المؤلفون: Pavlina Chuntova, Kira Downey, Ryusuke Hatae, Tiffany A Chen, Abigail L Mende, Megan Montoya, Bjoern Schwer, Jayne Skinner, Hideho Okada, Gary Kohanbash, Takahide Nejo, Yitzhar E. Goretsky, Yafei Hou, Hong-Erh Liang, David Diebold, Akane Yamamichi, Ryosuke Naka

المصدر: Neuro-oncology, vol 24, iss 2
Neuro Oncol

مصطلحات موضوعية: EGFRvIII, Genetically modified mouse, Cancer Research, Transgene, medicine.medical_treatment, Adoptive, Oncology and Carcinogenesis, Mice, Transgenic, Biology, Inbred C57BL, Immunotherapy, Adoptive, Transgenic, Cell Line, Viral vector, Vaccine Related, Mice, Rare Diseases, In vivo, Cell Line, Tumor, Receptors, Genetics, medicine, Animals, Cytotoxic T cell, Oncology & Carcinogenesis, Epidermal growth factor receptor, Cancer, Receptors, Chimeric Antigen, Tumor, CART cells, glioblastoma, Neurosciences, Chimeric Antigen, Gene Therapy, Immunotherapy, Chimeric antigen receptor, Brain Disorders, Mice, Inbred C57BL, ErbB Receptors, Brain Cancer, Oncology, Basic and Translational Investigations, Cancer research, biology.protein, Immunization, immunotherapy, Neurology (clinical), Glioblastoma

الوصف: Background Rigorous preclinical studies of chimeric antigen receptor (CAR) immunotherapy will require large quantities of consistent and high-quality CAR-transduced T (CART) cells that can be used in syngeneic mouse glioblastoma (GBM) models. To this end, we developed a novel transgenic (Tg) mouse strain with a fully murinized CAR targeting epidermal growth factor receptor variant III (EGFRvIII). Methods We first established the murinized version of EGFRvIII-CAR and validated its function using a retroviral vector (RV) in C57BL/6J mice bearing syngeneic SB28 GBM expressing EGFRvIII. Next, we created C57BL/6J-background Tg mice carrying the anti-EGFRvIII-CAR downstream of a Lox-Stop-Lox cassette in the Rosa26 locus. We bred these mice with CD4-Cre Tg mice to allow CAR expression on T cells and evaluated the function of the CART cells both in vitro and in vivo. To inhibit immunosuppressive myeloid cells within SB28 GBM, we also evaluated a combination approach of CART and an anti-EP4 compound (ONO-AE3-208). Results Both RV- and Tg-CART cells demonstrated specific cytotoxic activities against SB28-EGFRvIII cells. A single intravenous infusion of EGFRvIII-CART cells prolonged the survival of glioma-bearing mice when preceded by a lymphodepletion regimen with recurrent tumors displaying profound EGFRvIII loss. The addition of ONO-AE3-208 resulted in long-term survival in a fraction of CART-treated mice and those survivors demonstrated delayed growth of subcutaneously re-challenged both EGFRvIII+ and parental EGFRvIII− SB28. Conclusion Our new syngeneic CAR Tg mouse model can serve as a useful tool to address clinically relevant questions and develop future immunotherapeutic strategies.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e413a9fb76c4ae0a30fdd3ad9738da0bTest
https://doi.org/10.1093/neuonc/noab182Test

المؤلفون: Christine E. Brown, Samantha Bucktrout, Lisa H. Butterfield, Olga Futer, Evanthia Galanis, Adilia Hormigo, Michael Lim, Hideho Okada, Robert Prins, Sara Siebel Marr, Kirk Tanner

المصدر: Journal of translational medicine, vol 20, iss 1

مصطلحات موضوعية: Adult, Pediatric Cancer, Immunology, Cell- and Tissue-Based Therapy, Brain tumors, Medical and Health Sciences, General Biochemistry, Genetics and Molecular Biology, Cell therapy, Vaccine Related, Rare Diseases, Clinical Research, Tumor Microenvironment, Animals, Humans, Immunologic Factors, Child, Cancer, Pediatric, Brain Neoplasms, Neurosciences, General Medicine, Brain Disorders, Brain Cancer, Orphan Drug, Good Health and Well Being, Immunization, Immunotherapy, Biotechnology

