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Seminars in Immunology Jun 2020Immunotherapies have become the first line of treatment for many cancer types. Unfortunately, only a small fraction of patients benefits from these therapies. This low... (Review)
Review
Immunotherapies have become the first line of treatment for many cancer types. Unfortunately, only a small fraction of patients benefits from these therapies. This low rate of success can be attributed to 3 main barriers: 1) low frequency of anti-tumor specific T cells; 2) lack of infiltration of the anti-tumor specific T cells into the tumor parenchyma and 3) accumulation of highly suppressive cells in the tumor mass that inhibit the effector function of the anti-tumor specific T cells. Thus, the identification of immunomodulators that can increase the frequency and/or the infiltration of antitumor specific T cells while reducing the suppressive capacity of the tumor microenvironment is necessary to ensure the effectiveness of T cell immunotherapies. In this review, we discuss the potential of poly-ICLC as a multi-functional immune modulator for treating cancer and its impact on the 3 above mentioned barriers. We describe the unique capacity of poly-ICLC in stimulating 2 separate pattern recognition receptors, TLR3 and cytosolic MDA5 and the consequences of these activations on cytokines and chemokines production. We emphasize the role of poly-ICLC as an adjuvant in the setting of peptide-based cancer vaccines and in situ tumor vaccination by mimicking natural immune responses to infections. Finally, we summarize the impact of poly-ICLC in enhancing T infiltration into the tumor parenchyma and address the implication of this finding in the clinic.
Topics: Animals; Antineoplastic Agents; Carboxymethylcellulose Sodium; Cytokines; Humans; Immunity, Innate; Immunologic Factors; Immunomodulation; Interferon-Induced Helicase, IFIH1; Lymphocytes, Tumor-Infiltrating; Neoplasms; Poly I-C; Polylysine; Receptors, Pattern Recognition; Toll-Like Receptor 3
PubMed: 33011064
DOI: 10.1016/j.smim.2020.101414 -
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 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 -
The Journal of Clinical Investigation Dec 2020BACKGROUNDPatients with diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M... (Clinical Trial)
Clinical Trial
BACKGROUNDPatients with diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M mutation as a shared neoantigen in HLA-A*02.01+, H3.3K27M+ DMGs. Within the Pacific Pediatric Neuro-Oncology Consortium, we assessed the safety and efficacy of an H3.3K27M-targeted peptide vaccine.METHODSNewly diagnosed patients, aged 3-21 years, with HLA-A*02.01+ and H3.3K27M+ status were enrolled in stratum A (DIPG) or stratum B (nonpontine DMG). Vaccine was administered in combination with polyinosinic-polycytidylic acid-poly-I-lysine carboxymethylcellulose (poly-ICLC) every 3 weeks for 8 cycles, followed by once every 6 weeks. Immunomonitoring and imaging were performed every 3 months. Imaging was centrally reviewed. Immunological responses were assessed in PBMCs using mass cytometry.RESULTSA total of 19 patients were enrolled in stratum A (median age,11 years) and 10 in stratum B (median age, 13 years). There were no grade-4 treatment-related adverse events (TRAEs). Injection site reaction was the most commonly reported TRAE. Overall survival (OS) at 12 months was 40% (95% CI, 22%-73%) for patients in stratum A and 39% (95% CI, 16%-93%) for patients in stratum B. The median OS was 16.1 months for patients who had an expansion of H3.3K27M-reactive CD8+ T cells compared with 9.8 months for their counterparts (P = 0.05). Patients with DIPG with below-median baseline levels of myeloid-derived suppressor cells had prolonged OS compared with their counterparts (P < 0.01). Immediate pretreatment dexamethasone administration was inversely associated with H3.3K27M-reactive CD8+ T cell responses.CONCLUSIONAdministration of the H3.3K27M-specific vaccine was well tolerated. Patients with H3.3K27M-specific CD8+ immunological responses demonstrated prolonged OS compared with nonresponders.TRIAL REGISTRATIONClinicalTrials.gov NCT02960230.FUNDINGThe V Foundation, the Pacific Pediatric Neuro-Oncology Consortium Foundation, the Pediatric Brain Tumor Foundation, the Mithil Prasad Foundation, the MCJ Amelior Foundation, the Anne and Jason Farber Foundation, Will Power Research Fund Inc., the Isabella Kerr Molina Foundation, the Parker Institute for Cancer Immunotherapy, and the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R35NS105068).
