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Benjamin Benzon, Stephanie A Glavaris, Brian W Simons, Robert M Hughes, Kamyar Ghabili, Patrick Mullane, Rebecca Miller, Katriana Nugent, Brian Shinder, Jeffrey Tosoian, Ephraim J Fuchs, Phuoc T Tran, Paula J Hurley, Milena Vuica-Ross, Edward M Schaeffer, Charles G Drake, Ashley E Ross
BACKGROUND: Prostate cancer remains the second leading cause of cancer related death in men. Immune check point blocking antibodies have revolutionized treatment of multiple solid tumors, but results in prostate cancer remain marginal. Previous reports have suggested that local therapies, in particular cryoablation might increase tumor immunogenicity. In this work, we examine potential synergism between tumor cryoabalation and check point blocking antibodies. METHODS: FVB/NJ mice were injected subcutaneously into each flank with either 1 × 106 or 0...
March 20, 2018: Prostate Cancer and Prostatic Diseases
Jessica Da Gama Duarte, Sagun Parakh, Miles C Andrews, Katherine Woods, Anupama Pasam, Candani Tutuka, Simone Ostrouska, Jonathan M Blackburn, Andreas Behren, Jonathan Cebon
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced melanoma. The first ICI to demonstrate clinical benefit, ipilimumab, targets cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4); however, the long-term overall survival is just 22%. More than 40 years ago intralesional (IL) bacillus Calmette-Guérin (BCG), a living attenuated strain of Mycobacterium bovis , was found to induce tumor regression by stimulating cell-mediated immunity following a localized and self-limiting infection...
2018: Frontiers in Immunology
Amanda Przespolewski, Andras Szeles, Eunice S Wang
Evasion of the host immune system is a key mechanism to promote malignant progression. Therapeutically targeting immune pathways has radically changed the treatment paradigm for solid and lymphoid tumors but has yet to be approved for myeloid malignancies. Here, we summarize the most recent advances in immunotherapy for acute myeloid leukemia. Topics reviewed here include adoptive cellular approaches (chimeric antigen receptor-T cells, natural killer and other immune cells), checkpoint inhibitors (anti-PD-1/PD-L1, anti-CTLA-4 and TIM-3) and vaccines (WT-1, HLA-A2 and hTERT)...
March 15, 2018: Future Oncology
Priyanka B Subrahmanyam, Zhiwan Dong, Daniel Gusenleitner, Anita Giobbie-Hurder, Mariano Severgnini, Jun Zhou, Michael Manos, Lauren M Eastman, Holden T Maecker, F Stephen Hodi
BACKGROUND: While immune checkpoint blockade has greatly improved clinical outcomes in diseases such as melanoma, there remains a need for predictive biomarkers to determine who will likely benefit most from which therapy. To date, most biomarkers of response have been identified in the tumors themselves. Biomarkers that could be assessed from peripheral blood would be even more desirable, because of ease of access and reproducibility of sampling. METHODS: We used mass cytometry (CyTOF) to comprehensively profile peripheral blood of melanoma patients, in order to find predictive biomarkers of response to anti-CTLA-4 or anti-PD-1 therapy...
March 6, 2018: Journal for Immunotherapy of Cancer
Audrey Humphries, Adil Daud
Although immunotherapy has been remarkably effective across multiple cancer types, there continues to be a significant number of non-responding patients. A possible factor proposed to influence the efficacy of immunotherapies is the gut microbiome. We discuss the results and implications of recent research on the relationship between the gut microbiome, our immune systems, and immune checkpoint inhibitor therapies including anti-CTLA-4 Ab and anti-PD-1 Ab. While the investigations all exhibit interesting results and conclusions, we find little congruence in the specific bacteria that were found favorable for antitumor responses...
