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Rescooped by Krishan Maggon from Top Selling Monoclonal Antibodies 2013
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Killing Cancer Through the Immune System - UCSF

Killing Cancer Through the Immune System - UCSF | Cancer Immunotherapy Review | Scoop.it
UCSF News Services
Killing Cancer Through the Immune System
UCSF News Services
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Krishan Maggon 's insight:
Krishan Maggon 's insight:

The marketing success of Ipilimumab has started the immunotherapy of cancer era.

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Krishan Maggon 's curator insight, February 4, 7:46 AM

The marketing success of Ipilimumab has started the immunotherapy of cancer era.

Gilbert Faure au nom de l'ASSIM's curator insight, February 4, 11:31 AM

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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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The TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer : Nature Reviews Cancer : Nature Publishing Group

The TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer : Nature Reviews Cancer : Nature Publishing Group | Cancer Immunotherapy Review | Scoop.it

The TYRO3, AXL (also known as UFO) and MERTK (TAM) family of receptor tyrosine kinases (RTKs) are aberrantly expressed in multiple haematological and epithelial malignancies. Rather than functioning as oncogenic drivers, their induction in tumour cells predominately promotes survival, chemoresistance and motility. The unique mode of maximal activation of this RTK family requires an extracellular lipid–protein complex. For example, the protein ligand, growth arrest-specific protein 6 (GAS6), binds to phosphatidylserine (PtdSer) that is externalized on apoptotic cell membranes, which activates MERTK on macrophages. This triggers engulfment of apoptotic material and subsequent anti-inflammatory macrophage polarization. In tumours, autocrine and paracrine ligands and apoptotic cells are abundant, which provide a survival signal to the tumour cell and favour an anti-inflammatory, immunosuppressive microenvironment. Thus, TAM kinase inhibition could stimulate antitumour immunity, reduce tumour cell survival, enhance chemosensitivity and diminish metastatic potential.

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The TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancerDouglas K. Graham,Deborah DeRyckere,Kurtis D. Davies& H. Shelton EarpAffiliationsCorresponding authorNature Reviews Cancer 14, 769–785 (2014) doi:10.1038/nrc3847Published online 24 November 2014
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Bispecific antibody platforms for cancer immunotherapy

Bispecific antibody platforms for cancer immunotherapy | Cancer Immunotherapy Review | Scoop.it

Abstract

Over the past decades advances in bioengineering and expanded insight in tumor immunology have resulted in the emergence of novel bispecific antibody (bsAb) constructs that are capable of redirecting immune effector cells to the tumor microenvironment. (Pre-) clinical studies of various bsAb constructs have shown impressive results in terms of immune effector cell retargeting, target dependent activation and the induction of anti-tumor responses. This review summarizes recent advances in the field of bsAb-therapy and limitations that were encountered. Furthermore, we will discuss potential future developments that can be expected to take the bsAb approach successfully forward.

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Krishan Maggon 's curator insight, November 24, 8:17 AM

Critical Reviews in Oncology/Hematology

Volume 92, Issue 3, December 2014, Pages 153–165

 Bispecific antibody platforms for cancer immunotherapyRoeland Lamerisa, Renée C.G. de Bruina, Famke L. Schneidersa, Paul M.P. van Bergen en Henegouwenb, Henk M.W. Verheula, Tanja D. de Gruijla, Hans J. van der Vlieta, ,   doi:10.1016/j.critrevonc.2014.08.003

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Peripheral T-Cell Inhibition

Peripheral T-Cell Inhibition | Cancer Immunotherapy Review | Scoop.it
The CTLA-4 checkpoint plays a key, distinct role in modulating the immune system.
Krishan Maggon 's insight:

From the leading immunotherapy company BMS

 

Ipilimumab and nivolumab

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'Huge breakthrough' in understanding how the immune system recognises cancer - Cancer Research UK

'Huge breakthrough' in understanding how the immune system recognises cancer - Cancer Research UK | Cancer Immunotherapy Review | Scoop.it
US researchers have revealed the identity of molecules on the surface of cancer cells which allow the body's immune system to identify and destroy them
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Discussed in previous scoops

 

Snyder A., Taha Merghoub, Jianda Yuan, Jesse M. Zaretsky, Alexis Desrichard, Logan A. Walsh, Michael A. Postow, Phillip Wong, Teresa S. Ho & Travis J. Hollmann & (2014). Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma, New England Journal of Medicine,141119140020009. DOI: http://dx.doi.org/10.1056/nejmoa1406498(link is external)

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Synthetic immunology: modulating the human immune system: Trends in Biotechnology

Synthetic immunology: modulating the human immune system: Trends in Biotechnology | Cancer Immunotherapy Review | Scoop.it
Highlights

 

•In synthetic immunology, biological devices are engineered to rationally modulate immune responses.•Molecules derived from the immune system are modified to capture cytokines or cells.•Autologous immune cells are designed to cure immunodeficiencies or eradicate tumors.

