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glioblastoma immunotherapy

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https://www.readbyqxmd.com/read/28724573/a-single-dose-of-peripherally-infused-egfrviii-directed-car-t-cells-mediates-antigen-loss-and-induces-adaptive-resistance-in-patients-with-recurrent-glioblastoma
#1
Donald M O'Rourke, MacLean P Nasrallah, Arati Desai, Jan J Melenhorst, Keith Mansfield, Jennifer J D Morrissette, Maria Martinez-Lage, Steven Brem, Eileen Maloney, Angela Shen, Randi Isaacs, Suyash Mohan, Gabriela Plesa, Simon F Lacey, Jean-Marc Navenot, Zhaohui Zheng, Bruce L Levine, Hideho Okada, Carl H June, Jennifer L Brogdon, Marcela V Maus
We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)-EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for over 18 months of follow-up...
July 19, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28718815/regional-delivery-of-chimeric-antigen-receptor-car-t-cells-for-cancer-therapy
#2
REVIEW
Praveen Sridhar, Fabio Petrocca
Chimeric Antigen Receptor (CAR) T-cells are T-cells with recombinant receptors targeted to tumor antigens. CAR-T cell therapy has emerged as a mode of immunotherapy and is now being extensively explored in hematologic cancer. In contrast, CAR-T cell use in solid tumors has been hampered by multiple obstacles. Several approaches have been taken to circumvent these obstacles, including the regional delivery of CAR-T cells. Regional CAR-T cell delivery can theoretically compensate for poor T-cell trafficking and tumor antigen specificity while avoiding systemic toxicity associated with intravenous delivery...
July 18, 2017: Cancers
https://www.readbyqxmd.com/read/28706148/expression-differences-of-programmed-death-ligand-1-in-de-novo-and-recurrent-glioblastoma-multiforme
#3
Sabrina Heynckes, Annette Gaebelein, Gerrit Haaker, Jürgen Grauvogel, Pamela Franco, Irina Mader, Maria Stella Carro, Marco Prinz, Daniel Delev, Oliver Schnell, Dieter Henrik Heiland
The biology of recurrent glioblastoma multiforme (GBM) is a dynamic process influenced by selection pressure induced by different antitumoural therapies. The poor clinical outcome of tumours in the recurrent stage necessitates the development of effective therapeutic strategies. Checkpoint-inhibition (PD1/PD-L1 Inhibition) is a hallmark of immunotherapy being investigated in ongoing clinical trials. The purpose of this study was to analyse the PD-L1 expression in de-novo and recurrent glioblastoma multiforme and to explore associated genetic alterations and clinical traits...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28690586/modulations-in-the-peripheral-immune-system-of-glioblastoma-patient-is-connected-to-therapy-and-tumor-progression-a-case-report-from-the-immo-glio-01-trial
#4
Paul F Rühle, Nicole Goerig, Roland Wunderlich, Rainer Fietkau, Udo S Gaipl, Annedore Strnad, Benjamin Frey
Immune responses are important for efficient tumor elimination, also in immune privileged organs such as the brain. Fostering antitumor immunity has therefore become an important challenge in cancer therapy. This cannot only be achieved by immunotherapies as already standard treatments such as radiotherapy and chemotherapy modify the immune system. Consequently, the understanding of how the tumor, the tumor microenvironment, and immune system are modulated by cancer therapy is required for prognosis, prediction, and therapy adaption...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28681349/pharmacotherapy-of-glioblastoma-established-treatments-and-emerging-concepts
#5
REVIEW
Enrico Franceschi, Santino Minichillo, Alba A Brandes
Glioblastoma is the most frequent malignant brain tumor and is characterized by poor prognosis, increased invasiveness, and high recurrence rates. Standard treatment for glioblastoma includes maximal safe surgical resection, radiation, and chemotherapy with temozolomide. Despite treatment advances, only 15-20% of glioblastoma patients survive to 5 years, and no therapies have demonstrated a durable survival benefit in recurrent disease. In the last 10 years, significant advances in knowledge of the biology and molecular pathology of the malignancy have opened the way to new treatment options...