الوصف: Harnessing the effector mechanisms of the immune system to combat brain tumors with antigen specificity and memory has been in research and clinical testing for many years. Government grant mechanisms and non-profit organizations have supported many innovative projects and trials while biotech companies have invested in the development of needed tools, assays and novel clinical approaches. The National Brain Tumor Society and the Parker Institute for Cancer Immunotherapy partnered to host a workshop to share recent data, ideas and identify both hurdles and new opportunities for harnessing immunotherapy against pediatric and adult brain tumors. Adoptively transferred cell therapies have recently shown promising early clinical results. Local cell delivery to the brain, new antigen targets and innovative engineering approaches are poised for testing in a new generation of clinical trials. Although several such advances have been made, several obstacles remain for the successful application of immunotherapies for brain tumors, including the need for more representative animal models that can better foreshadow human trial outcomes. Tumor and tumor microenvironment biopsies with multiomic analysis are critical to understand mechanisms of response and patient stratification, yet brain tumors are especially challenging for such biopsy collection. These workshop proceedings and commentary shed light on the status of immunotherapy in pediatric and adult brain tumor patients, including current research as well as opportunities for improving future efforts to bring immunotherapy to the forefront in the management of brain tumors.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::76e23ae7c36a983774317a15f6deedc9Test
https://escholarship.org/uc/item/1968r34gTest

المؤلفون: Hirokazu Ogino, Jennie W. Taylor, Takahide Nejo, David Gibson, Payal B. Watchmaker, Kaori Okada, Atsuro Saijo, Meghan R. Tedesco, Anny Shai, Cynthia M. Wong, Jane E. Rabbitt, Michael R. Olin, Christopher L. Moertel, Yasuhiko Nishioka, Andres M. Salazar, Annette M. Molinaro, Joanna J. Phillips, Nicholas A. Butowski, Jennifer L. Clarke, Nancy Ann Oberheim Bush, Shawn L. Hervey-Jumper, Philip Theodosopoulos, Susan M. Chang, Mitchel S. Berger, Hideho Okada

المصدر: The Journal of clinical investigation, vol 132, iss 3
The Journal of Clinical Investigation

مصطلحات موضوعية: Adult, Male, and promotion of well-being, Clinical Trials and Supportive Activities, Immunology, T cells, Cancer immunotherapy, CD8-Positive T-Lymphocytes, Brain cancer, Cancer Vaccines, Medical and Health Sciences, Vaccine Related, Rare Diseases, Clinical Research, Tumor Microenvironment, Humans, Polylysine, Aged, Cancer, Vaccines, Prevention, Vaccination, Neurosciences, Evaluation of treatments and therapeutic interventions, General Medicine, Glioma, Middle Aged, Prevention of disease and conditions, Neoadjuvant Therapy, Brain Disorders, Poly I-C, Orphan Drug, Good Health and Well Being, Oncology, 3.4 Vaccines, Carboxymethylcellulose Sodium, 6.1 Pharmaceuticals, Female, Immunization, Clinical Medicine, Infection, Biotechnology

الوصف: BACKGROUND Long-term prognosis of WHO grade II low-grade gliomas (LGGs) is poor, with a high risk of recurrence and malignant transformation into high-grade gliomas. Given the relatively intact immune system of patients with LGGs and the slow tumor growth rate, vaccines are an attractive treatment strategy. METHODS We conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGGs. Patients were randomized to receive the vaccines before surgery (arm 1) or not (arm 2) and all patients received adjuvant vaccines. Coprimary outcomes were to evaluate safety and immune response in the tumor. RESULTS A total of 17 eligible patients were enrolled — 9 in arm 1 and 8 in arm 2. This regimen was well tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines and increased activated CD8+ T cells in peripheral blood. Single-cell RNA/T cell receptor sequencing detected CD8+ T cell clones that expanded with effector phenotype and migrated into the tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident–like CD8+ T cells with effector memory phenotype in the TME after the neoadjuvant vaccination. CONCLUSION The regimen induced effector CD8+ T cell response in peripheral blood and enabled vaccine-reactive CD8+ T cells to migrate into the TME. Further refinements of the regimen may have to be integrated into future strategies. TRIAL REGISTRATION ClinicalTrials.gov NCT02549833. FUNDING NIH (1R35NS105068, 1R21CA233856), Dabbiere Foundation, Parker Institute for Cancer Immunotherapy, and Daiichi Sankyo Foundation of Life Science.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7be027edfe85ce3bf383e785759b0027Test
https://escholarship.org/uc/item/00d0f4fmTest