Topics: Adolescent; Adult; Amino Acid Substitution; Brain Stem Neoplasms; CD8-Positive T-Lymphocytes; Cancer Vaccines; Child; Child, Preschool; Female; Flow Cytometry; Glioma; Histones; Humans; Immunity, Cellular; Male; Mutation, Missense; Neoplasm Proteins
PubMed: 32817593
DOI: 10.1172/JCI140378 -
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 -
Journal For Immunotherapy of Cancer Jun 2020In vivo targeting of human papillomavirus (HPV) derived antigens to dendritic cells might constitute an efficient immunotherapeutic strategy against cervical cancer. In...
BACKGROUND
In vivo targeting of human papillomavirus (HPV) derived antigens to dendritic cells might constitute an efficient immunotherapeutic strategy against cervical cancer. In previous works, we have shown that the extra domain A from murine fibronectin (mEDA) can be used to target antigens to toll-like receptor 4 (TLR4) expressing dendritic cells and induce strong antigen-specific immune responses. In the present study, we have produced a bivalent therapeutic vaccine candidate consisting of the human EDA (hEDA) fused to E7 proteins from HPV16 and HPV18 (hEDA-HPVE7-16/18) and evaluate its potential as a therapeutic vaccine against cervical cancer.
MATERIALS AND METHODS
Recombinant fusion proteins containing HPV E7 proteins from HPV16 and HPV18 virus subtypes fused to hEDA were produced and tested in vitro on their capacity to bind TLR4 and induce the production of tumor necrosis factor-α or interleukin (IL)-12 by human monocytes and dendritic cells. The immunogenicity and potential therapeutic activity of the vaccine in combination with cisplatin or with the TLR3 agonist molecules polyinosinic-polycytidylic acid (Poly IC) or Poly ICLC was evaluated in mice bearing subcutaneous or genital orthotopic HPV16 TC-1 tumors.
RESULTS
hEDA-HPVE7-16/18 prototype vaccine binds human TLR4 and stimulate TLR4-dependent signaling pathways and IL-12 production by human monocyte-derived dendritic cell. Vaccination with hEDA-HPVE7-16/18 induced strong HPVE7-specific Cytotoxic T lymphocyte (CTL) responses and eliminated established tumors in the TC-1-based tumor model. The antitumor efficacy was significantly improved by combining the fusion protein with cisplatin or with the TLR-3 ligand Poly IC and especially with the stabilized analog Poly ICLC. Moreover, hEDA-HPVE7-16/18+Poly ICLC induced full tumor regression in 100% of mice bearing orthotopic genital HPV tumors.
CONCLUSION
Our results suggest that this therapeutic vaccine formulation may be an effective treatment for cervical tumors that do not respond to current therapies.
Topics: Animals; Cancer Vaccines; DNA-Binding Proteins; Dendritic Cells; Female; Fibronectins; Human papillomavirus 16; Human papillomavirus 18; Humans; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Oncogene Proteins, Viral; Papillomavirus E7 Proteins; Papillomavirus Infections; T-Lymphocytes, Cytotoxic
PubMed: 32581060
DOI: 10.1136/jitc-2020-000704 -
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 -
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 -
Cancer Immunology, Immunotherapy : CII Aug 2020This phase I study aimed to evaluate the safety, peptide-specific immune responses, and anti-tumor effects of a novel vaccination therapy comprising multi-HLA-binding...
A phase I study of multi-HLA-binding peptides derived from heat shock protein 70/glypican-3 and a novel combination adjuvant of hLAG-3Ig and Poly-ICLC for patients with metastatic gastrointestinal cancers: YNP01 trial.
BACKGROUND
This phase I study aimed to evaluate the safety, peptide-specific immune responses, and anti-tumor effects of a novel vaccination therapy comprising multi-HLA-binding heat shock protein (HSP) 70/glypican-3 (GPC3) peptides and a novel adjuvant combination of hLAG-3Ig and Poly-ICLC against metastatic gastrointestinal cancers.
