Cancer Immunotherapy Review
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TIL Melanoma Program (Lion Biotech) 54% ORR in Phase II metastatic melanoma. ASH 2014

TIL Melanoma Program (Lion Biotech)  54% ORR in Phase II metastatic melanoma. ASH 2014 | Cancer Immunotherapy Review | Scoop.it

 Lion Biotechnologies, Inc. (LBIO), a biotechnology company that is developing novel cancer immunotherapies based on tumor-infiltrating lymphocytes (TILs) under a Cooperative Research and Development Agreement with the National Cancer Institute (NCI), today announced that Steven A. Rosenberg, MD, PhD, chief of surgery at the NCI, presented positive, new data from a Phase 2 clinical trial of TIL therapy in metastatic melanoma. The updated results were presented on December 7, 2014 in a scientific symposium on adoptive T-cell therapy (ACT) at the American Society of Hematology annual meeting in San Francisco, CA.

New data from a Phase 2 clinical trial in patients with Stage 4 metastatic melanoma, which NCI is conducting with Lion under a collaborative research and development agreement, confirmed that TIL treatment was associated with high, durable objective response rates (ORR), including in patients who were refractory to checkpoint inhibitors.

In the randomized, 101-patient study, ORR was 54%, representing a significant improvement over data from recent clinical studies of ipilimumab (ORR 10-15%) and anti-PD-1 therapy (ORR 31-41%).  Fourteen patients had complete responses, 13 of which are ongoing beyond two years.  Of the 41 partial responders, 22 are ongoing beyond one year and 15 are ongoing beyond two years. Additionally, Dr. Rosenberg noted, TILs produced objective response rates in 19/45 (ORR 42%) patients who were ipilimumab refractory, and 5/10 (ORR 50%) patients who had previously progressed on anti-PD1.

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Krishan Maggon 's curator insight, December 8, 2014 9:43 AM

TILs Demonstrate 54% Objective Response Rate in Phase 2 Metastatic Melanoma Trial

Cancer Immunotherapy Review
A magic life saving cure for advanced metastatic melanoma.  
Curated by Krishan Maggon
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Ipilimumab (BMS) Review: A Cancer Breakthrough? - un knol de Krishan Maggon

Ipilimumab (BMS) Review: A Cancer Breakthrough? - un knol de Krishan Maggon | Cancer Immunotherapy Review | Scoop.it
FDA has approved Yervoy (ipilimumab, BMS) under REMS for the treatment of metastatic melanoma. The European expert panel CHMP...
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rosywills's comment, September 22, 2017 4:07 AM
Cancer Immunotherapy Market is expected to reach USD 119.39 Billion by 2021
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Computational measurement of tumor immune microenvironment in gastric adenocarcinomas

Computational measurement of tumor immune microenvironment in gastric adenocarcinomas | Cancer Immunotherapy Review | Scoop.it
The use of four groups of tumor immune microenvironments (TME) based on PD-L1 and tumor-infiltrating T lymphocytes (TIL) is a reliable biomarker for anti-PD-1/PD-L1 inhibitor therapy. We classified the TME in 241 gastric cancers which were subdivided according to 40 EBV+, 76 microsatellite instability-high (MSI-H), and 125 EBV-/microsatellite-stable (MSS) subtypes by quantitative image analysis (QIA) and correlated the results with mRNA expression levels. The mean PD-L1 ratio and CD8 ratio in EBV+, MSI-H, and EBV−/MSS GCs were significantly different (P < 0.006). The PD-L1 ratio and CD8 ratio obtained by QIA correlated well with the RNA levels of PD-L1 (r = 0.63) and CD8 (r = 0.67), respectively. The TME were type I (PD-L1H/CD8H) in 45, type II (PD-L1L/CD8L) in 106, type III (PD-L1H/CD8L) in 8, and type IV (PD-L1L/CD8H) in 82 cases. The type I TME was significantly associated with high TIL (P = 3.0E-11) and EBV+ status (P = 8.55E-08). In conclusion, QIA results correlated well with the mRNA expression levels and classified TME of gastric cancers.
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Future of Immune Checkpoint Inhibitors - ScienceDirect

Future of Immune Checkpoint Inhibitors - ScienceDirect | Cancer Immunotherapy Review | Scoop.it
Cancer immunotherapies that target the T-cell immune checkpoints, such as CTLA-4, PD-1, and PD-L1, have shown unprecedented success for the treatment of a variety of malignancies. Although a significant number of patients benefit from immune checkpoint inhibitors (ICIs), only a subset of patients receives durable clinical benefit and many patients eventually develop therapeutic resistance after an initial response to ICIs. Additionally, these therapeutic agents often elicit immune-related adverse events that may result in substantial morbidities, some of which are life-threatening. Although the targets of ICIs are well defined, gaps in understanding the exact mechanism of action are a major impediment in efforts to improve ICI therapy. In this chapter, we summarize rationale for combining ICIs with other treatment and novel therapeutics modulating costimulatory and coinhibitory molecules on immune cells.
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Boehringer Ingelheim Acquires Viral-Based Cancer Immunotherapy Developer ViraTherapeutics