 

Humans have manipulated the immune system to dampen or boost the immune response for thousands of years. As our understanding of fundamental immunology and biotechnological methodology accumulates, we can capitalize on this combined knowledge to engineer biological devices with the aim of rationally manipulating the immune response. We address therapeutic approaches based on the principles of synthetic immunology that either ameliorate disorders of the immune system by interfering with the immune response, or improve diverse pathogenic conditions by exploiting immune cell effector functions. We specifically highlight synthetic proteins investigated in preclinical and clinical trials, summarize studies that have used engineered immune cells, and finish with a discussion of possible future therapeutic concepts.

Krishan Maggon 's insight:
Synthetic immunology: modulating the human immune systemBarbara Geering, Martin Fussenegger   Trends In BiotechnologyDOI: http://dx.doi.org/10.1016/j.tibtech.2014.10.006Publication stage: In Press Corrected Proof
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STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors: Immunity

STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors: Immunity | Cancer Immunotherapy Review | Scoop.it
Highlights

 

•Spontaneous T cell responses against tumors require the host STING pathway in vivo•Tumor-derived DNA can induce type I interferon production via STING•Tumor DNA can be identified in host APCs in the tumor microenvironment in vivo

 

Summary

Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8+T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-β production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-β production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy.

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ESMO Symposium on Immuno-Oncology 2014 | OncologyPRO

ESMO Symposium on Immuno-Oncology 2014 | OncologyPRO | Cancer Immunotherapy Review | Scoop.it
Abstracts from the ESMO Symposium on Immuno-Oncology 2014 are now available
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Gilbert Faure au nom de l'ASSIM's curator insight, November 22, 5:06 AM
Oncology Meeting Resources

21 Nov - 22 Nov, Geneva, Switzerland

Abstracts from the ESMO Symposium on Immuno-Oncology 2014 are now available here. Presentations and webcasts from the meeting will be available shortly after the Symposium.

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Cancer Cure Inc. Seattle Based Immunotherapy Companies and Research Institutes.

Cancer Cure Inc. Seattle Based Immunotherapy Companies and Research Institutes. | Cancer Immunotherapy Review | Scoop.it
RT @jamesian: Great #immunotherapy story http://t.co/8clIva1pUs Cover of @seattlebusiness from @aapfel #seattle @wbba @fredhutch @AdaptiveB…
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Great article focussing on how Seattle is becoming the epicenter of the new Immunotherpy Gold Rush.

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AJMC Panel Explores Immuno-oncology, and What Making Cancer a Chronic a Chronic Condition Means for Payers.

AJMC Panel Explores Immuno-oncology, and What Making Cancer a Chronic  a Chronic Condition Means for Payers. | Cancer Immunotherapy Review | Scoop.it
AJMC Panel Explores Immuno-oncology, and What Making Cancer a Chronic ...
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Gilbert Faure au nom de l'ASSIM's curator insight, November 19, 3:11 AM

The emergence of immuno-oncology, in which a patient’s own immune system is activated to fight the cancer, has shown promise in certain tumor subtypes, notably with therapies such as ipilimumab, which has been approved for metastatic melanoma.

But immuno-oncology presents certain challenges. Patients may not be “cured” in the conventional sense; rather, the disease may be converted to a chronic condition. In some cases the person can return to work, but in others, that’s not possible. This raises important policy choices when employers pay for healthcare. - See more at: http://www.ajmc.com/publications/evidence-based-oncology/2014/November-2014/AJMC-Panel-Explores-Immuno-oncology-and-What-Making-Cancer-a-Chronic-Condition-Means-for-Payers#sthash.Cr9sqCWa.dpuf

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PD-L1 Blockade overcomes Acquired Resistance to Fractionated Radiotherapy

PD-L1 Blockade overcomes Acquired Resistance to Fractionated Radiotherapy | Cancer Immunotherapy Review | Scoop.it

Treating cancers with immunotherapy and radiotherapy at the same time could stop them from becoming resistant to treatment,


