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PEREGRINE PHARMACEUTICALS INC FILES -- 8-K
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http://pdf.reuters.com/htmlnews/8knews.asp?i=43059c3bf0e37541&u=urn:newsml:reuters.com:20170911:EDG_0001683168-17-002334
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits. The following material is filed as an exhibit to this Current Report on Form 8-K:
Exhibit
Number
99.1 Press Release issued September 11, 2017.
Item 8.01 Other Events.
On September 11, 2017, Peregrine Pharmaceuticals, Inc. (the "Company") issued a press release announcing the appointment of Roger J. Lias, Ph.D. as the new president of Avid Bioservices, Inc., the Company’s wholly-owned contract development and manufacturing organization subsidiary, and his appointment to the Company’s Board of Directors. A copy of the press release is attached hereto as Exhibit 99.1.
Important Additional Information
Peregrine intends to file a proxy statement with the Securities and Exchange Commission (SEC) in connection with the solicitation of proxies for Peregrine’s 2017 Annual Meeting (Proxy Statement) with an associated WHITE proxy card. Peregrine, its directors and certain of its executive officers will be participants in the solicitation of proxies from stockholders in respect of the 2017 Annual Meeting. Information regarding the names of Peregrine’s directors and executive officers and their respective interests in Peregrine by security holdings or otherwise is set forth in the Annual Report on Form 10-K of Peregrine, for the fiscal year ended April 30, 2017, filed with the SEC on July 14, 2017, and Peregrine’s proxy statement for the 2016 Annual Meeting, filed with the SEC on August 26, 2016. To the extent holdings of such participants in Peregrine’s securities are not reported, or have changed since the amounts described, in the 2016 proxy statement, such changes have been reflected on Initial Statements of Beneficial Ownership on Form 3 or Statements of Change in Ownership on Form 4 filed with the SEC. Details concerning the nominees of Peregrine’s Board of Directors for election at the 2017 Annual Meeting will be included in the Proxy Statement. BEFORE MAKING ANY VOTING DECISION, INVESTORS AND STOCKHOLDERS OF THE COMPANY ARE URGED TO READ ALL RELEVANT DOCUMENTS FILED WITH OR FURNISHED TO THE SEC, INCLUDING THE COMPANY’S DEFINITIVE PROXY STATEMENT AND ANY SUPPLEMENTS THERETO, BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION. Investors and stockholders will be able to obtain a copy of the definitive proxy statement and other documents filed by Peregrine free of charge from the SEC’s website, http://www.sec.gov. Peregrine’s stockholders will also be able to obtain, without charge, a copy of the definitive Proxy Statement and other relevant filed documents by directing a request by mail to Peregrine, Corporate Secretary’s Office, 14282 Franklin Avenue, Tustin, CA 92780, by calling Peregrine’s proxy solicitor, MacKenzie Partners, Inc., toll-free at (800) 322-2885, or from Peregrine’s website at http://www.peregrineinc.com.
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PEREGRINE PHARMACEUTICALS INC FILES AMENDED PROXY STATEMENT -- DEFA14A
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http://pdf.reuters.com/htmlnews/8knews.asp?i=43059c3bf0e37541&u=urn:newsml:reuters.com:20170911:EDG_0001683168-17-002335
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Short covering
AstraZeneca - 5 Important Things to Know About Lung Cancer AZN.L - ENP Newswire
11-Sep-2017 15:50:46
ENPNEWSWIRE-(C)2017 ENPUBLISHING
Release date- 08092017 - In 2017, an estimated 222,500 people in the United States will be diagnosed with lung cancer and while that makes it the second most common type of cancer, it will cause more deaths than any other type.
And more deaths than colon, breast and prostate cancers combined.
At AstraZeneca, our scientists are working furiously to find important new treatments for lung cancer, with the hope of curbing these devastating statistics. Here is what you need to know about how researchers are approaching lung cancer.
There is more than one type of lung cancer.
It's easy to think that lung cancer is one disease, but in truth, there are many different types. This starts with two main categories: non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC is the most common type, accounting for about 80% to 85% of all lung cancers, while SCLC accounts for about 15% to 20%. Then, there are more subtypes: NSCLC can be adenocarcinoma, squamous cell carcinoma, or large cell carcinoma - each subtype starts from different types of lung cells.
Within each subtype, there are four main stages of lung cancer.
Lung cancer stage is determined by tumor size and whether it has grown to nearby areas, lymph nodes, or other organs. Some of these stages have second names, which can make lung cancer research news confusing. For example, 'locally advanced' lung cancer is typically Stage III. And cancer that is 'metastatic' - meaning it has spread or metastasized - is Stage IV.
And then there are biomarkers.
Lung cancer biomarkers are unique traits of lung cancer that can help determine what types of medicines the cancer is most likely to respond to. These can be mutations, or specific types of proteins and molecules that are present in a person's tumor or blood. Biomarkers can be identified through testing - sometimes called 'genetic testing' or 'diagnostic testing' - to help determine the treatment approach for each patient. And since lung cancer can change and mutate over time, it's often important to test more than once to ensure doctors are keeping up with the cancer.
Personalized medicine means treating each patient based on the details of their disease.
These diverse types, stages and subsets of lung cancer make every patient's tumor and experience unique. 'Personalized medicine' is a way of creating and selecting treatments that are designed to treat specific types of lung cancer. When it comes to lung cancer, one size does not fit all.
AstraZeneca is researching personalized medicines in a broad range of lung cancers.
At AstraZeneca, we're leveraging our expertise in lung cancer and building on our existing medicines to investigate important new treatments across different types of lung cancer. We currently have over 32 ongoing clinical trials looking at many different stages, lines of treatment, and types of disease.
Our vision is to one day eliminate cancer as a cause of death. With hard work and a deep-rooted determination to follow the science of the disease, we are committed to making that vision a reality.
Contact:
Michele Meixell
11-Sep-2017 14:05 - PEREGRINE PHARMACEUTICALS ANNOUNCES APPOINTMENT OF ROGER J. LIAS, PH.D. AS PRESIDENT OF AVID BIOSERVICES
PEREGRINE PHARMACEUTICALS ANNOUNCES APPOINTMENT OF ROGER J. LIAS, PH.D. AS PRESIDENT OF AVID BIOSERVICES - RTRS
11-Sep-2017 14:05
Cancer immunotherapy proves itself in earlier-stage disease - RTRS
11-Sep-2017 11:32
Immuno-oncology moving beyond metastatic cancer
Shift promises to expand market for blockbuster medicines
Astra, Bristol trials show drugs work in earlier disease
By Ben Hirschler
MADRID, Sept 11 (Reuters) - Cancer doctors are widening the net for immunotherapy, a hot new class of drugs that enlist the body's defences in the fight against tumours.
The latest research shared with 23,000 experts at Europe's top oncology meeting shows how medicines that have already delivered durable benefits in metastatic disease can also work well at an earlier stage.
The findings promise to expand the market for established immuno-oncology (I-O) drugs from companies like Merck MRK.N, Bristol-Myers Squibb BMY.N and Roche ROG.S, while opening up a window for relative latecomers such as AstraZeneca AZN.L.
AstraZeneca stole much of the limelight at the European Society for Medical Oncology (ESMO) congress in Madrid after clinical trial results showed its I-O drug Imfinzi helped lung cancer patients with mid-stage disease. (Full Story)
Bristol-Myers, meanwhile, proved that Opdivo, which is already used widely in advanced cancer, can prevent relapses in melanoma patients if given straight after surgery. This earlier setting is known as adjuvant therapy. L8N1LN3QV
The data on both drugs highlight how so-called PD-1 and PD-L1 drugs are moving down the treatment curve to earlier-stage disease.
"The aim is to help more and more patients in earlier phases of the disease, like in adjuvant therapy," ESMO President Fortunato Ciardiello told Reuters.
"I think this will be a trend that will increase over the next few years, though we have to cautious because we have to do the proper clinical trials to prove this in each case."