March 1, 2018: Human Vaccines & Immunotherapeutics
Michiru Shiba, Hidefumi Inaba, Hiroyuki Ariyasu, Shintaro Kawai, Yuko Inagaki, Shohei Matsuno, Hiroshi Iwakura, Yuki Yamamoto, Masahiro Nishi, Takashi Akamizu
An 80-year-old woman with malignant melanoma received 20 cycles of anti-PD-1 antibody (nivolumab) treatment and showed normal glucose tolerance. Three weeks after switching to anti-CTLA-4 antibody (ipilimumab), her plasma glucose level was elevated to 639 mg/dL, her HbA1c was 7.7%, and her fastening serum CPR was undetectable. Anti-GAD and IA-2 antibodies were negative. She was diagnosed with fulminant type 1 diabetes mellitus (F1DM). Remarkably, her anti-insulin antibody was positively converted, and her KL-6 levels increased after ipilimumab therapy...
February 28, 2018: Internal Medicine
Ryo Koda, Hirofumi Watanabe, Masafumi Tsuchida, Noriaki Iino, Kazuo Suzuki, Go Hasegawa, Naofumi Imai, Ichiei Narita
BACKGROUND: Acute tubulointerstitial nephritis (ATIN) has been increasingly recognized as an important manifestation of kidney injury associated with the use of immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4). While the exact pathophysiology remains unknown, corticosteroids are the mainstay of management. CASE PRESENTATION: We describe a 67-year-old man with stage IV non-small-cell lung cancer who developed kidney injury during treatment with the anti-PD-1 antibody nivolumab...
February 27, 2018: BMC Nephrology
Rui Kuai, Xiaoqi Sun, Wenmin Yuan, Yao Xu, Anna Schwendeman, James J Moon
While cancer immunotherapy provides new exciting treatment options for patients, there is an urgent need for new strategies that can synergize with immune checkpoint blockers and boost the patient response rates. We have developed a personalized vaccine nanodisc platform based on synthetic high-density lipoproteins for co-delivery of immunostimulatory agents and tumor antigens, including tumor-specific neoantigens. Here we examined the route of delivery, safety profiles, and therapeutic efficacy of nanodisc vaccination against established tumors...
February 27, 2018: Bioconjugate Chemistry
Yared Hailemichael, Amber Woods, Tihui Fu, Qiuming He, Michael C Nielsen, Farah Hasan, Jason Roszik, Zhilan Xiao, Christina Vianden, Hiep Khong, Manisha Singh, Meenu Sharma, Faisal Faak, Derek Moore, Zhimin Dai, Scott M Anthony, Kimberly S Schluns, Padmanee Sharma, Victor H Engelhard, Willem W Overwijk
Anticancer vaccination is a promising approach to increase the efficacy of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1) checkpoint blockade therapies. However, the landmark FDA registration trial for anti-CTLA-4 therapy (ipilimumab) revealed a complete lack of benefit of adding vaccination with gp100 peptide formulated in incomplete Freund's adjuvant (IFA). Here, using a mouse model of melanoma, we found that gp100 vaccination induced gp100-specific effector T cells (Teffs), which dominantly forced trafficking of anti-CTLA-4-induced, non-gp100-specific Teffs away from the tumor, reducing tumor control...
February 26, 2018: Journal of Clinical Investigation
Hiroyuki Ariyasu, Hidefumi Inaba, Takayuki Ota, Hiroyuki Yamaoka, Yasushi Furukawa, Hiroshi Iwakura, Naotaka Doi, Yuki Yamamoto, Takashi Akamizu
BACKGROUND: Immune-checkpoint inhibitors (ICIs) are novel promising agents for the treatment of malignant tumors. However, critical endocrine immune-related adverse events (irAEs) by ICIs often occur. CASE REPORT: A 63-year-old woman with advanced malignant melanoma had received anti-PD-1 antibody (nivolumab, 2 mg/kg every 3 weeks) for 8 cycles (from day 0 to day 147). On day 168, nivolumab was switched to anti-CTLA-4 antibody (ipilimumab, 3mg/kg every 3 weeks)...