المؤلفون: Ashok Panigrahy, Regina I. Jakacki, Ian F. Pollack, Rafael Ceschin, Hideho Okada, Marvin D. Nelson, Gary Kohanbash, Girish Dhall, Stefan Bluml

المصدر: Cancers, vol 14, iss 23
Cancers; Volume 14; Issue 23; Pages: 5995

مصطلحات موضوعية: Cancer Research, myo-inositol, Prevention, MR spectroscopy, brainstem glioma, pediatric brain tumor, Oncology and Carcinogenesis, Neurosciences, Brain Disorders, Brain Cancer, Vaccine Related, creatine, Orphan Drug, Rare Diseases, Good Health and Well Being, Oncology, choline, Clinical Research, immunotherapy, vaccine therapy, Biomedical Imaging, Immunization, Cancer, Biotechnology

الوصف: Purpose: Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive tumors with no currently available curative therapy. This study evaluated whether measurements of in vivo cell metabolites using magnetic resonance spectroscopy (MRS) may serve as biomarkers of response to therapy, including progression. Methods: Single-voxel MR spectra were serially acquired in two cohorts of patients with DIPG treated with radiation therapy (RT) with or without concurrent chemotherapy and prior to progression: 14 participants were enrolled in a clinical trial of adjuvant glioma-associated antigen peptide vaccines and 32 patients were enrolled who did not receive adjuvant vaccine therapy. Spearman correlations measured overall survival associations with absolute metabolite concentrations of myo-inositol (mI), creatine (Cr), and n-acetyl-aspartate (NAA) and their ratios relative to choline (Cho) during three specified time periods following completion of RT. Linear mixed-effects regression models evaluated the longitudinal associations between metabolite ratios and time from death (terminal decline). Results: Overall survival was not associated with metabolite ratios obtained shortly after RT (1.9–3.8 months post-diagnosis) in either cohort. In the vaccine cohort, an elevated mI/Cho ratio after 2–3 doses (3.9–5.2 months post-diagnosis) was associated with longer survival (rho = 0.92, 95% CI 0.67–0.98). Scans performed up to 6 months before death showed a terminal decline in the mI/Cho ratio, with an average of 0.37 ratio/month in vaccine patients (95% CI 0.11–0.63) and 0.26 (0.04–0.48) in the non-vaccine cohort. Conclusion: Higher mI/Cho ratios following RT, consistent with less proliferate tumors and decreased cell turnover, were associated with longer survival, suggesting that this ratio can serve as a biomarker of prognosis following RT. This finding was seen in both cohorts, although the association with OS was detected earlier in the vaccine cohort. Increased mI/Cho (possibly reflecting immune-effector cell influx into the tumor as a mechanism of tumor response) requires further study.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7d596941f56fa7427bfd88dec24f36ffTest
https://doi.org/10.3390/cancers14235995Test

المؤلفون: Hideho Okada, Takahide Nejo, Abigail L Mende

المصدر: Japanese journal of clinical oncology, vol 50, iss 11
Jpn J Clin Oncol

مصطلحات موضوعية: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_treatment, immune checkpoint inhibitor, 0302 clinical medicine, glioma, vaccine, Tumor Microenvironment, brain metastasis, Cancer, Clinical Trials as Topic, Brain Neoplasms, General Medicine, 030220 oncology & carcinogenesis, Immunotherapy, immunotherapy, brain tumor, Review Article (Invited), medicine.medical_specialty, Oncology and Carcinogenesis, Antigen presentation, Brain tumor, Context (language use), Cancer Vaccines, cellular immunotherapy, Vaccine Related, 03 medical and health sciences, Rare Diseases, Immune system, Internal medicine, Glioma, medicine, Humans, Radiology, Nuclear Medicine and imaging, Oncology & Carcinogenesis, Tumor microenvironment, viral immunotherapy, business.industry, glioblastoma, Neurosciences, central nervous system, medicine.disease, Brain Disorders, Brain Cancer, antigen presentation, Orphan Drug, Good Health and Well Being, 030104 developmental biology, Immunization, Glioblastoma, business, Brain metastasis