I-O drugs are now being investigated in the adjuvant setting in a range of cancers, including lung, kidney and bladder - and some trials are even underway in the neoadjuvant or pre-surgery setting in the case of breast and head and neck cancers.
BRAKES OFF
By taking the brakes off the immune system and allowing the body's natural killer cells to home in on tumours, immunotherapy offers a different approach to toxic chemotherapy, which causes collateral damage to healthy tissue.
It is not without side effects, some of which can be serious, but it is generally a kinder option - especially when PD-1 and PD-L1 drugs are given on their own.
"There is now a potential to use immunotherapy to change the course of early disease. I think that is one of the most important pieces of news for patients at this ESMO meeting," said Fouad Namouni, Bristol-Myers's head of medical oncology development.
By giving immunotherapy earlier, when immune systems are healthier, the hope is that more patients will be lifted into long-term remission.
"Earlier treatment does seem to produce higher responses, although I'm not sure that is going to be true all of the time," said Roy Baynes, who heads clinical development at Merck.
Some analysts forecast potential sales of immunotherapy drugs at as much as $50 billion a year. However, significant challenges remain, including deciding which patients will benefit most from infused medicines with typical list prices of near $150,000 a year. (Full Story)
The possibility of early intervention also raises questions about screening to spot cancer early on - something that becomes more relevant once potentially curative options are available.
AstraZeneca's chief executive, Pascal Soriot, who expects multibillion-dollar sales of Imfinzi in non-metastatic stage III lung cancer, is hopeful screening will pick up in future.
"If you have a good early treatment then the incentive for screening is massive," he said in an interview.
Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade
Tavi Nathanson, Arun Ahuja, Alexander Rubinsteyn, Bulent Arman Aksoy, Matthew D. Hellmann, Diana Miao, Eliezer Van Allen, Taha Merghoub, Jedd D. Wolchok, Alexandra Snyderand Jeff Hammerbacher
DOI: 10.1158/2326-6066.CIR-16-0019 Published January 2017
ArticleFigures & DataInfo & Metrics PDF
Abstract
Immune checkpoint inhibitors are promising treatments for patients with a variety of malignancies. Toward understanding the determinants of response to immune checkpoint inhibitors, it was previously demonstrated that the presence of somatic mutations is associated with benefit from checkpoint inhibition. A hypothesis was posited that neoantigen homology to pathogens may in part explain the link between somatic mutations and response. To further examine this hypothesis, we reanalyzed cancer exome data obtained from our previously published study of 64 melanoma patients treated with CTLA-4 blockade and a new dataset of RNA-Seq data from 24 of these patients. We found that the ability to accurately predict patient benefit did not increase as the analysis narrowed from somatic mutation burden, to inclusion of only those mutations predicted to be MHC class I neoantigens, to only including those neoantigens that were expressed or that had homology to pathogens. The only association between somatic mutation burden and response was found when examining samples obtained prior to treatment. Neoantigen and expressed neoantigen burden were also associated with response, but neither was more predictive than somatic mutation burden. Neither the previously described tetrapeptide signature nor an updated method to evaluate neoepitope homology to pathogens was more predictive than mutation burden. Cancer Immunol Res; 5(1); 84–91. ©2016 AACR.
Introduction
Checkpoint blockade therapies are improving outcomes for patients with metastatic solid tumors (1–4). As only a subset of patients responds, there is a critical need to identify determinants of response. Expression of programmed death ligand one (PD-L1) is the lead companion diagnostic for PD-1/PD-L1 blockade therapies, but sensitivity and specificity are limited (5–7). An association between elevated tumor mutation burden and benefit from checkpoint blockade therapies has been demonstrated (8–11).
In our study of melanomas treated with checkpoint blockade agents targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4; ref. 8), we present the hypothesis that responding tumors may share features with each other or with infectious agents and that such resemblance may predict response. In this report, we reanalyzed the data in that study using updated methods and integrating new RNA sequencing (RNA-Seq) data from a subset of 24 samples.
We found that in this small dataset, nonsynonymous mutation burden was associated with clinical benefit from therapy in samples collected before, but not after, treatment with CTLA-4 blockade. Predicted neoantigen burden and percentage of C?T transitions characteristic of ultraviolet damage were associated with, but did not outperform, mutation burden. We developed a publicly available tool, Topeology (https://github.com/hammerlab/topeology), to compare neoantigens to known pathogens. Neither the resemblance of tumor neoantigens to known antigens nor the previously published tetrapeptide signature outperformed mutation burden as a predictor of response.
Materials and Methods
Patient samples
All analyzed samples were collected in accordance with local Internal Review Board policies as described in ref. 8 and summarized in Table 1. Thirty-four patients had tumor samples collected prior to initiating CTLA-4 blockade, and 30 patients had samples collected after initiating CTLA-4 blockade. Clinical benefit was defined as progression-free survival lasting for greater than 24 weeks after initiation of therapy (Online Data File 1). Nine discordant lesions were present, where overall patient benefit did not match individual tumor progression. See Table 1 for details about this patient cohort.
http://cancerimmunolres.aacrjournals.org/content/5/1/84.long
Microparticles in the blood of patients with systemic lupus erythematosus (SLE): phenotypic characterization and clinical associations.
From 2016
Mobarrez F1, Vikerfors A1, Gustafsson JT1, Gunnarsson I1, Zickert A1, Larsson A2, Pisetsky DS3, Wallén H4, Svenungsson E1.
Author information
Abstract
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by circulating autoantibodies and the formation of immune complexes. In these responses, the selecting self-antigens likely derive from the remains of dead and dying cells, as well as from disturbances in clearance. During cell death/activation, microparticles (MPs) can be released to the circulation. Previous MP studies in SLE have been limited in size and differ regarding numbers and phenotypes. Therefore, to characterize MPs more completely, we investigated 280 SLE patients and 280 individually matched controls. MPs were measured with flow cytometry and phenotyped according to phosphatidylserine expression (PS+/PS-), cellular origin and inflammatory markers. MPs, regardless of phenotype, are 2-10 times more abundant in SLE blood compared to controls. PS- MPs predominated in SLE, but not in controls (66% vs. 42%). Selectively in SLE, PS- MPs were more numerous in females and smokers. MP numbers decreased with declining renal function, but no clear association with disease activity was observed. The striking abundance of MPs, especially PS- MPs, suggests a generalized disturbance in SLE. MPs may be regarded as "liquid biopsies" to assess the production and clearance of dead, dying and activated cells, i.e. pivotal events for SLE pathogenesis.
https://www.ncbi.nlm.nih.gov/pubmed/27777414
The Multi-Purpose Tool of Tumor Immunotherapy: Gene-Engineered T Cells
http://www.jcancer.org/v08p1690.htm
....
Combination therapy for cancer
In the course of cancer treatment, the ACT can be existed alone, or acted as a part of the combination therapy. For example, a human IgG1 T-cell receptor mimic monoclonal antibody directed to a peptide (RMFPNAPYL) of WT1 in HLA-A*02 dependent was therapeutically effective, alone and in combination with tyrosine kinase inhibitors (TKIs), against a leukemia with the most common, pan-TKI, gatekeeper resistance mutation, T315I [111]. Whether WT1-targeted TCR and the mimic monoclonal antibody combination therapy will produce a similar effect? If so, this strategy will become an option for TKIs resistance in cancer therapy. As noted above, tumor vaccines have a unique advantage in inducing TAA-specific TCR. The tumor radiotherapy can produce a similar effect. The vaccine-similar effect was contributed non-redundant immune mechanisms in cancer by a combination of radiotherapy and dual checkpoint blockade [121]. Maybe it is a very imaginative treatment combination that ACT is combined with radiation therapy.
.............
Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research-practice gaps, challenges, and insights.
Zheng PP1,2, Li J3, Kros JM2.