METHODS
HSP70/GPC3 peptides with high binding affinities for three HLA types (A*24:02, A*02:01, and A*02:06) were identified with our peptide prediction system. The peptides were intradermally administered with combined adjuvants on a weekly basis. This study was a phase I dose escalation clinical trial, which was carried out in a three patients' cohort; in total, 11 patients were enrolled for the recommended dose.
RESULTS
Seventeen patients received this vaccination therapy without dose-limiting toxicity. All treatment-related adverse events were of grades 1 to 2. Peptide-specific CTL induction by HSP70 and GPC3 proteins was observed in 11 (64.7%) and 13 (76.5%) cases, respectively, regardless of the HLA type. Serum tumor marker levels were decreased in 10 cases (58.8%). Immunological analysis using PBMCs indicated that patients receiving dose level 3 presented with significantly reduced T cell immunoglobulin and mucin-domain containing-3 (TIM3)-expressing CD4 + T cells after one course of treatment. PD-1 or TIM3-expressing CD4 + T cells and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT)-expressing CD8 + T cells in PBMCs before vaccination were negative predictive factors for survival.
CONCLUSIONS
This novel peptide vaccination therapy was safe for patients with metastatic gastrointestinal cancers.
Topics: Adjuvants, Immunologic; Adult; Aged; Aged, 80 and over; Carboxymethylcellulose Sodium; Cohort Studies; Female; Follow-Up Studies; Gastrointestinal Neoplasms; Glypicans; HLA-A Antigens; HLA-G Antigens; HSP70 Heat-Shock Proteins; Humans; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Recurrence, Local; Peptide Fragments; Poly I-C; Polylysine; Prognosis; Survival Rate
PubMed: 32219501
DOI: 10.1007/s00262-020-02518-7 -
Cancer Immunology Research Jan 2020Given its ability to induce both humoral and cellular immune responses, NY-ESO-1 has been considered a suitable antigen for a cancer vaccine. Despite promising results... (Randomized Controlled Trial)
Randomized Controlled Trial
Given its ability to induce both humoral and cellular immune responses, NY-ESO-1 has been considered a suitable antigen for a cancer vaccine. Despite promising results from early-phase clinical studies in patients with melanoma, NY-ESO-1 vaccine immunotherapy has not been widely investigated in larger trials; consequently, many questions remain as to the optimal vaccine formulation, predictive biomarkers, and sequencing and timing of vaccines in melanoma treatment. We conducted an adjuvant phase I/II clinical trial in high-risk resected melanoma to optimize the delivery of poly-ICLC, a TLR-3/MDA-5 agonist, as a component of vaccine formulation. A phase I dose-escalation part was undertaken to identify the MTD of poly-ICLC administered in combination with NY-ESO-1 and montanide. This was followed by a randomized phase II part investigating the MTD of poly-ICLC with NY-ESO-1 with or without montanide. The vaccine regimens were generally well tolerated, with no treatment-related grade 3/4 adverse events. Both regimens induced integrated NY-ESO-1-specific CD4 T-cell and humoral responses. CD8 T-cell responses were mainly detected in patients receiving montanide. T-cell avidity toward NY-ESO-1 peptides was higher in patients vaccinated with montanide. In conclusion, NY-ESO-1 protein in combination with poly-ICLC is safe, well tolerated, and capable of inducing integrated antibody and CD4 T-cell responses in most patients. Combination with montanide enhances antigen-specific T-cell avidity and CD8 T-cell cross-priming in a fraction of patients, indicating that montanide contributes to the induction of specific CD8 T-cell responses to NY-ESO-1.
Topics: Adjuvants, Immunologic; Aged; Antigens, Neoplasm; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cancer Vaccines; Carboxymethylcellulose Sodium; Cross-Priming; Female; Humans; Immunity, Cellular; Immunity, Humoral; Interferon Inducers; Male; Mannitol; Melanoma; Membrane Proteins; Middle Aged; Oleic Acids; Patient Safety; Poly I-C; Polylysine; Skin Neoplasms; Treatment Outcome
PubMed: 31699709
DOI: 10.1158/2326-6066.CIR-19-0545