Abstract

Radiotherapy is a major part in the treatment of most common cancers, but many patients experience local recurrence with metastatic disease. In evaluating response biomarkers, we found that low doses of fractionated radiotherapy led to PD-L1 upregulation on tumor cells in a variety of syngeneic mouse models of cancer. Notably, fractionated radiotherapy delivered in combination with αPD-1 or αPD-L1 mAbs generated efficacious CD8+ T-cell responses that improved local tumor control, long-term survival, and protection against tumor rechallenge. These favorable outcomes were associated with induction of a tumor antigen–specific memory immune response. Mechanistic investigations showed that IFNγ produced by CD8+ T cells was responsible for mediating PD-L1 upregulation on tumor cells after delivery of fractionated radiotherapy. Scheduling of anti–PD-L1 mAb was important for therapeutic outcome, with concomitant but not sequential administration with fractionated radiotherapy required to improve survival. Taken together, our results reveal the mechanistic basis for an adaptive response by tumor cells that mediates resistance to fractionated radiotherapy and its treatment failure. With attention to scheduling, combination immunoradiotherapy with radiotherapy and PD-1/PD-L1 signaling blockade may offer an immediate strategy for clinical evaluation to improve treatment outcomes.Cancer Res; 74(19); 5458–68. ©2014 AACR.


Krishan Maggon 's insight:
doi: 10.1158/0008-5472.CAN-14-1258Cancer Res October 1, 2014 74;5458

 

 

Acquired Resistance to Fractionated Radiotherapy Can Be Overcome by Concurrent PD-L1 BlockadeSimon J. Dovedi1,*, Amy L. Adlard2, Grazyna Lipowska-Bhalla1, Conor McKenna1,Sherrie Jones1, Eleanor J. Cheadle1, Ian J. Stratford2, Edmund Poon3,Michelle Morrow3, Ross Stewart3, Hazel Jones3, Robert W. Wilkinson3,Jamie Honeychurch1, and Tim M. Illidge1

+Author Affiliations

1Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.2Experimental Oncology Group, School of Pharmacy, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.3MedImmune Ltd, Granta Park, Cambridge, United Kingdom.↵*Corresponding Author:
Simon J. Dovedi, University of Manchester, Paterson Building, Wilmslow Road, Manchester M20 4BX, United Kingdom. Phone: 161-9187024; Fax: 161-4463109; E-mail:Simon.Dovedi@ics.manchester.ac.uk
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Juno Therapeutics CAR Technology

Juno Therapeutics CAR Technology | Cancer Immunotherapy Review | Scoop.it

Juno is advancing two next-generation CAR technologies that incorporate mechanisms to either dampen or amplify T cell activation signals present on the cancer cells or in the tumor microenvironment.


Our bispecific CAR technology, which includes a second binding domain on the CAR T cell that can lead to either an inhibitory or amplifying signal, can increase specificity of our CAR T cells for cancer cells versus normal cells. For example, a CAR T cell can be engineered such that it would be triggered in the presence of one target protein, but if a second protein is present it would be inhibited. Alternatively, it could also be engineered such that two target proteins would be required for maximal activation. These approaches may increase the specificity of the CAR for tumor relative to normal tissue.

Krishan Maggon 's insight:

Juno therapeutics was launched by 3 top cancer research centers.

 

Memorial Sloan Kettering cancer Center

Fred Hutchinson Cancer Center

Seattle Children Research Institute

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Pfizer bets $2 billion on Merck AG Anti-PD-L1 in Immuno-Oncology and forms a Global Strategic Alliance

Pfizer bets $2 billion on Merck AG  Anti-PD-L1  in Immuno-Oncology and forms a Global Strategic Alliance | Cancer Immunotherapy Review | Scoop.it

 Merck (MRK GY) announced today that it has entered into a global agreement with Pfizer Inc. (NYSE:PFE) to co-develop and co-commercialize MSB0010718C, an investigational anti-PD-L1 antibody currently in development by Merck as a potential treatment for multiple tumor types to accelerate the two companies’ presence in immuno-oncology.

The asset will be developed as a single agent as well as in various combinations with Pfizer’s and Merck’s broad portfolio of approved and investigational pipeline candidates. The two companies will also combine resources and expertise to advance Pfizer’s anti-PD-1 antibody into Phase 1 trials.  There are currently two clinical development programs underway evaluating Merck’s anti-PD-L1 antibody. In a Phase 1 trial, more than 550 patients have been treated with MSB0010718C across multiple types of cancers. As part of the Analyst and Investor Day hosted by Merck on September 18, 2014, interim data were presented from the ongoing Phase 1 study demonstrating a complete response and partial responses in patients with non-small cell lung cancer and ovarian cancer. Additional data are expected to be presented at medical congresses in 2015. There is also an ongoing Phase 2 trial evaluating this antibody in patients with m-Merkel cell carcinoma, a rare form of skin cancer. For more information, please visitwww.clinicaltrials.gov.