Author information
Abstract
To date, five cancer treatment modalities have been defined. The three traditional modalities of cancer treatment are surgery, radiotherapy, and conventional chemotherapy, and the two modern modalities include molecularly targeted therapy (the fourth modality) and immunotherapy (the fifth modality). The cardiotoxicity associated with conventional chemotherapy and radiotherapy is well known. Similar adverse cardiac events are resurging with the fourth modality. Aside from the conventional and newer targeted agents, even the most newly developed, immune-based therapeutic modalities of anticancer treatment (the fifth modality), e.g., immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy, have unfortunately led to potentially lethal cardiotoxicity in patients. Cardiac complications represent unresolved and potentially life-threatening conditions in cancer survivors, while effective clinical management remains quite challenging. As a consequence, morbidity and mortality related to cardiac complications now threaten to offset some favorable benefits of modern cancer treatments in cancer-related survival, regardless of the oncologic prognosis. This review focuses on identifying critical research-practice gaps, addressing real-world challenges and pinpointing real-time insights in general terms under the context of clinical cardiotoxicity induced by the fourth and fifth modalities of cancer treatment. The information ranges from basic science to clinical management in the field of cardio-oncology and crosses the interface between oncology and onco-pharmacology. The complexity of the ongoing clinical problem is addressed at different levels. A better understanding of these research-practice gaps may advance research initiatives on the development of mechanism-based diagnoses and treatments for the effective clinical management of cardiotoxicity.
© 2017 The Authors Medicinal Research Reviews Published by Wiley Periodicals, Inc.
https://www.ncbi.nlm.nih.gov/pubmed/28862319
ANALYSIS-CANCER MUTATION GAINS GROUND AS TEST FOR IMMUNOTHERAPY DRUGS
RTRS
09/08/2017 4:02 PM
Medics want better ways to see if pricey drugs will work
Tumour mutation burden in focus as new drug biomarker
Simple blood test raises hopes, but more evidence needed
By Ben Hirschler
MADRID, Sept 8 (Reuters) - Scientists are stepping up the hunt for better diagnostic tests to predict if cancer patients will benefit from costly modern immunotherapy drugs, which are transforming cancer care but remain a hit-and-miss affair.
Research presented at Europe's biggest oncology congress in Madrid adds to evidence that patients with an above average number of genetic mutations in their tumours have a better chance of responding to the new treatments, and drugmakers are racing to confirm the idea.
Immuno-oncology (I-O) drugs such as Merck & Co's Keytruda and Bristol-Myers Squibb's BMY.N Opdivo, which help the immune system attack tumours, can have dramatic effects and yet only around 20 to 30 percent of patients show a lasting improvement.
Analysing the number of mutations within a tumour makes sense: the more there are, the more the patient's killer T-cells
whose action is enhanced by I-O medicines - will recognise the cancer as foreign to the body and therefore attack it.
Such analysis to measure what is known as tumour mutation burden (TMB) should lead to better targeting of medicines that have a typical list price of near $150,000 a year. It could also mean subgroups of patients with tumours where immunotherapy is not normally considered, like breast cancer, might get them.
Progress is being made in applying the idea in practice, with Roche ROG.S - a global leader in diagnostics as well as the top maker of cancer drugs - demonstrating for the first time on Friday that a blood-based test for TMB can accurately measure mutations. (Full Story)
The Swiss group, which developed the test with majority-owned Foundation Medicine FMI.O, presented data linking high TMB to improved results for patients in two lung cancer trials at the European Society for Medical Oncology (ESMO) congress.
Doctors welcomed the results but said more evidence was still needed.
Roche is not alone in seeking to use TMB as a new measurable biological signature, or biomarker, with which to personalise I-O treatment.
Bristol-Myers also has a deal with Foundation Medicine and the U.S. drugmaker's head of medical oncology development, Fouad Namouni, sees TMB testing emerging as a powerful new tool.
"We are moving the needle pretty fast and I am sure in the next few years patients will be tested for TMB and will be treated on the basis of that," he said. "We are looking at TMB in every major study we are doing."
BLUNT INSTRUMENT
At present, the one established way of selecting patients for drugs like Keytruda, Opdivo and Roche's Tecentriq is to test for a protein called PDL-1 in their tumours.
But that involves scientists looking at cells through a microscope and making a qualitative assessment based on their judgment. Clinical trials suggest it is a relatively blunt instrument for predicting a patient's response to a given treatment.
A quantitative blood test is a quicker and simpler option, doing away with the need to take a tissue biopsy, which until now has been the only reliable way to measure TMB levels.
Thomas Buechele, Roche's head of global medical affairs in haematology and oncology, believes this may eventually lead to patients with a high level of mutations needing only one I-O drug while those with lower levels get a combination therapy.
Oncologists in Madrid said prospective clinical trials still needed to prove the tests could accurately predict responses, rather than just correlating to outcomes after the event.
"It's early days but this is clearly one way to go to address the shortcomings of PD-L1 testing," said Stefan Zimmermann, senior oncologist at Switzerland's HFR Fribourg-Cantonal Hospital.
While a blood-based test would be a boon for convenience and affordability, the genetic detail it provides is inevitably less than with the more costly and time-consuming process of taking a tissue sample and sequencing tumour DNA.
"It's clear it is a biomarker – the only question is how good a biomarker is it?" said Jeffrey Weber, professor of medicine at NYU School of Medicine.
Nonetheless, the more researchers learn about the complexities of cancer immunotherapy, the more it becomes apparent that treatment needs to be customised according to the different profiles of individual patients.
One sign of that came last May when Keytruda became the first cancer treatment ever to win U.S. approval based on whether a patient's tumour carried a specific genetic glitch, irrespective of its location. (Full Story)
Solange Peters of the Centre Hospitalier Universitaire Vaudois in Lausanne said an important issue would be establishing that TMB testing didn't miss patients who might benefit.
"What we don't want is to have a test with a very low negative predictive value and thereby prevent patients getting immunotherapy because the biomarker wasn't good enough."
(Reporting by Ben Hirschler; editing by David Stamp) ((ben.hirschler@thomsonreuters.com; +44 7771 575 829; Reuters Messaging: ben.hirschler.thomsonreuters.com@reuters.net))
Keywords: HEALTH CANCER/BIOMARKER (ANALYSIS, PIX)
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I'v never seen this from that side. Thanks!
ASTRAZENECA PLC - CELGENE AND ASTRAZENECA PROVIDE UPDATE ON THE FUSION CLINICAL TRIAL PROGRAMME
PUBT
09/07/2017 2:10 PM
AstraZeneca and MedImmune, its global biologics research and development arm, have been informed by partner Celgene that the US Food and Drug Administration (FDA) has placed a partial clinical hold on five trials and a full clinical hold on one trial in the Celgene FUSION programme. The trials are testing Imfinzi (durvalumab), an anti-PD-L1 agent, in combination with immunomodulatory agents, with or without chemotherapy, in blood cancers such as multiple myeloma, chronic lymphocytic leukaemia and lymphoma.
The decision by the FDA was based on risks identified in other trials for an anti-PD-1 agent, pembrolizumab, in patients with multiple myeloma in combination with immunomodulatory agents. No imbalance has been observed in the FUSION programme; however, the clinical holds allow for additional information to be collected to further understand the risk benefit profile of the programme. The FDA has taken similar action with other combination trials in patients with multiple myeloma.
Patients enrolled in the trials on partial clinical hold who are receiving clinical benefit from treatment may remain on treatment. Patients enrolled in the trial on full clinical hold will be discontinued from treatment. No new patients will be enrolled into the listed trials.
Other trials with Imfinzi in haematological malignancies and other tumour types continue unchanged.