July 5, 2017: CNS Drugs
https://www.readbyqxmd.com/read/28668896/systemic-intravenous-adoptive-transfer-of-autologous-lymphokine-activated-%C3%AE-%C3%AE-t-cells-improves-temozolomide-induced-lymphopenia-in-patients-with-glioma
#6
Yonehiro Kanemura, Miho Sumida, Yoshiko Okita, Ema Yoshioka, Atsuyo Yamamoto, Daisuke Kanematsu, Yukako Handa, Hayato Fukusumi, Yui Inazawa, A I Takada, Masahiro Nonaka, Shin Nakajima, Kanji Mori, Shigenori Goto, Takashi Kamigaki, Tomoko Shofuda, Shusuke Moriuchi, Mami Yamasaki
In this clinical study, we investigated the safety and clinical usefulness of systemic adoptive immunotherapy using autologous lymphokine-activated αβ T-cells (αβ T-cells), combined with standard therapies, in patients with malignant brain tumors. Twenty-three patients with different malignant brain tumors, consisting of 14 treated with temozolomide (TMZ group) and 9 treated without temozolomide (non-TMZ group), received systemic intravenous injections of αβ T-cells (mean=10.4 injections/patient for the TMZ group, and 4...
July 2017: Anticancer Research
https://www.readbyqxmd.com/read/28666020/modulating-glioma-mediated-myeloid-derived-suppressor-cell-development-with-sulforaphane
#7
Ravi Kumar, Tristan de Mooij, Timothy E Peterson, Tatiana Kaptzan, Aaron J Johnson, David J Daniels, Ian F Parney
Glioblastoma is the most common primary tumor of the brain and has few long-term survivors. The local and systemic immunosuppressive environment created by glioblastoma allows it to evade immunosurveillance. Myeloid-derived suppressor cells (MDSCs) are a critical component of this immunosuppression. Understanding mechanisms of MDSC formation and function are key to developing effective immunotherapies. In this study, we developed a novel model to reliably generate human MDSCs from healthy-donor CD14+ monocytes by culture in human glioma-conditioned media...
2017: PloS One
https://www.readbyqxmd.com/read/28651374/cd70-a-novel-target-of-car-t-cell-therapy-for-gliomas
#8
Linchun Jin, Haitao Ge, Yu Long, Changlin Yang, Yifan Emily Chang, Luyan Mu, Elias J Sayour, Gabriel De Leon, Qiong J Wang, James C Yang, Paul S Kubilis, Hongbo Bao, Songsong Xia, Dunyue Lu, Yingjun Kong, Li Hu, Yujiao Shang, Chencheng Jiang, Jing Nie, Shimin Li, Yunhe Gu, Jiahang Sun, Duane A Mitchell, Zhiguo Lin, Jianping Huang
Background: Cancer immunotherapy represents a promising treatment approach for malignant-gliomas, but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified CD70 as a novel immunosuppressive ligand and glioma target. Methods: Normal tissues derived from 52 different organs, and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression...
June 23, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28640704/immunotherapy-for-brain-tumors
#9
John H Sampson, Marcela V Maus, Carl H June
Glioblastoma (GBM) is the most lethal form of brain tumor and remains a large, unmet medical need. This review focuses on recent advances in the neurosciences that converge with the broader field of immuno-oncology. Recent findings in neuroanatomy provide a basis for new approaches of cellular therapies for tumors that involve the CNS. The ultimate success of immunotherapy in the CNS will require improved imaging technologies and methods for analysis of the tumor microenvironment in patients with GBM. It is likely that combinatorial approaches with targeted immunotherapies will be required to exploit the vulnerabilities of GBM and other brain tumors...
July 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28583430/the-egfr-variant-iii-mutant-as-a-target-for-immunotherapy-of-glioblastoma-multiforme
#10
REVIEW
Dimitry A Chistiakov, Ivan V Chekhonin, Vladimir P Chekhonin
In epithelial tumors, the epidermal growth factor receptor (EGFR) controls key signaling pathways responsible for growth, proliferation, migration, and survival of tumor cells. The epidermal growth factor receptor variant III (EGFRvIII) is the most common EGFR mutation that occurs in up to 30% of high-grade gliomas especially glioblastoma multiforme (GBM). EGFRvIII arises from the deletion of exon 2-7 that leads to the formation of the constitutively activated mutant receptor incapable of binding any known ligand...