الوصف: Treatment and resolution of primary and metastatic brain tumors have long presented a challenge to oncologists. In response to the dismal survival outcomes associated with conventional therapies, various immunotherapy modalities, such as checkpoint inhibitors, vaccine, cellular immunotherapy and viral immunotherapy have been actively explored over the past couple of decades. Although improved patient survival has been more frequently noted in treatment of brain metastases, little progress has been made in improving patient survival in cases of primary brain tumors, specifically glioblastoma, which is the representative primary brain tumor discussed in this review. Herein, we will first overview the findings of recent clinical studies for treatment of primary and metastatic brain tumors with immunotherapeutic interventions. The clinical efficacy of these immunotherapies will be discussed in the context of their ability or inability to overcome inherent characteristics of the tumor as well as restricted antigen presentation and its immunosuppressive microenvironment. Additionally, this review aims to briefly inform clinicians in the field of neuro-oncology on the relevant aspects of the immune system as it pertains to the central nervous system, with special focus on the differing modes of antigen presentation and tumor microenvironment of primary and metastatic brain tumors and the role these differences may play in the efficacy of immunotherapy in eradicating the tumor.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c980d38ebb724c9448d0c9c5c780c410Test
https://doi.org/10.1093/jjco/hyaa164Test

المؤلفون: Erin R Bonner, Lisa H. Butterfield, Annette M. Molinaro, Nicholas S Whipple, Michael D. Prados, Jared Taitt, Andres M. Salazar, Ryan Gilbert, Sabine Mueller, Javad Nazarian, Neil D. Almeida, Anu Banerjee, Hideho Okada, Susan N. Chi, Karen Gauvain, Javier Villanueva-Meyer, Kellie J. Nazemi, John Robertson Crawford, Rishi Lulla, Payal Watchmaker, Takahide Nejo, Kaori Okada, Stewart Goldman

المساهمون: University of Zurich, Okada, Hideho

المصدر: J Clin Invest
The Journal of clinical investigation, vol 130, iss 12

مصطلحات موضوعية: 0301 basic medicine, Oncology, Male, Cancer immunotherapy, 2700 General Medicine, CD8-Positive T-Lymphocytes, Brain cancer, Medical and Health Sciences, Histones, 0302 clinical medicine, Brain Stem Neoplasms, Child, Stroke, Cancer, Pediatric, Vaccines, Immunity, Cellular, Brain Neoplasms, General Medicine, Glioma, Flow Cytometry, Neoplasm Proteins, medicine.anatomical_structure, 6.1 Pharmaceuticals, 030220 oncology & carcinogenesis, Child, Preschool, Female, Corrigendum, medicine.drug, Adult, medicine.medical_specialty, Adolescent, T cell, Immunology, Clinical Trials and Supportive Activities, Mutation, Missense, 610 Medicine & health, Peripheral blood mononuclear cell, Cancer Vaccines, Vaccine Related, 03 medical and health sciences, Rare Diseases, Clinical Research, Internal medicine, Injection site reaction, medicine, Humans, Preschool, Adverse effect, Dexamethasone, business.industry, Immunity, Neurosciences, Evaluation of treatments and therapeutic interventions, medicine.disease, Brain Disorders, Good Health and Well Being, 030104 developmental biology, Amino Acid Substitution, 10036 Medical Clinic, Mutation, Immunization, Cellular, Missense, Clinical Medicine, business, CD8

الوصف: BACKGROUND: Patients 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. METHODS: Newly 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. RESULTS: A 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. CONCLUSION: Administration of the H3.3K27M-specific vaccine was well tolerated. Patients with H3.3K27M-specific CD8(+) immunological responses demonstrated prolonged OS compared with nonresponders. TRIAL REGISTRATION: ClinicalTrials.gov NCT02960230. FUNDING: The 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).

وصف الملف: Nazarian-Okada-JCI.pdf - application/pdf; jci_132_162283.pdf - application/pdf; application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::84a8e6a5f77d04da4104612962026915Test

المؤلفون: Hideho Okada, Darwin Kwok

المصدر: Journal of neuro-oncology, vol 147, iss 2
J Neurooncol

مصطلحات موضوعية: Cancer Research, T-Lymphocytes, medicine.medical_treatment, Adoptive, Oncology and Carcinogenesis, Brain tumor, Immunotherapy, Adoptive, Article, Vaccine Related, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Immune system, T-cell, Cancer immunotherapy, Glioma, Tumor Microenvironment, medicine, Animals, Humans, Oncology & Carcinogenesis, Cancer, Immunosuppression Therapy, Tumor microenvironment, Brain Neoplasms, business.industry, Neurosciences, Immunosuppression, Immunotherapy, medicine.disease, Chimeric antigen receptor, CAR, Brain Disorders, Brain Cancer, Orphan Drug, Neurology, Oncology, 030220 oncology & carcinogenesis, Cancer research, Immunization, Neurology (clinical), Glioblastoma, business, Vaccine, 030217 neurology & neurosurgery