The trials placed on partial clinical hold are:
* MEDI4736-MM-001: A Phase Ib multicenter, open-label study to determine
the recommended dose and regimen of durvalumab either as monotherapy or in
combination with pomalidomide with or without low-dose dexamethasone in
patients with relapsed and refractory multiple myeloma
* MEDI4736-MM-003: A Phase II, multicenter, open-label study to determine
the safety and efficacy for the combination of durvalumab and daratumumab in
patients with relapsed and refractory multiple myeloma
* MEDI4736-MM-005: A Phase II, multicenter, single-arm study to determine
the efficacy for the combination of durvalumab plus daratumumab in patients
with relapsed and refractory multiple myeloma that have progressed while on
current treatment regimen containing daratumumab
* MEDI4736-NHL-001: A Phase I/II, open-label, multi-center study to
assess the safety and tolerability of durvalumab as monotherapy and in
combination therapy in subjects with lymphoma or chronic lymphocytic
leukaemia. The only arm in this trial for which enrolment is suspended is the
arm with the durvalumab, REVLIMID and rituximab combination
* MEDI4736-DLBCL-001: A Phase II, open-label, multicenter study to
evaluate the safety and clinical activity of durvalumab in combination with
rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) or
with lenalidomide plus R-CHOP (R2 CHOP) in patients with previously untreated,
high risk diffuse large B Cell lymphoma
The trial placed on full clinical hold is:
* MEDI4736-MM-002: A Phase Ib multicenter, open-label study to determine
the recommended dose and regimen of durvalumab in combination with
lenalidomide with and without low-dose dexamethasone in subjects with newly
diagnosed multiple myeloma
The trials that will continue to enrol are:
* MEDI4736-MDS-001: A randomised, multicenter, open-label, Phase II trial
evaluating the efficacy and safety of azacitidine subcutaneous in combination
with durvalumab in previously untreated subjects with higher-risk
myelodysplastic syndromes or in elderly (>= 65 Years) acute myeloid leukaemia
subjects not eligible for haematopoietic stem cell transplantation
* CC-486-MDS-006: A Phase II, international, multicenter, randomised,
open-label, parallel group to evaluate the efficacy and safety of CC-486 alone
in combination with durvalumab in subjects with myelodysplastic syndromes who
fail to achieve an objective response to treatment with azacitidine for
injection or decitabine
In April 2015, Celgene entered into a strategic collaboration with MedImmune
to develop and commercialise durvalumab for haematologic malignancies. The use
of durvalumab in combination with other agents for the treatment of patients
with haematologic malignancies is not approved by the FDA, and the safety and
efficacy of those combinations have not been established.
NOTES TO EDITORS
About Celgene
Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global biopharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through next-generation solutions in protein homeostasis, immuno-oncology, epigenetics, immunology and neuro-inflammation. For more information, please visit http://www.celgene.com.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three main therapy areas - Oncology, Cardiovascular & Metabolic Diseases and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit http://www.astrazeneca.com and follow us on Twitter @AstraZeneca.
AstraZeneca plc published this content on 07 September 2017 and is solely responsible for the information contained herein. Distributed by Public, unedited and unaltered, on 07 September 2017 12:10:07 UTC.
Original document
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NCCN ANNOUNCES FIRST PATIENT DOSED IN NCCN-PEREGRINE PHARMACEUTICALS COLLABORATIVE STUDY OF BAVITUXIMAB
PRN
09/07/2017 2:05 PM
NCCN Announces First Patient Dosed in NCCN-Peregrine Pharmaceuticals Collaborative Study of BavituximabAn NCCN ORP-funded study, examining effectiveness of bavituximab combination in patients with newly diagnosed glioblastomas, enrolled its first patient at Dana-Farber Cancer Institute in Boston, Massachusetts.
PR Newswire
FORT WASHINGTON, Pa., Sept. 7, 2017
FORT WASHINGTON, Pa., Sept. 7, 2017 /PRNewswire-USNewswire/ -- Glioblastoma is the most common malignant primary brain tumor and is a uniformly fatal disease with five-year survival rates less than four percent despite aggressive treatment with surgery, radiation, and chemotherapy.(1) Consequently, new therapies for this patient population are desperately needed.
The National Comprehensive Cancer Network(®) (NCCN (http://www.nccn.org/)(®;)) today announced the dosing of the first patient in its Oncology Research Program (ORP (http://www.nccn.org/ORP))-funded study to investigate the effectiveness of bavituximab with radiation and temozolomide in patients with newly diagnosed glioblastomas.
The study, initiated by Elizabeth Gerstner, MD, Massachusetts General Hospital Cancer Center (http://www.massgeneral.org/cancer/), is one of three studies funded through a collaboration between NCCN ORP and Peregrine Pharmaceuticals—this patient marks the first enrollment into an NCCN ORP-funded investigator-initiated bavituximab trial.
"NCCN ORP congratulates Dr. Gerstner and Dana-Farber/Brigham and Women's Cancer Center (http://www.youhaveus.org/) | Massachusetts General Hospital Cancer Center for initiation of this study, as well as the other investigators who will soon embark on their research of bavituximab in patients with cancer," said Susan Most, MBA, RN, Director, Clinical Operations, NCCN ORP. "The fact that Peregrine Pharmaceuticals has entrusted the NCCN ORP with these investigator-initiated studies is an honor, and we are happy that patients at our esteemed institutions will have access to this novel immunotherapy."
The following researchers received funding through a grant from Peregrine Pharmaceuticals:
Elizabeth Gerstner, MD, Massachusetts General Hospital Cancer Center, "Phase II Clinical Trial of Bavituximab with Radiation and Temozolomide for Patients with Newly Diagnosed Glioblastoma"
Jessica Frakes, MD, Moffitt Cancer Center (http://www.moffitt.org/), "A Phase I Trial of Sorafenib and Bavituximab Plus Stereotactic Body Radiation Therapy (SBRT) for First Line Treatment of Unresectable Hepatocellular Carcinoma"
Ranee Mehra, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (http://www.hopkinsmedicine.org/kimmel_cancer_center/), "Phase II Study of Pembrolizumab and Bavituximab for Progressive Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck" Drs. Frakes and Mehra will begin enrolling patients in the coming months.
"We are hopeful that results from this trial, as well as from the two additional studies at NCCN Member Institutions, will continue to support our belief that bavituximab works to create a more immune active tumor microenvironment in which other therapies are able to have a greater anti-tumor effect," said Joseph Shan, MPH, Vice President, Clinical and Regulatory Affairs of Peregrine. "We look forward to following this important study at the Massachusetts General Hospital Cancer Center, as well as the planned trials at the Moffitt Cancer Center and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins."
Bavituximab is an investigational immune-modulatory monoclonal antibody that targets phosphatidylserine (PS), a phospholipid that inhibits the ability of immune cells to recognize and fight tumors. Bavituximab is believed to reverse PS-mediated immunosuppression by blocking the engagement of PS with its receptors, as well as by sending an alternate immune activating signal.(2) According to Peregrine, PS-targeting antibodies have been shown to shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor immune responses. This mechanism may play an important role in allowing other cancer therapies to more effectively attack tumors by reversing the immunosuppression that limits the impact of those treatments.
Importantly, bavituximab has also demonstrated a favorable safety and tolerability profile across several clinical trials conducted to date, which may offer the compound a key advantage as the evolving cancer treatment landscape continues to shift to a combination therapy approach.
The awardees responded to a Request for Proposals issued by ORP to the NCCN Member Institutions and their affiliate hospitals. Submissions were peer reviewed by the NCCN Bavituximab Scientific Review Committee. The funded concepts were selected based on several criteria, including scientific merit, existing data, and the types of studies necessary to further evaluate the efficacy of bavituximab.
NCCN ORP draws on the expertise of investigators from NCCN Member Institutions and their affiliated hospitals to facilitate all phases of clinical research. The research is made possible by collaborations with pharmaceutical and biotechnology companies in order to advance therapeutic options for patients with cancer.
For more information about NCCN ORP, visit NCCN.org/ORP (http://www.nccn.org/ORP).
About the National Comprehensive Cancer Network The National Comprehensive Cancer Network(®) (NCCN(®)), a not-for-profit alliance of 27 leading cancer centers devoted to patient care, research, and education, is dedicated to improving the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers.