June 2, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28574813/an-immunocompetent-mouse-model-of-human-glioblastoma
#11
Samantha Semenkow, Shen Li, Ulf D Kahlert, Eric H Raabe, Jiadi Xu, Antje Arnold, Miroslaw Janowski, Byoung Chol Oh, Gerald Brandacher, Jeff W M Bulte, Charles G Eberhart, Piotr Walczak
Orthotopic xenotransplantation studies represent the final stage in preclinical cancer research and could facilitate the implementation of precision medicine. To date, these xenografts have been tested in immunodeficient animals, but complete elimination of the adaptive immunity is a significant drawback. We present a method of efficient human glioblastoma (GBM) cell engraftment in adult mice with intact immune systems, mediated by a transient blockade of T-cell co-stimulation. Compared to transplants grown in immunodeficient hosts, the resulting tumors more accurately resemble the clinical pathophysiology of patient GBMs, which are characterized by blood-brain-barrier leakage and strong neo-vascularization...
May 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28567588/immunotherapy-and-radiation-in-glioblastoma
#12
REVIEW
Solmaz Sahebjam, Andrew Sharabi, Michael Lim, Pravin Kesarwani, Prakash Chinnaiyan
Radiation therapy plays a central role in the management of glioblastoma. Although primarily thought of as modality to provide local tumor control through DNA damage, the capacity of ionizing radiation to modulate tumor immune response has long been recognized. The recent emergence of clinically active immunotherapies offers exciting potential for harnessing the immune modulatory effects or radiation through combinatorial strategies designed to enhance clinical outcomes. In this Review, we provide background describing the unique immune environment within the central nervous system, how ionizing radiation may modulate the tumor immune response, preclinical and clinical data testing the combination of radiation and immune modulating agents, and highlight some of the current challenges in extending these findings clinically...
May 31, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28564668/updates-on-chimeric-antigen-receptor-mediated-glioblastoma-immunotherapy
#13
George Mao, Prakash Sampath, Sadhak Sengupta
Glioblastoma multiforme (GBM) is the most malignant of the primary central nervous system (CNS) neoplasms, accounting for nearly 80% of all primary brain tumors and is associated with high morbidity and mortality. Immunotherapy is proving to be a fertile ground for next-generation GBM therapy, with large translational research projects and clinical trials currently underway. One particularly promising area is the chimeric antigen receptors (CARs) in the context of lymphocyte adoptive cell therapy (ACT), which has achieved success in the treatment of hematological malignancies...
June 1, 2017: Rhode Island Medical Journal
https://www.readbyqxmd.com/read/28554666/human-cytomegalovirus-mediated-immunomodulation-effects-on-glioblastoma-progression
#14
REVIEW
Haidn Foster, Ilya V Ulasov, Charles S Cobbs
The presence of human cytomegalovirus (HCMV) and glioblastoma multiforme (GBM), first established in 2002, has developed into an area of considerable interest and controversy. Numerous studies have found evidence of possible HCMV infection of GBM tumor cells as well as myriad onco- and immunomodulatory properties exhibited by HCMV antigens and transcripts, while recent reports have failed to detect HCMV particles in GBM and question the virus' role in tumor progression. This review highlights the known immunomodulatory properties of HCMV, independent of GBM infection status, that help drive the virus from peripheral blood into the vital tissues and subsequently dampen local immune response, assisting GBM tumors in evading immune surveillance and contributing to the disease's poor prognosis...
May 26, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28550091/transgenic-expression-of-il15-improves-antiglioma-activity-of-il13ralpha2-car-t-cells-but-results-in-antigen-loss-variants
#15
Giedre Krenciute, Brooke L Prinzing, Zhongzhen Yi, Meng-Fen Wu, Hao Liu, Gianpietro Dotti, Irina V Balyasnikova, Stephen Gottschalk
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen receptors (CARs) is an attractive approach to improve outcomes. Although CAR T cells targeting GBM antigens such as IL13Ralpha2 (interleukin 13 Receptor Subunit Alpha 2), HER2 (human epidermal growth factor receptor 2), and EGFRvIII (epidermal growth factor receptor variant III) have had antitumor activity in preclinical models, early phase clinical testing has demonstrated limited antiglioma activity...