الوصف: Glioblastoma remains as the most common and aggressive primary adult brain tumor to date. Within the last decade, cancer immunotherapy surfaced as a broadly successful therapeutic approach for a variety of cancers. However, due to the neuroanatomical and immunosuppressive nature of malignant gliomas, conventional chemotherapy and radiotherapy treatments garner limited efficacy in patients with these tumors. The intricate structure of the blood brain barrier restricts immune accessibility into the tumor microenvironment, and malignant gliomas can activate various adaptive responses to subvert anticancer immune responses and reinstate an immunosuppressive milieu. Yet, evidence of lymphocyte infiltration within the brain and recent advancements made in cell engineering technologies implicate the vast potential in the future of neuro-oncological immunotherapy. Previous immunotherapy platforms have paved way to improved modalities, which includes but is not limited to personalized vaccines and chimeric antigen receptor T-cell therapy. This review will cover the various neuroanatomical and immunosuppressive features of central nervous system tumors and highlight the innovations made in T-cell based therapies to overcome the challenges presented by the glioblastoma microenvironment.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1215d76c106065d08228d633c8a0090eTest
https://doi.org/10.1007/s11060-020-03450-7Test

المؤلفون: Noriyuki Kasahara, Hideho Okada, Megan Montoya

المصدر: Neurooncol Pract
Neuro-oncology practice, vol 7, iss 5

مصطلحات موضوعية: Oncology, medicine.medical_specialty, medicine.medical_treatment, Brain tumor, Reviews, Medicine (miscellaneous), Vaccine Related, checkpoint, Rare Diseases, Clinical Research, glioma, vaccine, Internal medicine, Glioma, medicine, Cancer, 5.2 Cellular and gene therapies, business.industry, glioblastoma, Neurosciences, Immunotherapy, medicine.disease, Chimeric antigen receptor, Brain Disorders, Oncolytic virus, Brain Cancer, Radiation therapy, Orphan Drug, Immunization, Chimeric Antigen Receptor T-Cell Therapy, immunotherapy, business

الوصف: Malignant gliomas, including glioblastoma (GBM) as the most aggressive type of adult CNS tumors, are notoriously resistant to current standard of care treatments, including surgery, systemic chemotherapy, and radiation therapy (RT). This lack of effective treatment options highlights the urgent need for novel therapies, including immunotherapies. The overarching goal of immunotherapy is to stimulate and activate the patient’s immune system in a targeted manner to kill tumor cells. The success of immunotherapeutic interventions in other cancer types has led to interest in and evaluation of various experimental immunotherapies in patients with malignant gliomas. However, these primary malignant brain tumors present a challenge because they exist in a vital and sensitive organ with a unique immune environment. The challenges and current status of experimental immunotherapeutic approaches, including vaccines, immune-checkpoint blockade, chimeric antigen receptor T-cell therapy, and oncolytic viruses will be discussed, as well as the potential for combinatorial therapies.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a861deeae146fa68402db7ad1ea1cfaaTest
https://doi.org/10.1093/nop/npaa007Test

المؤلفون: Paula Alcaide-Leon, Janine M. Lupo, Jennifer Clarke, Tracy Luks, Marisa Lafontaine, Javier Villanueva-Meyer, Hideho Okada