The NCCN Member Institutions are: Fred & Pamela Buffett Cancer Center, Omaha, NE; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; City of Hope Comprehensive Cancer Center, Los Angeles, CA; Dana-Farber/Brigham and Women's Cancer Center | Massachusetts General Hospital Cancer Center, Boston, MA; Duke Cancer Institute, Durham, NC; Fox Chase Cancer Center, Philadelphia, PA; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, WA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Mayo Clinic Cancer Center, Phoenix/Scottsdale, AZ, Jacksonville, FL, and Rochester, MN; Memorial Sloan Kettering Cancer Center, New York, NY; Moffitt Cancer Center, Tampa, FL; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Columbus, OH; Roswell Park Cancer Institute, Buffalo, NY; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center, Memphis, TN; Stanford Cancer Institute, Stanford, CA; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; UC San Diego Moores Cancer Center, La Jolla, CA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of Colorado Cancer Center, Aurora, CO; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; Vanderbilt-Ingram Cancer Center, Nashville, TN; and Yale Cancer Center/Smilow Cancer Hospital, New Haven, CT.
Clinicians, visit NCCN.org (http://www.nccn.org/). Patients and caregivers, visit NCCN.org/patients (http://www.nccn.org/patients). Media, visit NCCN.org/news (http://www.nccn.org/news).
(1) CBTRUS (2008) Statistical report: primary brain tumors in the United States, 2000-2004. Central Brain Tumor Registry of the United States. (2) Yin Y, Huang X, Lynn KD, Thorpe PE. Phosphatidylserine-targeting antibody induces M1 macrophage polarization and promotes myeloid-derived suppressor cell differentiation. Cancer immunology research 2013 Oct; 1(4): 256-268.
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Emerging Treatment Strategies in Nonsquamous NSCLC
Published Online: Sep 05,2017
....
PPHM 1501, a randomized, open-label phase II trial, was evaluating the combination of durvalumab (Imfinzi) with or without bavituximab in patients with previously treated metastatic NSCLC.32 However, the trial was suspended. Durvalumab is a human monoclonal antibody that inhibits the binding of PD-L1 to PD-1. Bavituximab is a monoclonal antibody that leads to production of pro-inflammatory cytokines and induction of tumor- specific cytotoxic T-lymphocyte immunity. A previous phase II trial reported 60% improved median OS in patients treated with bavituximab compared with the control arm.
.......
http://www.targetedonc.com/publications/evolving-paradigms/2017/nsclc/emerging-treatment-strategies-in-nonsquamous-nsclc
Anti-Human Phosphatidylserine Therapeutic Antibody Bavituximab) from Creative Biolabs
http://www.biocompare.com/9776-Antibodies/8718097-Anti-Human-Phosphatidylserine-Therapeutic-Antibody-Bavituximab/?pda=9776|8718097_0_0|1529|15|Phosphatidylserine
Insights into the cytoadherence phenomenon of Plasmodium vivax: the putative role of phosphatidylserine
Paulo R. Totino1* and Stefanie C. Lopes2
1Oswaldo Cruz Foundation, Brazil2Instituto Leônidas & Maria Deane (ILMD/Fiocruz Amazônia), Brazil
Plasmodium vivax is the most geographically widespread and the dominant human malaria parasite in most countries outside of sub-Saharan Africa and, although it was classically recognized to cause benign infection, severe cases and deaths caused by P. vivax have remarkably been reported. In contrast to P. falciparum, which well-known ability to bind to endothelium and placental tissue and form rosettes is related to severity of the disease, it has been a dogma that P. vivax is unable to undergo cytoadherent phenomena. However, some studies have demonstrated that red blood cells infected by P. vivax can cytoadhere to host cells, while the molecules participating in this host-parasite interaction are still a matter of speculation. In the present overview we address the evidences currently supporting the adhesive profile of P. vivax and, additionally, discuss the putative role of phosphatidylserine – a cell membrane phospholipid with cytoadhesive properties that has been detected on the surface of Plasmodium-parasitized red blood cells.
http://journal.frontiersin.org/article/10.3389/fimmu.2017.01148/abstract
Phosphatidylserine: A cancer cell targeting biomarker
Bhupender Sharma, Shamsher S. Kanwar, Department of Biotechnology, Himachal Pradesh University, Summer Hill, Shimla, 171 005, India
Received 12 April 2017, Revised 12 August 2017, Accepted 30 August 2017, Available online 1 September 2017
Show less
https://doi.org/10.1016/j.semcancer.2017.08.012Get rights and content
Abstract
Cancer is a leading cause of mortality and morbidity globally. Many prominent cancer-associated molecules have been identified over the recent years which include EGFR, CD44, TGFbRII, HER2, miR-497, NMP22, BTA, Fibrin/FDP etc. These biomarkers are often used for screening, detection, diagnosis, prognosis, prediction and monitoring of cancer development. Phosphatidylserine (PS) is an essential component in all human cells which is present on the inner leaflet of the cell membrane. The oxidative stress causes exposure of PS on the surface of the vascular endothelium in the cancer cells (lung, breast, pancreatic, bladder, skin, brain metastasis, rectal adenocarcinoma etc.) but not on the normal cells. The external PS is regulated by calcium-dependent flippase activity. Cancer cell lines with high surface PS have low flippase activity and high intracellular calcium content. Human Annexin-V, PS targeting antibodies (PGN635 and bavituximab and mch1N11), lysosomal protein, phospholipid Saposin C dioleoylphosphatidylserine (SapC–DOPS), peptide-peptoid hybrid PPS1, PS-binding 14-mer peptide (PSBP-6) and hexapeptide (E3) have been reported to target PS present on cancer cell surface. High expression of CD47 inhibits tumor cell phagocytosis by macrophages. The PS cancer biomarker has also been used to target the drugs to cancer cells specifically without affecting other healthy cells. Currently, the fusion protein (FP) consisting of L-methionase linked to human Annexin-V has been reported to target the cancer cells. The FP catalyzes the conversion of non-toxic prodrug selenomethionine into toxic methyl selenol which thus also prevents the methionine (essential amino acid) supplementation to the cancer cells.
KeywordsCancer-biomarkers; Phosphatidylserine; Human annexin-V; Fusion protein; Methionase
http://www.sciencedirect.com/science/article/pii/S1044579X17300585
Blockade of surface-bound TGF-ß on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment.
Budhu S1,2, Schaer DA1, Li Y3, Toledo-Crow R3, Panageas K4, Yang X1,2, Zhong H1,2, Houghton AN1, Silverstein SC5, Merghoub T6,2,Wolchok JD6,2,7.
Author information
1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA.Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. merghout@mskcc.org wolchokj@mskcc.org.
Abstract
Regulatory T cells (Tregs) suppress antitumor immunity by inhibiting the killing of tumor cells by antigen-specific CD8+ T cells. To better understand the mechanisms involved, we used ex vivo three-dimensional collagen-fibrin gel cultures of dissociated B16 melanoma tumors. This system recapitulated the in vivo suppression of antimelanoma immunity, rendering the dissociated tumor cells resistant to killing by cocultured activated, antigen-specific T cells. Immunosuppression was not observed when tumors excised from Treg-depleted mice were cultured in this system. Experiments with neutralizing antibodies showed that blocking transforming growth factor-ß (TGF-ß) also prevented immunosuppression. Immunosuppression depended on cell-cell contact or cellular proximity because soluble factors from the collagen-fibrin gel cultures did not inhibit tumor cell killing by T cells. Moreover, intravital, two-photon microscopy showed that tumor-specific Pmel-1 effector T cells physically interacted with tumor-resident Tregs in mice. Tregs isolated from B16 tumors alone were sufficient to suppress CD8+ T cell-mediated killing, which depended on surface-bound TGF-ß on the TregsImmunosuppression of CD8+ T cells correlated with a decrease in the abundance of the cytolytic protein granzyme B and an increase in the cell surface amount of the immune checkpoint receptor programmed cell death protein 1 (PD-1). These findings suggest that contact between Tregs and antitumor T cells in the tumor microenvironment inhibits antimelanoma immunity in a TGF-ß-dependent manner and highlight potential ways to inhibit intratumoral Tregs therapeutically.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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CAR-T CANCER THERAPY: SUPERCHARGING A PATIENT’S OWN CELLS TO BATTLE CANCER
BSW
09/01/2017 7:22 PM
CAR-T Cancer Therapy: Supercharging a Patient’s Own Cells to Battle Cancer
The U.S. Food and Drug Administration has approved a novel cancer treatment that resulted in 83% of patients with resistant leukemia going into remission, and the majority remaining cancer free after a year. The approach is called CAR-T therapy, and it uses a patient’s own white blood cells that have been genetically re-engineered to specifically target and kill cancer cells. The newly licensed therapy, called Kymriah, is produced by Novartis and has been approved to treat children and young adults with relapsed acute lymphoblastic leukemia.