March 2018: In Vivo
Xuexiang Du, Fei Tang, Mingyue Liu, Juanjuan Su, Yan Zhang, Wei Wu, Martin Devenport, Christopher A Lazarski, Peng Zhang, Xu Wang, Peiying Ye, Changyu Wang, Eugene Hwang, Tinghui Zhu, Ting Xu, Pan Zheng, Yang Liu
It is assumed that anti-CTLA-4 antibodies cause tumor rejection by blocking negative signaling from B7-CTLA-4 interactions. Surprisingly, at concentrations considerably higher than plasma levels achieved by clinically effective dosing, the anti-CTLA-4 antibody Ipilimumab blocks neither B7 trans-endocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Consequently, Ipilimumab does not increase B7 on dendritic cells (DCs) from either CTLA4 gene humanized (Ctla4h/h ) or human CD34+ stem cell-reconstituted NSG™ mice...
February 22, 2018: Cell Research
Xuexiang Du, Mingyue Liu, Juanjuan Su, Peng Zhang, Fei Tang, Peiying Ye, Martin Devenport, Xu Wang, Yan Zhang, Yang Liu, Pan Zheng
Anti-CTLA-4 monoclonal antibodies (mAbs) confer a cancer immunotherapeutic effect (CITE) but cause severe immunotherapy-related adverse events (irAE). Targeting CTLA-4 has shown remarkable long-term benefit and thus remains a valuable tool for cancer immunotherapy if the irAE can be brought under control. An animal model, which recapitulates clinical irAE and CITE, would be valuable for developing safer CTLA-4-targeting reagents. Here, we report such a model using mice harboring the humanized Ctla4 gene. In this model, the clinically used drug, Ipilimumab, induced severe irAE especially when combined with an anti-PD-1 antibody; whereas another mAb, L3D10, induced comparable CITE with very mild irAE under the same conditions...
February 20, 2018: Cell Research
Muhammad Zubair Afzal, Rodwell Mabaera, Keisuke Shirai
BACKGROUND: Uveal melanoma accounts for 85% of the ocular melanomas and has an increased risk of hematogenous spread, most commonly to the liver. After curative intent therapy like surgery and radiation, fifty percent of patients present with distant metastasis. Metastatic uveal melanoma (MUM) does not harbor typically targetable mutations, e.g., BRAF as in cutaneous melanoma. As a result, there is no proven therapy for MUM. Various chemotherapy and immunotherapy regimens have been tried and only partial response (PR) is the best that has been achieved in most of the cases...
February 12, 2018: Journal for Immunotherapy of Cancer
Eleonora De Martin, Jean-Marie Michot, Barbara Papouin, Stéphane Champiat, Christine Mateus, Olivier Lambotte, Bruno Roche, Teresa Maria Antonini, Audrey Coilly, Salim Laghouati, Caroline Robert, Aurélien Marabelle, Catherine Guettier, Didier Samuel
BACKGROUND & AIMS: Immunotherapy for metastatic cancer may be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-PD-1/PD-L1 and anti-CTLA-4 monoclonal antibodies (mAb). METHODS: Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade ≥ 3 hepatitis. Among 16 included patients: 9 received anti-PD-1/PD-L1 while 7 received anti-CTLA-4 mAb, in monotherapy or in combination with anti-PD-1...
February 7, 2018: Journal of Hepatology
Aurélie Durgeau, Yasemin Virk, Stéphanie Corgnac, Fathia Mami-Chouaib
Recent advances in cancer treatment have emerged from new immunotherapies targeting T-cell inhibitory receptors, including cytotoxic T-lymphocyte associated antigen (CTLA)-4 and programmed cell death (PD)-1. In this context, anti-CTLA-4 and anti-PD-1 monoclonal antibodies have demonstrated survival benefits in numerous cancers, including melanoma and non-small-cell lung carcinoma. PD-1-expressing CD8+ T lymphocytes appear to play a major role in the response to these immune checkpoint inhibitors (ICI). Cytotoxic T lymphocytes (CTL) eliminate malignant cells through recognition by the T-cell receptor (TCR) of specific antigenic peptides presented on the surface of cancer cells by major histocompatibility complex class I/beta-2-microglobulin complexes, and through killing of target cells, mainly by releasing the content of secretory lysosomes containing perforin and granzyme B...