Under the terms of the agreement, Merck will receive an upfront payment of $ 850 million (around € 680 million) and is eligible to receive regulatory and commercial milestone payments up to $ 2.0 billion. Both companies will jointly fund all development and commercialization costs and all revenues obtained from selling any anti-PD-L1 or anti-PD-1 products generated from this collaboration will be shared.
Krishan Maggon 's insight:
Merck and Pfizer will jointly develop and commercialize Merck’s anti-PD-L1Joint investment and combined strengths and capabilities will further maximize potential of Merck’s asset in the highly competitive anti-PD-1 / anti-PD-L1 spaceUp to 20 high priority immuno-oncology clinical development programs expected to commence in 2015, including pivotal registration studiesAlliance accelerates Merck’s entry into the US oncology market
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The Inherent Premise of Immunotherapy for Cancer Dormancy

The Inherent Premise of Immunotherapy for Cancer Dormancy | Cancer Immunotherapy Review | Scoop.it
#endcancer #cancer
The Inherent Premise of #Immunotherapy for #CancerDormancy
http://t.co/cz6ZfioDYK

 

Abstract

Clinical cancer dormancy is evident from the detection of circulating tumor cells in the blood and tissue-residing disseminated tumor cells in the bone marrow of cancer survivors who have been clinically disease free. Emerging evidence from clinical and preclinical studies suggests that tumor dormancy is a critical step in the development of both primary cancer and advanced-stage disease. In this review, it is shown that (i) naturally occurring tumor dormancy precedes occurrence of primary cancer, and (ii) conventional cancer therapies result in treatment-induced tumor dormancy, which in turn could lead to distant recurrence of cancer or permanent tumor dormancy, depending on immunogenic status of dormancy. Given that cellular dormancy is an evolutionary conserved survival mechanism in biologic systems, any stress or cytotoxic therapy could trigger cellular dormancy. Therefore, a successful cancer therapy is likely to be achieved by establishing permanent tumor dormancy and preventing distant recurrence of cancer or by eliminating dormant tumor cells. This could be accomplished by cancer immunotherapy because of the establishment of long-term memory responses. Cancer Res; 74(23); 1–5. ©2014 AACR.

Krishan Maggon 's insight:
The Inherent Premise of Immunotherapy for Cancer DormancyMasoud H. Manjili*

+Author Affiliations

Department of Microbiology and Immunology, Virginia Commonwealth University, Massey Cancer Center, Richmond, Virginia.↵*Corresponding Author:
Masoud H. Manjili, Department of Microbiology and Immunology, Virginia Commonwealth University, Massey Cancer Center, 401 College Street, Box 980035, Richmond, VA 23298. Phone: 804-828-8779; Fax: 804-828-8453; E-mail: mmanjili@vcu.edu
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BMS tie up with Five Prime Therapeutics FPA008 mab+ nivolumab clinical trials

BMS tie up with Five Prime Therapeutics FPA008 mab+ nivolumab clinical trials | Cancer Immunotherapy Review | Scoop.it
FPA008 is an anti-CSF1R antibody, which we designed to block the ability of IL-34 and CSF1 to bind to and activate CSF1R.

 

FivePrime discovered a novel protein target called interleukin 34 (IL-34), which is a key regulator of monocyte and macrophage numbers and activity and that is found in inflamed joints of RA patients. Once we discovered IL-34, we were able to use our protein library and our receptor-ligand matching technology to identify its receptor, CSF1R. This receptor is known to be expressed on the surface of monocytes and macrophages. Before our discovery of IL-34, CSF1R was thought to have only one ligand called CSF1. Both CSF1 and IL-34 bind to and activate CSF1R and therefore promote the survival and activity of monocytes and macrophages. FPA008 blocks the binding of both CSF1 and IL-34 to CSF1R and thereby inhibits the activity and survival of these cells.