المصدر: Journal of neuro-oncology, vol 146, iss 1
J Neurooncol

مصطلحات موضوعية: Male, Cancer Research, Pathology, medicine.medical_treatment, 0302 clinical medicine, Neoplasms, Heat-Shock Proteins, Cancer, screening and diagnosis, medicine.diagnostic_test, Brain Neoplasms, Neoplasms, Second Primary, Chemoradiotherapy, Middle Aged, Prognosis, Combined Modality Therapy, Survival Rate, Detection, Second Primary, Neurology, Oncology, 030220 oncology & carcinogenesis, Disease Progression, Biomedical Imaging, Female, Immunotherapy, Biotechnology, 4.2 Evaluation of markers and technologies, Adult, medicine.medical_specialty, Active, Clinical Trials and Supportive Activities, Oncology and Carcinogenesis, Article, Vaccine Related, Necrosis, 03 medical and health sciences, Magnetic resonance imaging, Rare Diseases, Clinical Research, medicine, Humans, Effective diffusion coefficient, Oncology & Carcinogenesis, Retrospective Studies, Aged, business.industry, Neurosciences, Immunotherapy, Active, medicine.disease, Vaccine therapy, Brain Disorders, Brain Cancer, Radiation therapy, Diffusion Magnetic Resonance Imaging, ROC Curve, Tumor progression, Immunization, Neurology (clinical), Glioblastoma, business, 030217 neurology & neurosurgery, Progressive disease, Follow-Up Studies

الوصف: OBJECTIVES: Treatment-induced lesions represent a great challenge in neuro-oncology. The aims of this study were (i) to characterize treatment induced lesions in glioblastoma patients treated with chemoradiotherapy and heat-shock protein (HSP) vaccine and (ii) to evaluate the diagnostic accuracy of diffusion weighted imaging (DWI) for differentiation between treatment-induced lesions and tumor progression. METHODS: Twenty-seven patients with newly diagnosed glioblastoma treated with heat-shock protein vaccine and chemoradiotherapy were included. Serial magnetic resonance imaging (MRI) evaluation was performed to detect treatment-induced lesions and assess their growth. Quantitative analysis of the apparent diffusion coefficient (ADC) was performed to discriminate treatment-induced lesions from tumor progression. Mann Whitney U-test and receiver operating characteristic (ROC) curves were used for analysis. RESULTS: Thirty-three percent of patients developed treatment-induced lesions. Five treatment-related lesions appeared between end of radiotherapy and the first vaccine administration; 4 lesions within the first 4 months from vaccine initiation and 1 at 3.5 years. Three patients with pathology proven treatment-induced lesions showed a biphasic growth pattern progressed shortly after. Apparent diffusion coefficient (ADC) ratio between the peripheral enhancing rim and central necrosis showed an accuracy of 0.84 (95%CI: 0.63–1) for differentiation between progression and treatment-induced lesions. CONCLUSION: Our findings do not support the iRANO recommendation of a 6-month time window in which progressive disease should not be declared after immunotherapy initiation. A biphasic growth pattern of pathologically proven treatment-induced lesions was associated with a dismal prognosis. The presence of lower ADC values in the central necrotic portion of the lesions compared to the enhancing rim shows high specificity for detection of treatment-induced lesions.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d288b7a1eac039bc5ae54073ad8c51feTest
https://doi.org/10.1007/s11060-019-03336-3Test

المؤلفون: Hideho Okada, Lawrence Fong, Christine E Brown, Shilpa A Shahani, Paul R Walker, Meenal Sinha, Eric V Liu, Erin F Simonds, Edbert D Lu, Oscar Badillo, Shokoufeh Karimi, Whitney Tamaki, Chiara Rancan, Kira M Downey, Jacob Stultz, Lauren K McHenry, Nicole M Nasholm, Pavlina Chuntova, Anders Sundström, Vassilis Genoud, Leo D Wang, Fredrik J Swartling, William A Weiss, Mats Hellström

المصدر: Journal for immunotherapy of cancer, vol 9, iss 6
Journal for Immunotherapy of Cancer
Journal for ImmunoTherapy of Cancer, Vol 9, Iss 6 (2021)

مصطلحات موضوعية: tumor, T-Lymphocytes, Programmed Cell Death 1 Receptor, T-Lymphocytes, Regulatory, Cell Line, Mice, Rare Diseases, Cell Line, Tumor, Animals, Humans, tumor microenvironment, CTLA-4 Antigen, dendritic cells, Immune Checkpoint Inhibitors, RC254-282, Cancer, Cancer och onkologi, brain neoplasms, Neurosciences, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunology in the medical area, Membrane Proteins, biomarkers, Basic Tumor Immunology, Xenograft Model Antitumor Assays, Regulatory, Brain Disorders, Brain Cancer, Good Health and Well Being, Cancer and Oncology, Immunologi inom det medicinska området, Tumor Escape, Immunization, immunotherapy, Glioblastoma

الوصف: Background Glioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed. Methods We used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations. Results ICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation. Conclusions Our data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::fea7cbcc923ca86da6007e509e13d57bTest
https://escholarship.org/uc/item/4vc1g5d2Test