This Smart News Release features multimedia. View the full release here: http://www.businesswire.com/news/home/20170901005633/en/ (http://www.businesswire.com/news/home/20170901005633/en/)
Alexis Bonilla participated in the Novartis CAR-T trial and has now been leukemia-free for nearly 20 months. (Photo: Business Wire)
“Despite the nearly continuous advances that have been made in the treatment of leukemia, this malignancy remains a leading cause of death in childhood,” says Alan Wayne, MD, director of the Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles and professor of Pediatrics and Medicine at the Keck School of Medicine of the University of Southern California. “At CHLA, we can now offer potent immunotherapies, like CAR-T, to children with the most resistant cancers.”
Children’s Hospital Los Angeles was one of a small number of sites that participated in the trial that led the FDA to approve Kymriah, and it is one of 32 hospitals in the U.S. that have been approved to treat patients with this therapy.
At CHLA, the Novartis CAR-T trial is being led by Michael Pulsipher, MD, section head of Blood and Marrow Transplantation. He and Wayne are leading a number of other CAR-T studies to determine the effectiveness of the treatment in different types of patients.
Treatment with CAR-T
Ninety percent of children diagnosed with acute lymphoblastic leukemia are cured. However, of those who relapse, only a minority survive long-term. So when Alexis Bonilla was 11 years old and his disease returned for the third time, his doctor immediately referred him to CHLA.
“I told Alexis’ parents that the good news is we have a new therapy, and after being treated with it, your son has nearly a 90 percent chance of remission,” says Pulsipher. “The not-so-good news is that it might initially make him very sick.” Pulsipher told the couple about a clinical trial for chimeric antigen receptor T cell (CAR-T) therapy.
Alexis’ mom, Daysi Bonilla, and his stepdad, Jorge, agreed right away to have their son in the study.
Personalized medicine
T cells are a type of white blood cell that is part of our defense against viruses, bacteria and to a lesser extent, cancer. CAR-T therapy harnesses the immune system by engineering the T cells to specifically attack cancer cells. The opposite of a “one size fits all” strategy, this treatment is individually created for each patient using his or her own cells.
A sample of Alexis’ blood was taken and sent to the lab so that his T cells could be genetically engineered to produce a chimeric antigen receptor (CAR) on their surface. The receptor directs the T cells to a protein, called CD19, present on leukemia cells. When the CAR-T cell connects with the CD19 protein, the leukemia cell is destroyed.
Alexis received several weeks of high-dose chemotherapy to kill as many leukemia cells as possible. Then his modified T cells were re-infused.
Waiting to see what happens
“Ninety percent of patients develop a fever after the cells are infused,” says Pulsipher. “It’s a side effect that we want to see because it indicates that the CAR-T cells are functioning appropriately.”
He explains that the greater number of tumor cells a patient has, the greater their immune response. Sometimes, the battle between the supercharged T cells and the large number of cancer cells becomes extreme, causing the patient’s blood pressure to plummet.
This reaction, known as cytokine release syndrome, or “cytokine storm,” occurred in Alexis. He was moved to the intensive care unit so that his response could be safely managed. “It was scary,” says Daysi.
What’s next for CAR-T?
When an experimental therapy is introduced into the clinic at the earliest stage of investigation, it is tested in people who have disease that is resistant to all other treatments—basically, the sickest patients.
“As we gain experience with CAR-T and trials are open to a wider variety of patients, I anticipate that we will see less-severe side effects in people with earlier-stage disease,” says Pulsipher, who is also a professor of Pediatrics at the Keck School of Medicine of USC. Until then, he and his colleagues are glad to have this truly life-changing therapy to offer their most seriously ill patients.
Alexis made a rapid recovery. Two months after starting treatment at CHLA, he was ready to return home. He always bounces back, Daysi says.
“He wants life,” adds Jorge.
Alexis has been in remission from leukemia for nearly 20 months.
View source version on businesswire.com: http://www.businesswire.com/news/home/20170901005633/en/ (http://www.businesswire.com/news/home/20170901005633/en/)
Children’s Hospital Los Angeles Ellin Kavanagh, 323-361-8505 ekavanagh@chla.usc.edu (mailto:ekavanagh@chla.usc.edu)
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PROFIT ON $475,000 NOVARTIS CANCER DRUG COULD BE A WHILE COMING
RTRS
08/31/2017 6:25 PM
Cancer game-changer Kymriah under fire for pricing
Break-even point remains uncertain
Rival treatments on the horizon
Novartis expects Kymriah to become $1 bln blockbuster
By John Miller
ZURICH, Aug 31 (Reuters) - Novartis's NOVN.S new gene-modifying cancer therapy's $475,000-per-patient sticker price has drawn fire from advocate groups calling for cheaper drugs, but analysts said the Swiss drugmaker could initially struggle to break even.
In a first for gene therapy in the United States, regulators approved Kymriah on Wednesday for patients up to 25 years of age who have relapsed or not been helped by previous treatment for B-cell acute lymphoblastic leukemia (ALL). (Full Story)
While patient groups hailed the potent immunotherapy as a potential cancer game-changer, the Swiss drugmaker was also criticised for setting a price that places Kymriah among the most-expensive drugs ever. It trails only a couple of gene therapies for ulta-rare diseases. (Full Story)
Since taxpayers have chipped in more than $200 million over the years for related research -- much early work on the drug was done at the University of Pennsylvania -- Novartis should have used more restraint, the Patients for Affordable Drugs lobby group said.
"We believe it is excessive," said David Mitchell, a cancer patient who founded the group. "Novartis should not get credit for bringing a $475,000 drug to market and claiming they could have charged people a lot more."
Novartis estimates that only 600 ALL patients a year would be eligible for Kymriah, making the initial pool for the treatment relatively scarce and worth less than $300 million.
The company is also targeting the several thousand people a year who have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) diagnosed, but it will not file Kymriah for that group until later this year.
BREAK-EVEN POINT?
Success with those patients is key to Novartis turning Kymriah into the $1 billion-a-year blockbuster drug the Swiss company predicts it will eventually become, but analysts say it is anyone's guess when it will start covering its costs.
"It is not clear what the break-even point for profitability is, as this is a very capital intensive endeavour," said Bernstein analyst Tim Anderson, adding that Novartis is likely to cut the price of Kymriah for DLBCL patients.
On Thursday Novartis said that its cost of goods per Kymriah treatment is confidential commercial information, but analysts estimate it could be as high as $200,000.
The process is complex. Doctors remove T cells from each cancer victim and ship the material to its factory in Morris Plains, New Jersey. After re-engineering them to attack cancer, frozen cells are returned a couple weeks later for reinfusion into patients.
Additionally, Novartis partner Oxford BioMedica OXB.L, which supplies a key ingredient, may be due $100 million over the next three years, plus royalties on sales. (Full Story)
Furthermore, competition is on the horizon. Gilead Sciences GILD.O this week announced an $11.9 billion deal to buy Kite Pharma KITE.O to gain access to a similar drug, while Bluebird Bio BLUE.O and Juno Therapeutics JUNO.O are all working on their own CAR-T therapies.
While Kymriah's price tag will grab headlines, it pales in comparison with some other gene therapy treatments.
For instance, UniQure's QURE.O Glybera, for a very rare blood disorder, runs at about $1 million per patient. Meanwhile, GlaxoSmithKline’s GSK.L Strimvelis, for so-called “bubble boy” disease, comes in at about $700,000 per patient.
OUTCOME PRICING
Novartis points out that some groups think the company could actually have charged more for Kymriah.
British health authorities, for instance, had said that up to $650,000 might have been justified if the treatment added years to children's lives.