FPA008 is an anti-CSF1R antibody, which we designed to block the ability of IL-34 and CSF1 to bind to and activate CSF1R. FPA008 reduces the numbers and activity of monocytes and macrophages that cause disease, and prevents the production and release of inflammatory factors. The advantage of this approach in comparison to, for example Humira® and Actemra®, is that the production of multiple deleterious factors is inhibited simultaneously, potentially resulting in better efficacy. Another advantage of blocking CSF1R is that osteoclasts, macrophages that break down bone, are inhibited. Therefore, not only could FPA008 potentially be superior in reducing inflammation, but it may also directly suppress bone destruction in the joints of patients with inflammatory diseases.

 

We completed the testing of single ascending doses of FPA008 in a Phase 1 clinical trial of healthy volunteer subjects. In March 2014, we began testing multiple ascending doses of FPA008 in healthy volunteers in the second part of the trial. We expect preliminary healthy volunteer data by the end of 2014 and plan to begin dosing in patients with active rheumatoid arthritis (RA) during the same time frame.  For more information on Five Prime's Phase 1 study of FPA008, please see:


Krishan Maggon 's insight:

BMS pays $ 30 million upfront and additional milestones and the cost of trials.

 

Bristol-Myers Squibb and Five Prime Therapeutics Announce Exclusive Clinical Collaboration to Evaluate the Combination of Investigational Immunotherapies Opdivo (nivolumab) and FPA008 in Six Tumor Types

 

 

NEW YORK & SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Bristol-Myers Squibb Company (NYSE:BMY) and Five Prime Therapeutics, Inc.(Nasdaq:FPRX) today announced that they have entered into an exclusive clinical collaboration agreement to evaluate the safety, tolerability and preliminary efficacy of combining Opdivo (nivolumab), Bristol-Myers Squibb's investigational PD-1 (programmed death-1) immune checkpoint inhibitor, with FPA008, Five Prime's monoclonal antibody that inhibits colony stimulating factor-1 receptor (CSF1R). The Phase 1a/1b study will evaluate the combination of Opdivo and FPA008 as a potential treatment option for patients with non-small cell lung cancer (NSCLC), melanoma, head and neck cancer, pancreatic cancer, colorectal cancer and malignant glioma. Bristol-Myers Squibb has proposed the name Opdivo, which, if approved by health authorities, will serve as the trademark for nivolumab.

 

Opdivo and FPA008 are part of a new class of cancer treatments known as immunotherapies that are designed to harness the body's own immune system to fight cancer. Opdivo is approved in Japan for the treatment of patients with unresectable melanoma, and is being developed in multiple tumor types in more than 50 clinical trials. FPA008, in development as a potential treatment for rheumatoid arthritis (RA) and solid tumors, has initiated dosing for a Phase 1 clinical trial in RA. Preclinical data suggest that combining antibodies targeting PD-1 and CSF1R may lead to an enhanced anti-tumor immune response compared to either approach alone in treating cancer.

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Possibilities For Personalized Cancer Vaccines Revealed At ESMO Symposium | Health

Possibilities For Personalized Cancer Vaccines Revealed At ESMO Symposium | Health | Cancer Immunotherapy Review | Scoop.it
The possibilities for personalised vaccines in all types of cancer are revealed today in a lecture from Dr Harpreet Singh at the ESMO Symposium on Immuno-Oncology 2014 in Geneva, Switzerland.
“One of the biggest hurdles in cancer immunotherapy is...
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Tertiary lymphoid structures in cancer and beyond: Trends in Immunology

Tertiary lymphoid structures in cancer and beyond: Trends in Immunology | Cancer Immunotherapy Review | Scoop.it
Highlights

 

•Tertiary lymphoid structures (TLS) are common at sites of chronic inflammation.•TLS shape local adaptive immune responses in inflamed and tumoral tissues.•TLS represent prognostic biomarkers and therapeutic targets in cancer.

 

Tertiary lymphoid structures (TLS) are ectopic lymphoid formations found in inflamed, infected, or tumoral tissues. They exhibit all the characteristics of structures in the lymph nodes (LN) associated with the generation of an adaptive immune response, including a T cell zone with mature dendritic cells (DC), a germinal center with follicular dendritic cells (FDC) and proliferating B cells, and high endothelial venules (HEV). In this review, we discuss evidence for the roles of TLS in chronic infection, autoimmunity, and cancer, and address the question of whether TLS present beneficial or deleterious effects in these contexts. We examine the relationship between TLS in tumors and patient prognosis, and discuss the potential role of TLS in building and/or maintaining local immune responses and how this understanding may guide therapeutic interventions.