May 26, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28544801/nanotherapeutic-systems-for-local-treatment-of-brain-tumors
#16
REVIEW
Rami Walid Chakroun, Pengcheng Zhang, Ran Lin, Paula Schiapparelli, Alfredo Quinones-Hinojosa, Honggang Cui
Malignant brain tumor, including the most common type glioblastoma, are histologically heterogeneous and invasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, chemotherapy, and immunotherapy, the disease inevitably recurs and is fatal. This lack of curative options has motivated researchers to explore new treatment strategies and to develop new drug delivery systems (DDSs); however, the unique anatomical, physiological, and pathological features of brain tumors greatly limit the effectiveness of conventional chemotherapy...
May 24, 2017: Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology
https://www.readbyqxmd.com/read/28539528/prospect-of-immunotherapy-for-glioblastoma-tumor-vaccine-immune-checkpoint-inhibitors-and-combination-therapy
#17
Eiichi Ishikawa, Tetsuya Yamamoto, Akira Matsumura
To date, clinical trials of various vaccine therapies using autologous tumor antigens or tumor-associated/specific antigen peptide with adjuvants have been performed to treat patients with high-grade gliomas (HGG). Furthermore, immune checkpoint pathway-targeted therapies including anti- programmed cell death 1 (PD-1) antibody have been remarkably effective in other neoplasms, and various clinical trials with anti-PD-1 antibody in patients with HGG have started to date. It is possible that up-regulation of immune checkpoint molecules in tumor tissues after vaccine therapy may be one of the mechanisms of vaccine failure...
May 24, 2017: Neurologia Medico-chirurgica
https://www.readbyqxmd.com/read/28536525/immune-checkpoint-in-glioblastoma-promising-and-challenging
#18
REVIEW
Jing Huang, Fangkun Liu, Zhixiong Liu, Hui Tang, Haishan Wu, Qianni Gong, Jindong Chen
Glioblastoma (GBM) is a severe malignant brain cancer with poor overall survival. Conventional intervention remains dismal to prevent recurrence and deterioration of GBM cell. Recent years have witnessed exciting breakthroughs in novel immune strategies, especially checkpoint inhibitors, some of which have become adjuvant setting after standard of care in melanoma. Several clinical trials of checkpoint inhibitors are ongoing in glioblastoma and other brain carcinomas. Plus, synergistic combinations of checkpoint inhibitors with conventional therapy strategies-radiotherapy, temozolomide, bevacizumab, and corticosteroids are now being exploited and applied in clinical settings...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28529551/history-and-current-state-of-immunotherapy-in-glioma-and-brain-metastasis
#19
REVIEW
Tresa McGranahan, Gordon Li, Seema Nagpal
Malignant brain tumors such as glioblastoma (GBM) and brain metastasis have poor prognosis despite conventional therapies. Successful use of vaccines and checkpoint inhibitors in systemic malignancy has increased the hope that immune therapies could improve survival in patients with brain tumors. Manipulating the immune system to fight malignancy has a long history of both modest breakthroughs and pitfalls that should be considered when applying the current immunotherapy approaches to patients with brain tumors...
May 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28521700/glioblastoma-multiforme-diagnosis-and-treatment-recent-literature-review
#20
Ron Batash, Noam Asna, Pamela Schaffer, Nicole Francis, Moshe Schaffer
BACKGROUND: Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor, with an incidence of 3.19 cases per 100,000 person years and remarkably poor prognosis showing a 5-year survival rate of 4-5%, and only a 26-33% survival rate at 2 years in clinical trials. OBJECTIVE: In this paper, we review the different types of treatment modalities based on the relevant databases. Methods of diagnosis will be described briefly. METHOD: Systemic compilation of the relevant literature...
May 16, 2017: Current Medicinal Chemistry
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