2018: Frontiers in Immunology
Parul Tandon, Samuel Bourassa-Blanchette, Kirles Bishay, Simon Parlow, Scott A Laurie, Jeffrey D McCurdy
Checkpoint inhibitors are a first-line therapy for advanced melanoma, though their use is limited by diarrhea and colitis. The aim of our study was to determine the risk of these toxicities associated with immunotherapy in advanced melanoma. Electronic databases were searched through June 2017 for prospective studies reporting the risk of diarrhea and colitis in advanced melanoma treated with anti-programmed death-1 (PD-1) or anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors. Standardized definitions assessed the grade of diarrhea and colitis...
February 2, 2018: Journal of Immunotherapy
Jessica da Gama Duarte, Katherine Woods, Miles C Andrews, Andreas Behren
Within the immune system multiple mechanisms balance the need for efficient pathogen recognition and destruction with the prevention of tissue damage by excessive, inappropriate or even self-targeting (auto)immune reactions. This immune homeostasis is a tightly regulated system which fails during tumor development, often due to the hijacking of its essential self-regulatory mechanisms by cancer cells. It is facilitated not only by tumor intrinsic properties, but also by the microbiome, host genetics and other factors...
February 2, 2018: Immunology and Cell Biology
David Taggart, Tereza Andreou, Karen J Scott, Jennifer Williams, Nora Rippaus, Rebecca J Brownlie, Elizabeth J Ilett, Robert J Salmond, Alan Melcher, Mihaela Lorger
Inhibition of immune checkpoints programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells results in durable antitumor activity in melanoma patients. Despite high frequency of melanoma brain metastases (BrM) and associated poor prognosis, the activity and mechanisms of immune checkpoint inhibitors (ICI) in metastatic tumors that develop within the "immune specialized" brain microenvironment, remain elusive. We established a melanoma tumor transplantation model with intracranial plus extracranial (subcutaneous) tumor, mimicking the clinically observed coexistence of metastases inside and outside the brain...
February 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
Lorraine Cafuir, David Lawson, Nilesh Desai, Vita Kesner, Alfredo Voloschin
BACKGROUND: Ipilimumab is an FDA-approved anti-CTLA-4 monoclonal antibody used in treatment of metastatic melanoma. We present an unusual neurological complication of Ipilimumab therapy and the diagnostic dilemma it caused. CASE PRESENTATION: A 42 year old male with Stage IV metastatic melanoma developed lower extremity weakness and sensory neuropathy following three doses of Ipilimumab. MRI of the lumbar spine was initially interpreted as diffuse leptomeningeal disease, and patient began Dexamethasone and radiation with improvement in symptoms...
January 30, 2018: Journal for Immunotherapy of Cancer
Priya Srinivasan, Xiaofang Wu, Mousumi Basu, Christopher Rossi, Anthony D Sandler
BACKGROUND: Adaptive immune resistance induces an immunosuppressive tumor environment that enables immune evasion. This phenomenon results in tumor escape with progression and metastasis. Programmed cell death-ligand 1 (PD-L1) expressed on tumors is thought to inhibit tumor-infiltrating lymphocytes (TILs) through programmed cell death 1 (PD1), enabling adaptive immune resistance. This study investigates the role of PD-L1 in both mouse and human neuroblastoma immunity. The consequence of PD-L1 inhibition is characterized in the context of an established whole tumor cell vaccine...
January 2018: PLoS Medicine
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