Krishan Maggon 's insight:
Tertiary lymphoid structures in cancer and beyondMarie-Caroline Dieu-Nosjean, Jérémy Goc, Nicolas A. Giraldo, Catherine Sautès-Fridman, Wolf Herman Fridman DOI: http://dx.doi.org/10.1016/j.it.2014.09.006
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Immuno-Oncology 2014 Press Release: Immunotherapy Set to Revolutionise Cancer Treatment | ESMO

Immuno-Oncology 2014 Press Release: Immunotherapy Set to Revolutionise Cancer Treatment | ESMO | Cancer Immunotherapy Review | Scoop.it
Immunotherapy is set to revolutionise the treatment of cancer, according to ESMO President Rolf A. Stahel.
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STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors: Immunity

STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors: Immunity | Cancer Immunotherapy Review | Scoop.it
Highlights

 

•STING but not MyD88 or TRIF is essential for therapeutic radiation•cGAS-STING axis mediates dendritic cell sensing of irradiated-tumor cells•STING is required for effective adaptive immune responses to radiation•Exogenous cGAMP treatment promotes antitumor efficacy of radiation

 

Summary

Ionizing radiation-mediated tumor regression depends on type I interferon (IFN) and the adaptive immune response, but several pathways control I IFN induction. Here, we demonstrate that adaptor protein STING, but not MyD88, is required for type I IFN-dependent antitumor effects of radiation. In dendritic cells (DCs), STING was required for IFN-β induction in response to irradiated-tumor cells. The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) mediated sensing of irradiated-tumor cells in DCs. Moreover, STING was essential for radiation-induced adaptive immune responses, which relied on type I IFN signaling on DCs. Exogenous IFN-β treatment rescued the cross-priming by cGAS or STING-deficient DCs. Accordingly, activation of STING by a second messenger cGAMP administration enhanced antitumor immunity induced by radiation. Thus radiation-mediated antitumor immunity in immunogenic tumors requires a functional cytosolic DNA-sensing pathway and suggests that cGAMP treatment might provide a new strategy to improve radiotherapy.

Krishan Maggon 's insight:

OA

 

STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic TumorsLiufu Deng, Hua Liang, Meng Xu, Xuanming Yang, Byron Burnette, Ainhoa Arina, Xiao-Dong Li, Helena Mauceri, Michael Beckett, Thomas Darga,Xiaona Huang, Thomas F. Gajewski, Zhijian J. Chen, Yang-Xin Fu, Ralph R. Weichselbaum DOI: http://dx.doi.org/10.1016/j.immuni.2014.10.019
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STING (STimulator of INterferon Genes) pathway key to tumor immunity - The University of Chicago Medicine

STING (STimulator of INterferon Genes) pathway key to tumor immunity - The University of Chicago Medicine | Cancer Immunotherapy Review | Scoop.it

November 20, 2014: 

 

A recently discovered protein complex known as STING plays a crucial role in detecting the presence of tumor cells and promoting an aggressive anti-tumor response by the body's innate immune system, according to two separate studies published in the Nov. 20 issue of the journal Immunity.

 

The studies, both from University of Chicago-based research teams, have major implications for the growing field of cancer immunotherapy. The findings show that when activated, the STING pathway triggers a natural immune response against the tumor. This includes production of chemical signals that help the immune system identify tumor cells and generate specific killer T cells. The research also found that targeted high-dose radiation therapy dials up the activation of this pathway, which promotes immune-mediated tumor control.

 

These findings could “enlarge the fraction of patients who respond to immunotherapy with prolonged control of the tumor,” according to a commentary on the papers by the University of Verona's Vincenzo Bronte, MD. “Enhancing the immunogenicity of their cancers might expand the lymphocyte repertoire that is then unleashed by interference with checkpoint blockade pathways,” such as anti-PD-1.

STING, short for STimulator of INterferon Genes complex, is a crucial part of the process the immune system relies on to detect threats -- such as infections or cancer cells -- that are marked by the presence of DNA that is damaged or in the wrong place, inside the cell but outside the nucleus.

Detection of such “cytosolic” DNA initiates a series of interactions that lead to the STING pathway. Activating the pathway triggers the production of interferon-beta, which in turn alerts the immune system to the threat, helps the system detect cancerous or infected cells, and ultimately sends activated T cells into the battle.