Boehringer Ingelheim Acquires Viral-Based Cancer Immunotherapy Developer ViraTherapeutics | Cancer Immunotherapy Review | Scoop.it
Boehringer Ingelheim has exercised its option to buy ViraTherapeutics for €210 million ($245 million), the buyer and the acquired company’s co-lead investor EMBL Ventures said today, in a deal that gives Boehringer complete control over a preclinical viral-based cancer immunotherapy the companies...
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The role of a monoclonal antibody 11C8B1 as a diagnostic marker of IDH2 -mutated sinonasal undifferentiated carcinoma

The role of a monoclonal antibody 11C8B1 as a diagnostic marker of IDH2 -mutated sinonasal undifferentiated carcinoma | Cancer Immunotherapy Review | Scoop.it

Cancer-associated IDH mutations: biomarker and therapeutic opportunities [...] Whole‐exome sequencing of oral mucosal melanoma reveals mutational profile and therapeutic targets [...]

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Humanized Mice for the Study of Immuno-Oncology

Humanized Mice for the Study of Immuno-Oncology | Cancer Immunotherapy Review | Scoop.it
Immunotherapy is revolutionizing cancer treatment; however, complete responses are
achieved in only a small fraction of patients and tumor types. Thus, there is an urgent
need for predictive preclinical models to drive rational immunotherapeutic drug development,
treatment combinations, and to minimize failures in clinical trials. Humanized mouse
models (HIS) have been developed to study and modulate the interactions between immune
components and tumors of human origin. In this review, we discuss recent advances
in the ‘humanization’ of mouse models to improve the quality of human immune cell
reconstitution.
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Rheumatic immune-related adverse events from cancer immunotherapy

Rheumatic immune-related adverse events from cancer immunotherapy | Cancer Immunotherapy Review | Scoop.it
Immunotherapy has revolutionized the treatment of cancer, but a rapid rise in the use of the family of therapeutic agents known as checkpoint inhibitors (CPIs) is associated with a new group of immune-related adverse events (irAEs) in almost any organ system. Among these irAEs, rheumatic complications are common and seem to have features that are distinct from irAEs in other organ systems, including a highly variable time of clinical onset and the capacity to persist, possibly indefinitely, even after cessation of CPI therapy. In this Review, mechanisms of action of CPIs and how they might cause rheumatic irAEs are described. Also covered are epidemiology and clinical descriptions of rheumatic irAEs, plus guiding principles for managing irAEs. Finally, we outline future directions that must be taken in response to a series of unanswered questions and unmet needs that now confront rheumatologists who are, or will be, engaged in this new area of rheumatology.
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Glucocorticoids and PD-1

Glucocorticoids and PD-1 | Cancer Immunotherapy Review | Scoop.it
Signaling by the glucocorticoid receptor in NK cells induces expression of the checkpoint inhibitor PD-1 to prevent immunopathology.
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Haematological toxicities with immunotherapy in patients with cancer: a systematic review and meta-analysis - ScienceDirect

Haematological toxicities with immunotherapy in patients with cancer: a systematic review and meta-analysis - ScienceDirect | Cancer Immunotherapy Review | Scoop.it

Incidence of PD-[L]1 inhibitor's haematological toxicity is presently unknown and under-reported.


We have performed a systematic review and meta-analysis of 47 trials among solid tumours.


Anaemia, neutropenia, febrile neutropenia and thrombocytopenia were 9.8, 0.9, 2.8 and 0.4%.


The risk of anaemia with anti-PD-(L)1 agents is not negligible, while that of neutropenia was rare.


Clinicians should check the complete blood cell count before every cycle of therapy.
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EMA restrict pembrolizumab/atezolizumab usage in urothelial cancer

EMA restrict pembrolizumab/atezolizumab usage in urothelial cancer | Cancer Immunotherapy Review | Scoop.it
The European Medicines Agency have announced their recommendation to restrict the use of pembrolizumab and atezolizumab to the first-line treatment of urothelial cancer patients with high PD-L1 expression.
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FDA-AACR Workshop on Non-clinical Models for Safety Assessment of Immuno-oncology Products

