells specific for pBCAR3 controlled outgrowth of a tumor xenograft. The pIRS2 peptide was identified by mass spectrometry from human hepatocellular carcinoma tumors. In the clinical trial, 15 participants were enrolled. All had grade 1 or 2 treatment-related AEs, but there were no grade 3-4 AEs, DLTs or deaths on study. T-cell responses were induced to the pIRS2 peptide in 5/12 patients (42%, 90% CI 18% to 68%) and to the pBCAR3 peptide in 2/12 patients (17%, 90% CI 3% to 44%).
CONCLUSION
This study supports the safety and immunogenicity of vaccines containing the cancer-associated phosphopeptides pBCAR3 and pIRS2, and the data support continued development of immune therapy targeting phosphopeptides. Future studies will define ways to further enhance the magnitude and durability of phosphopeptide-specific immune responses.
TRIAL REGISTRATION NUMBER
NCT01846143.
Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Aged, 80 and over; Animals; Antigens, Neoplasm; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cell Line, Tumor; Female; Guanine Nucleotide Exchange Factors; HLA-A2 Antigen; Humans; Immunogenicity, Vaccine; Immunotherapy; Insulin Receptor Substrate Proteins; Male; Melanoma; Mice; Mice, Transgenic; Middle Aged; Phosphopeptides; Pilot Projects; Proof of Concept Study; Skin Neoplasms; Vaccines, Subunit; Xenograft Model Antitumor Assays
PubMed: 32385144
DOI: 10.1136/jitc-2019-000262 -
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