Krishan Maggon 's insight:

University of Chicago Medicine 

 

STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors Gajewski and colleagues STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors Weichselbaum and colleagues
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Epic Sciences | Detecting PD-L1 in Circulating Tumor Cells Could Improve Immunotherapies

Epic Sciences | Detecting PD-L1 in Circulating Tumor Cells Could Improve Immunotherapies | Cancer Immunotherapy Review | Scoop.it
RT @EpicSciences: Thx @myESMO & @EORTC 4 noting #immunotherapy revolution #CTCs will be impt to which/when to use.
http://t.co/L1HNycSFTS
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Immune cells: more than simple carriers for systemic delivery of oncolytic viruses | OV

Immune cells: more than simple carriers for systemic delivery of oncolytic viruses | OV | Cancer Immunotherapy Review | Scoop.it

Abstract:

 

Oncolytic virotherapy on its own has numerous drawbacks, including an inability of the virus to actively target tumor cells and systemic toxicities at the high doses necessary to effectively treat tumors. Addition of immune cell-based carriers of oncolytic viruses holds promise as a technique in which oncolytic virus can be delivered directly to tumors in smaller and less toxic doses. Interestingly, the cell carriers themselves have also demonstrated antitumor effects, which can be augmented further by tailoring the appropriate oncolytic virus to the appropriate cell type. This review discusses the multiple factors that go into devising an effective, cell-based delivery system for oncolytic viruses.Keywords: oncolytic virus, cell carrier, immune cells, cancer therapy, myeloid-derived suppressor cells

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Immune cells: more than simple carriers for systemic delivery of oncolytic viruses

Eisenstein S, Chen SH, Pan PY

Oncolytic Virotherapy 2014, 3:83-91

Published Date: 6 November 2014


Published Date November 2014 Volume 2014:3 Pages 83—91

DOI http://dx.doi.org/10.2147/OV.S47143

Received 15 May 2014, Accepted 8 August 2014, Published 6 November 2014

Approved for publication by Dr Faris Farassati


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Recent advances in the development of breast cancer vaccines | BCTT

Recent advances in the development of breast cancer vaccines | BCTT | Cancer Immunotherapy Review | Scoop.it
Recent advances in the development of breast cancer vaccines Andrea Milani,1 Dario Sangiolo,1 Massimo Aglietta,1,2 Giorgio Valabrega1,2 1Department of Oncology, University of Torino, Torino, Italy; 2FPO, Candiolo Cancer Institute, IRCCS, Torino, Italy Abstract: The manipulation of the immune system through the administration of a vaccine to direct an effective and long-lasting immune response against breast cancer (BC) cells is an attractive strategy. Vaccines would have several theoretical advantages over standard therapies, including low toxicities, high specificity, and long-lasting efficacy due to the establishment of immunological memory. However, BC vaccines have failed to demonstrate meaningful results in clinical trials so far. This reflects the intrinsic difficulty in breaking the complex immune-escaping mechanisms developed by cancer cells. New vaccines should be able to elicit complex immunologic response involving multiple immune effectors such as cytotoxic and antibody-secreting B cells, innate immunity effectors, and memory cells. Moreover, especially in patients with large tumor burdens and metastatic disease, combining vaccines with other strategies, such as systemic BC therapies, passive immunotherapy, or immunomodulatory agents, could increase the effectiveness of each approach. Here, we review recent advances in BC vaccines, focusing on suitable targets and innovative strategies. We report results of most recent trials investigating active immunotherapy in BC and provide possible future perspectives in this field of research. Keywords: breast cancer, cancer vaccines, cancer immunology, HER2, MUC-1, hTERT
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Breast Cancer: Targets and Therapy Dovepress


Review
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/BCTT.S38428
Recent advances in the development
of breast cancer vaccines

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TCR Technology

TCR Technology | Cancer Immunotherapy Review | Scoop.it

Our high-affinity TCR technology has the potential to recognize proteins expressed inside cancer cells or proteins on the cell surface, which may allow us to target a broad range of tumors. The gene sequence we introduce into T cells with our TCR technology encodes for the proteins required to assemble a TCR that recognizes a specific major histocompatibility complex (MHC) / peptide structure. Beyond the fact that TCRs can recognize peptides derived from intracellular proteins, another advantage of TCRs is that they are fully human and therefore may be less likely to elicit an immune response against the infused TCR cells.

 

The engagement of a TCR is restricted to a certain MHC type. Due to the variability of MHC types across the human population, different TCRs will be required for various segments of the population. Our TCR constructs are selected by screening healthy donors for naturally-occurring high-affinity TCRs against a MHC/peptide combination of interest. Depending on the binding affinity of the selected TCR construct, it is either used directly or modified by mutating a specific region, the hypervariable domain, of the TCR binding pocket to create a higher affinity construct. Based on the limited number of patients who have received any TCR treatment to date, these TCR cells appear to behave like endogenous T cells after re-infusion back into the patient. They undergo a process similar to an endogenous T cell of multiplication and cytotoxic activation upon recognition of their defined cancer-associated proteins.