FDA-AACR Workshop on Non-clinical Models for Safety Assessment of Immuno-oncology Products | Cancer Immunotherapy Review | Scoop.it
Home Government Affairs FDA-AACR Workshop on Non-clinical Models for Safety Assessment of Immuno-oncology Products ​FDA-AACR Regulatory Science and Policy Workshop  FDA-AACR Workshop on Non-clinical Models for Safety Assessment of Immuno-oncology Products Date: Sept. 6, 2018.  Location: Marriott Wardman Park, Maryland Ballroom, 2660 Woodley Rd NW, Washington, D.C. 20008 Advance in-person registration is now closed for this event, but you may still register to attend in person by directly emailing trevan.locke@aacr.org. Register to view the webcast below. Register for webcast participation. Read the agenda. Read the speaker bios. See the shareable flyer. Purpose: Discuss current challenges and opportunities for non-clinical models to predict toxicities of immune checkpoint inhibitors and stimulators in patients. The workshop will provide a forum for academic, industry, and regulatory experts to discuss developing non-clinical models that are both predictive and practical for human safety assessment. Background:  The development of non-clinical models that can predict toxicities of immune checkpoint inhibitors and stimulators in patients is an extremely important and timely issue for the cancer community. There are 50 agents targeting PD-1 or PD-L1 in clinical development, and more than 1100 trials combining anti-PD-1/L1 agents with other therapies, yet retrospective analyses indicate that animal toxicity for many of these agents is minimal and does not predict adverse effects in patients. In addition, the recent observation of worse overall survival in two randomized trials that evaluated anti-PD-1/L1 agents in combination with immunomodulatory drugs underscores the need for cross-sector collaboration in this area. With advances in nonclinical models to study the pharmacodynamics of immune checkpoint inhibitors and stimulators, the question remains whether any of these models could be adapted to assess the safety of immuno-oncology products. ​
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Pursuing an Effective Ovarian Cancer Vaccine | Cancer Screening, Prevention, Control | JAMA | JAMA Network

In this Medical News article, researchers discuss the outlook for developing effective therapeutic vaccines to treat ovarian cancer.
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Immune checkpoint inhibitors and cardiovascular toxicity

Immune checkpoint inhibitors and cardiovascular toxicity | Cancer Immunotherapy Review | Scoop.it
Immune checkpoint inhibitors are a new class of anticancer therapies that amplify
T-cell-mediated immune responses against cancer cells. Immune checkpoint inhibitors
have shown important benefits in phase 3 trials, and several agents have been approved
for specific malignancies.
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NKILA lncRNA promotes tumor immune evasion by sensitizing T cells to activation-induced cell death

NKILA lncRNA promotes tumor immune evasion by sensitizing T cells to activation-induced cell death | Cancer Immunotherapy Review | Scoop.it
Activation-induced cell death (AICD) of T lymphocytes can be exploited by cancers to escape immunological destruction. We demonstrated that tumor-specific cytotoxic T lymphocytes (CTLs) and type 1 helper T (TH1) cells, rather than type 2 helper T cells and regulatory T cells, were sensitive to AICD in breast and lung cancer microenvironments. NKILA, an NF-κB-interacting long noncoding RNA (lncRNA), regulates T cell sensitivity to AICD by inhibiting NF-κB activity. Mechanistically, calcium influx in stimulated T cells via T cell–receptor signaling activates calmodulin, thereby removing deacetylase from the NKILA promoter and enhancing STAT1-mediated transcription. Administering CTLs with NKILA knockdown effectively inhibited growth of breast cancer patient-derived xenografts in mice by increasing CTL infiltration. Clinically, NKILA overexpression in tumor-specific CTLs and TH1 cells correlated with their apoptosis and shorter patient survival. Our findings underscore the importance of lncRNAs in determining tumor-mediated T cell AICD and suggest that engineering lncRNAs in adoptively transferred T cells might provide a novel antitumor immunotherapy.
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Natural killer cells and other innate lymphoid cells in cancer

Natural killer cells and other innate lymphoid cells in cancer | Cancer Immunotherapy Review | Scoop.it
Immuno-oncology is an emerging field that has revolutionized cancer treatment. Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions. NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells. Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies. The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored. This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies.
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Engineered natural killer cells may be the next great cancer immunotherapy

Engineered natural killer cells may be the next great cancer immunotherapy | Cancer Immunotherapy Review | Scoop.it
Inspired by success with T cells, scientists equip other immune cells with cancer-homing protein...
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Cyclin-Dependent Kinase 12, Immunity, and Prostate Cancer | NEJM

Cyclin-Dependent Kinase 12, Immunity, and Prostate Cancer | NEJM | Cancer Immunotherapy Review | Scoop.it
Somatic inactivating variants in the gene CDK12, encoding cyclin-dependent kinase 12, generate fusion-induced neoantigens in prostate cancer. This finding supports the hypothesis that prostate cancers with variant CDK12 will have a response to checkpoint inhibitor drugs.
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Cancers | Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy | HTML