Novartis plans to charge insurers and payers only when the drug proves to be effective one month into treatment, a so-called "outcome-based" pricing scheme that puts some of the risk of the drug on its manufacturer.
Even so, analysts hardly expect that to shield Novartis from criticism.
"Expect turbulent public discussions on drug pricing, demonstrating that the road to hell is paved with good intentions," said Bruno Bulic of equity research firm Baader Helvea.
Bulic forecasts that Kymriah will start adding to Novartis's bottom line only after 2019, when it is expected to be given to more patient groups.
<^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Novartis gene therapy approval signals new cancer treatment era
(Full Story)
Profit finally in sight for gene therapy specialist Oxford Bio
(Full Story)
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(Additional reporting by Ben Hirschler; Editing by David Goodman)
((J.Miller@thomsonreuters.com; +41 58 306 7734; Reuters Messaging: j.miller.thomsonreuters.com@reuters.net))
Keywords: NOVARTIS FDA/PRICE (PIX)
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FDA APPROVES FIRST-EVER T-CELL CANCER TREATMENT, PIONEERED AT PENN, CHOP
PHILAI
08/31/2017 11:16 AM
Calling its endorsement a 'historic action,' the U.S. Food and Drug Administration on Wednesday approved the world's first genetically engineered immune therapy, Novartis Pharmaceuticals' T-cell treatment for pediatric leukemia.
handout Carl June pioneered the therapy at Penn.
The technology behind Novartis' personalized drug, called Kymriah, or tisagenlecleucel, was developed at the University of Pennsylvania by a team led by gene therapy pioneer Carl June. Each patient's immune system T cells are removed, programmed to attack acute lymphoblastic leukemia cells, then returned to the patient.
The therapy showed unparalleled effectiveness, putting more than 80 percent of terminally ill youths into remission in clinical tests at Children's Hospital of Philadelphia beginning in 2012, and in a pivotal study of 68 children at 25 medical centers around the world.
'We're entering a new frontier in medical innovation with the ability to reprogram a patient's own cells to attack a deadly cancer,' FDA Commissioner Scott Gottlieb said in a news release. 'New technologies such as gene and cell therapies hold out the potential to transform medicine.'
Novartis announced a hefty price tag - $475,000 for the onetime treatment - but said it is working with private insurers and the federal Centers for Medicaid and Medicare to develop a novel payment policy based on patient outcomes.
'There will be no charge for the therapy if the patient doesn't respond within the first month after treatment,' Novartis CEO Joseph Jimenez said during a media call.
Whether the therapy works or not, patients' insurance will have to cover the costs of the lengthy hospitalization involved in preparing for, and recovering from, the T-cell therapy.
The company also said it will help uninsured patients get access, and will offer eligible families assistance with travel costs, because the treatment will be available only at select hospitals.
Kymriah is approved for patients up to age 25 with B-cell acute lymphoblastic leukemia who have relapsed at least once with conventional treatment - chemotherapy, radiation, and bone-marrow transplant.
While Kymriah has not shown the kind of long-term toxicities that make conventional therapy such a double-edged sword for children, it typically causes severe, temporary side effects within days of infusion, including fevers, low blood pressure, and neurological problems. The FDA expanded its previous approval of a rheumatoid arthritis drug, Actemra, to help manage these side effects.
The market for the breakthrough drug is relatively small; about 600 children a year in the United States may be candidates. Novartis is also seeking approval from the European Medicines Agency.
But the promise of T-cell therapy is believed to be vast. Novartis and other companies are racing to develop T-cell therapies for other blood disorders, as well as for solid-tumor cancers, which have so far defied this immune-boosting approach.
'We hope the momentum behind the technology builds as we continue to investigate the abilities of personalized cellular therapeutics in blood cancers and solid tumors to help patients with many other types of cancer,' June said in a statement issued by Penn.
The Kymriah approval came just over three months after the first patient to receive it, 12-year-old Emily Whitehead of Philipsburg, Pa., celebrated five years cancer-free in May.
Tweet from @EWhiteheadFdn 'We delivered engineered T-cell therapy at CHOP for the first pediatric patient in the world, Emily Whitehead, who was only 6 years old when her leukemia stopped responding to conventional treatments,' said Stephan Grupp, the CHOP pediatrician who led the effort. 'Emily's cancer remains in remission, and in larger trials, we're seeing overall remission rates over 80 percent, which is a remarkable improvement upon previous treatment success rates.'
The T-cell therapy was first tested at Penn in 2010, in three adults with advanced chronic lymphocytic leukemia. It was so effective that Novartis partnered with Penn in 2012 to research and commercialize bioengineered T-cell therapies, starting with Kymriah.
Although the manufacturing and delivery of the living drug poses huge challenges, Novartis' global clinical trial proved the feat can be achieved. Each patient's T cells will be collected at a hospital certified to have the necessary expertise. The cells will be frozen and shipped to Novartis' plant in Morris Plains, N.J., where they will be bioengineered and multiplied, refrozen, and shipped back to be infused into the patient.
Novartis expects to have 25 hospitals certified within a month, and 32 by the end of the year. Patients will be followed for 15 years to evaluate the long-term safety of Kymriah.
'We are so proud to be part of this historic moment in cancer treatment and are deeply grateful to our researchers, collaborators, and the patients and families who participated in the Kymriah clinical program,' said Bruno Strigini, CEO of Novartis Oncology, in a statement.
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FIRST FDA-APPROVED CELL THERAPY FOR LEUKEMIA UTILIZES THERMO FISHER SCIENTIFIC'S CTS DYNABEADS TECHNOLOGY
PRN
08/30/2017 8:58 PM
For best results when printing this announcement, please click on link below: http://pdf.reuters.com/htmlnews/htmlnews.asp?i=43059c3bf0e37541&u=urn:newsml:reuters.com:20170830:nPn3BlcpZa
First FDA-Approved Cell Therapy for Leukemia Utilizes Thermo Fisher Scientific's CTS Dynabeads TechnologyKymriah™ (tisagenlecleucel, formerly CTL019), the first FDA-approved CAR-T cell therapy, uses CTS Dynabeads CD3/CD28 spherical beads to isolate, activate and expand T cells PR Newswire
WALTHAM, Mass., Aug. 30, 2017
WALTHAM, Mass., Aug. 30, 2017 /PRNewswire/ -- The U.S. Food and Drug Administration (FDA) has approved a new cell therapy for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. The Novartis chimeric antigen receptor T cell (CAR-T) cell therapy, Kymriah™ (tisagenlecleucel, formerly CTL019), is the first FDA-approved CAR-T immunotherapy, and uses specifically developed Cell Therapy Systems (CTS™ (https://www.thermofisher.com/us/en/home/clinical/clinical-translational-research/cell-therapy/cell-therapy-systems.html)) Dynabeads™
(https://www.thermofisher.com/order/catalog/product/40203D?SID=srch-srp-40203D) technology, part of Thermo Fisher's Cell Therapy Systems (CTS) portfolio. The magnetic beads isolate, activate and expand T cells that have been genetically engineered to recognize and fight cancer cells in each individual patient. Thermo Fisher's longstanding partnership with Novartis is an example of its commitment to accelerate precision medicine.
The company's collaboration with Novartis was originally announced on July 31, 2013 and has since evolved from exclusive to non-exclusive providing the opportunity for other CAR-T cell therapy developers to adopt Thermo Fisher's "ready for commercial drug manufacturing" T cell isolation, activation and expansion platform.
Thermo Fisher's proprietary magnetic bead platform is already enabling research, development and commercial manufacturing of other cancer-treating CAR-T cell therapies globally. In cell therapy manufacturing, CTS Dynabeads CD3/CD28 beads deliver a scalable platform that streamlines production while ensuring high reproducibility.
"Kymriah is an example of the rigor required to deliver viable cell therapies to physicians and their patients," said Alan Sachs, chief scientific officer at Thermo Fisher Scientific. "We established a dedicated facility and a validated aseptic manufacturing process to ensure that our technology met the strict quality standards set by Novartis."