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FDA has granted orphan drug designation to Juno Therapeutis lead product CAR-TCR therapy Autologous CD3+ T cells transduced with retroviral vector containing a chimeric antigen receptor directed against CD19 (Autologous CD3+ T cells containing CD19 chimeric antigen receptor) for Acute Lymphoblastic Leukemia ALL. 

 

Juno therapeutics was launched by 3 top cancer research centers.

 

Memorial Sloan Kettering cancer Center

Fred Hutchinson Cancer Center

Seattle Children Research Institute

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Cavatak (Viralytics) Common cold Coxsackievirus Type A21 (CVA21) Poster. SITC-2014

Cavatak (Viralytics) Common cold Coxsackievirus Type A21 (CVA21)  Poster. SITC-2014 | Cancer Immunotherapy Review | Scoop.it

Cavatak (Viralytics) Common cold Coxsackievirus Type A21 (CVA21) OncoVaccine Poster. SITC-2014 | @scoopit http://sco.lt/...

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SITC   Meeting 2014

 

 

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Nivolumab in Previously Untreated Melanoma without BRAF Mutation — NEJM

Nivolumab in Previously Untreated Melanoma without BRAF Mutation — NEJM | Cancer Immunotherapy Review | Scoop.it
Original Article from The New England Journal of Medicine — Nivolumab in Previously Untreated Melanoma without BRAF Mutation

 

METHODS

We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival.

Full Text of Methods...

 RESULTS

At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine.

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 CONCLUSIONS

Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number,NCT01721772.)

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Nivolumab in Previously Untreated Melanoma without BRAFMutation

Caroline Robert, M.D., Ph.D., Georgina V. Long, M.D., Ph.D., Benjamin Brady, M.D., Caroline Dutriaux, M.D., Michele Maio, M.D., Laurent Mortier, M.D., Jessica C. Hassel, M.D., Piotr Rutkowski, M.D., Ph.D., Catriona McNeil, M.D., Ph.D., Ewa Kalinka-Warzocha, M.D., Ph.D., Kerry J. Savage, M.D., Micaela M. Hernberg, M.D., Ph.D., Celeste Lebbé, M.D., Ph.D., Julie Charles, M.D., Ph.D., Catalin Mihalcioiu, M.D., Vanna Chiarion-Sileni, M.D., Cornelia Mauch, M.D., Ph.D., Francesco Cognetti, M.D., Ana Arance, M.D., Ph.D., Henrik Schmidt, M.D., D.M.Sc., Dirk Schadendorf, M.D., Helen Gogas, M.D., Lotta Lundgren-Eriksson, M.D., Christine Horak, Ph.D., Brian Sharkey, Ph.D., Ian M. Waxman, M.D., Victoria Atkinson, M.D., and Paolo A. Ascierto, M.D.

November 16, 2014DOI: 10.1056/NEJMoa1412082

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Nivolumab in Previously Untreated Melanoma without BRAFMutation

Caroline Robert, M.D., Ph.D., Georgina V. Long, M.D., Ph.D., Benjamin Brady, M.D., Caroline Dutriaux, M.D., Michele Maio, M.D., Laurent Mortier, M.D., Jessica C. Hassel, M.D., Piotr Rutkowski, M.D., Ph.D., Catriona McNeil, M.D., Ph.D., Ewa Kalinka-Warzocha, M.D., Ph.D., Kerry J. Savage, M.D., Micaela M. Hernberg, M.D., Ph.D., Celeste Lebbé, M.D., Ph.D., Julie Charles, M.D., Ph.D., Catalin Mihalcioiu, M.D., Vanna Chiarion-Sileni, M.D., Cornelia Mauch, M.D., Ph.D., Francesco Cognetti, M.D., Ana Arance, M.D., Ph.D., Henrik Schmidt, M.D., D.M.Sc., Dirk Schadendorf, M.D., Helen Gogas, M.D., Lotta Lundgren-Eriksson, M.D., Christine Horak, Ph.D., Brian Sharkey, Ph.D., Ian M. Waxman, M.D., Victoria Atkinson, M.D., and Paolo A. Ascierto, M.D.

November 16, 2014DOI: 10.1056/NEJMoa1412082