Cancers | Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy | HTML | Cancer Immunotherapy Review | Scoop.it
Abstract: This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy––a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4+ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) and CD8+ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc.); intracellular markers (FOXP3); epigenetic and genetic programs; and metabolic pathways (catabolic or anabolic); and these differences can be modulated to improve CAR-T therapy. In addition, CD4+ Treg cells suppress the efficacy of CAR-T cell therapy, and different approaches to overcome this suppression are discussed in this review. Thus, next-generation CAR-T immunotherapy can be improved, based on our knowledge of T cell subsets functions, differentiation, proliferation, and signaling pathways to generate more active CAR-T cells against tumors.
Keywords: chimeric antigen receptor (CAR); immunotherapy; cancer; CD4 T cells; CD8 T cells
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An RNA toolbox for cancer immunotherapy

An RNA toolbox for cancer immunotherapy | Cancer Immunotherapy Review | Scoop.it
Cancer immunotherapy has revolutionized oncology practice. However, current protein and cell therapy tools used in cancer immunotherapy are far from perfect, and there is room for improvement regarding their efficacy and safety. RNA-based structures have diverse functions, ranging from gene expression and gene regulation to pro-inflammatory effects and the ability to specifically bind different molecules. These functions make them versatile tools that may advance cancer vaccines and immunomodulation, surpassing existing approaches. These technologies should not be considered as competitors of current immunotherapies but as partners in synergistic combinations and as a clear opportunity to reach more efficient and personalized results. RNA and RNA derivatives can be exploited therapeutically as a platform to encode protein sequences, provide innate pro-inflammatory signals to the immune system (such as those denoting viral infection), control the expression of other RNAs (including key immunosuppressive factors) post-transcriptionally and conform structural scaffoldings binding proteins that control immune cells by modifying their function. Nascent RNA immunotherapeutics include RNA vaccines encoding cancer neoantigens, mRNAs encoding immunomodulatory factors, viral RNA analogues, interference RNAs and protein-binding RNA aptamers. These approaches are already in early clinical development with promising safety and efficacy results.
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Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses | Cancer Immunotherapy Review | Scoop.it
Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1,2,3,4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5,6,7,8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3′ untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5′ long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.
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Immunomodulation of Tumor Vessels: It Takes Two to Tango

Immunomodulation of Tumor Vessels: It Takes Two to Tango | Cancer Immunotherapy Review | Scoop.it
The density of intratumoral CD8+ T cells predicts patient survival and responsiveness
to immunotherapy. Effector T cell infiltration in turn is controlled by the tumor
vasculature which co-evolves together with an immune-suppressive environment. At the
T cell–vascular interface, endothelial cells actively suppress T cell trafficking
and function. Conversely, forced activation, normalization, and differentiation of
tumor vessels into high endothelial venule entrance portals for lymphocytes can facilitate
T cell extravasation.
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A homing system targets therapeutic T cells to brain cancer

A homing system targets therapeutic T cells to brain cancer | Cancer Immunotherapy Review | Scoop.it
Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer.
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Pembrolizumab—Latest Data on its use as Monotherapy and in Combination with Chemotherapy in Non-small Cell Lung Cancer

Pembrolizumab—Latest Data on its use as Monotherapy and in Combination with Chemotherapy in Non-small Cell Lung Cancer | Cancer Immunotherapy Review | Scoop.it
Insights into the KEYNOTE-189 Study presented at American Association for Cancer Research Annual Meeting, Chicago, IL, US, April 14–18, 2018.
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Special delivery by “armored” CAR-T

Special delivery by “armored” CAR-T | Cancer Immunotherapy Review | Scoop.it
The integration of immune checkpoint blockade with CAR-T cell therapy improves antitumor efficacy with potential for reduced side effects.
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Vaccines |  Endometrial Stromal Sarcomas: A Revision of Their Potential as Targets for Immunotherapy

Vaccines |  Endometrial Stromal Sarcomas: A Revision of Their Potential as Targets for Immunotherapy | Cancer Immunotherapy Review | Scoop.it
Endometrial stromal sarcomas are a subtype of uterine sarcomas that are characterized by recurrent chromosomal translocations, resulting in the expression of tumor-specific fusion proteins that contribute to their tumorigenicity.
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Killer cell immunotherapy offers potential cure for advanced pancreatic cancer: new research

Killer cell immunotherapy offers potential cure for advanced pancreatic cancer: new research | Cancer Immunotherapy Review | Scoop.it
Researchers from UNSW Sydney and the California Institute of Biomedical Research (CALIBR) have demonstrated the success of a new, cell-bas...
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