The process for manufacturing Kymriah requires removing blood cells from the patient, isolating and reprogramming the T cells to recognize and attack cancer cells before infusing them back into the patient. CAR-T treatment embodies precision medicine because each patient's therapy is manufactured expressly for them using their own cells.
Dynabeads products are for research use only or for the manufacturing of cell-, gene- or tissue-based products.
Kymriah is a trademark of Novartis.
About Thermo Fisher Scientific
Thermo Fisher Scientific Inc. (NYSE: TMO) is the world leader in serving science, with revenues of more than $20 billion and approximately 65,000 employees globally. Our mission is to enable our customers to make the world healthier, cleaner and safer. We help our customers accelerate life sciences research, solve complex analytical challenges, improve patient diagnostics, deliver medicines to market and increase laboratory productivity. Through our premier brands – Thermo Scientific, Applied Biosystems, Invitrogen, Fisher Scientific and Unity Lab Services – we offer an unmatched combination of innovative technologies, purchasing convenience and comprehensive services. For more information, please visit http://www.thermofisher.com.
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That's it - I hope. And I like Swiss
Mouse macrophages show different requirements for phosphatidylserine receptor Tim4 in efferocytosis.
Yanagihashi Y1, Segawa K1, Maeda R2, Nabeshima YI2, Nagata S3.
Author information
Abstract
Protein S (ProS) and growth arrest-specific 6 (Gas6) bind to phosphatidylserine (PtdSer) and induce efferocytosis upon binding TAM-family receptors (Tyro3, Axl, and Mer). Here, we produced mouse ProS, Gas6, and TAM-receptor extracellular region fused to IgG fragment crystallizable region in HEK293T cells. ProS and Gas6 bound Ca2+ dependently to PtdSer (Kd 20-40 nM), Mer, and Tyro3 (Kd 15-50 nM). Gas6 bound Axl strongly (Kd < 1.0 nM), but ProS did not bind Axl. Using NIH 3T3-based cell lines expressing a single TAM receptor, we showed that TAM-mediated efferocytosis was determined by the receptor-binding ability of ProS and Gas6. Tim4 is a membrane protein that strongly binds PtdSer. Tim4 alone did not support efferocytosis, but enhanced TAM-dependent efferocytosis. Resident peritoneal macrophages, Kupffer cells, and CD169+ skin macrophages required Tim4 for TAM-stimulated efferocytosis, whereas efferocytosis by thioglycollate-elicited peritoneal macrophages or primary cultured microglia was TAM dependent, but not Tim4 dependent. These results indicate that TAM and Tim4 collaborate for efficient efferocytosis in certain macrophage populations.
https://www.ncbi.nlm.nih.gov/pubmed/28768810
Cell surface binding, uptaking and anticancer activity of L-K6, a lysine/leucine-rich peptide, on human breast cancer MCF-7 cells
http://www.nature.com/articles/s41598-017-08963-2
Abstract
Cell surface binding and internalization are critical for the specific targeting and biofunctions of some cationic antimicrobial peptides (CAPs) with anticancer activities. However, the detailed cellular process for CAPs interacting with cancer cells and the exact molecular basis for their anticancer effects are still far from being fully understood. In the present study, we examined the cell surface binding, uptaking and anti-cancer activity of L-K6, a lysine/leucine-rich CAP, in human MCF-7 breast cancer cells. We found that L-K6 preferentially interact with MCF-7 cells. This tumor-targeting property of L-K6 might be partially due to its interactions with the surface exposed and negatively charged phosphatidylserine. Subsequently, L-K6 could internalize into MCF-7 cells mainly through a clathrin-independent macropinocytosis, without significant cell surface disruption. Finally, the internalized L-K6 induced a dramatic nuclear damage and MCF-7 cell death, without significant cytoskeleton disruption and mitochondrial impairment. This cytotoxicity of L-K6 against MCF-7 cancer cells could be further confirmed by using a mouse xenograft model. In summary, all these findings outlined the cellular process and cytotoxicity of L-K6 in MCF-7 cancer cells, and might help understand the complicated interactions between CAPs and cancer cells.
......We found that the negatively charged phosphatidylserine (PS), which has been reported to be abundantly exposed on cancer cells surface19, 20, might contribute to the preferential binding of L-K6 with MCF-7 cancer cells......
From 2017 Aug. 8 - not new.
Detection of phosphatidylserine-positive exosomes for the diagnosis of early-stage malignancies.
Sharma R1, Huang X1, Brekken RA1,2, Schroit AJ3,4.
Author information
Abstract
BACKGROUND:
There has been increasing interest in the detection of tumour exosomes in blood for cancer diagnostics. Most studies have focussed on miRNA and protein signatures that are surrogate markers for specific tumour types. Because tumour cells and tumour-derived exosomes display phosphatidylserine (PS) in their outer membrane leaflet, we developed a highly sensitive ELISA-based system that detects picogram amounts of exosomal phospholipid in plasma as a cancer biomarker.
METHODS:
This report describes the development of a highly specific and sensitive ELISA for the capture of PS-expressing tumour exosomes in the blood of tumour-bearing mice. To monitor the relationship between tumour burden and tumour exosome plasma concentrations, plasma from one transplantable breast cancer model (MDA-MB-231) and three genetic mouse models (MMTV-PyMT; breast and KIC and KPC; pancreatic) were screened for captured exosomal phospholipid.
RESULTS:
We show that quantitative assessment of PS-expressing tumour exosomes detected very early-stage malignancies before clinical evidence of disease in all four model systems. Tumour exosome levels showed significant increases by day 7 after tumour implantation in the MDA-MB-231 model while palpable tumours appeared only after day 27. For the MMTV-PyMT and KIC models, tumour exosome levels increased significantly by day 49 (P?0.0002) and day 21 (P?0.001) while tumours developed only after days 60 and 40, respectively. For the KPC model, a significant increase in blood exosome levels was detected by day 70 (P=0.023) when only preinvasive lesions are microscopically detectable.
CONCLUSIONS:
These data indicate that blood PS exosome levels is a specific indicator of cancer and suggest that blood PS is a biomarker for early-stage malignancies.
https://www.ncbi.nlm.nih.gov/pubmed/28641308
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And the one from Feb. 2017
https://www.ncbi.nlm.nih.gov/pubmed/28122335
Detection of phosphatidylserine-positive exosomes as a diagnostic marker for ovarian malignancies: a proof of concept study.
Lea J1, Sharma R2, Yang F2, Zhu H1, Ward ES3,4, Schroit AJ1,3.
SHARES OF CAR-T DEVELOPERS UP AFTER GILEAD ANNOUNCES DEAL TO BUY KITE PHARMA FOR $11.9 BLN; BLUEBIRD BIO UP 11 PCT AND JUNO THERAPEUTICS UP 17.8 PCT
RTRS
08/28/2017 3:44 PM
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Time and Effort Required for Tissue Acquisition and Submission in Lung CancerClinical Trials.
Garcia S1, Saltarski JM2, Yan J3, Xie XJ4, Gerber DE5.
Author information
1School of Medicine, University of Texas Southwestern Medical Center, Dallas, TX.Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX.Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX.Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX; Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX.Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX; Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX. Electronic address: david.gerber@utsouthwestern.edu.
Abstract
BACKGROUND:
Increasingly, analysis of tumor tissue samples for predictive and pharmacodynamic biomarkers is incorporated into lung cancer clinical trials. We determined the time and effort required for tissue acquisition and submission.
PATIENTS AND METHODS:
We analyzed data from patients enrolled from 2009 to 2016 at UT Southwestern onto lung cancer trials with mandatory or optional submission of tumor tissue. We collected dates of treatment-related events and staff communications; nature of tissue requirement and biomarker analysis; and location of archival tissue. Associations between case characteristics, clinical intervals, and number of staff communications were analyzed by Fisher's exact test, Wilcoxon 2-sample test, and Kruskal-Wallis test.
RESULTS:
We identified 129 patients enrolled onto 19 clinical trials, of whom 108 (84%) ultimately received study therapy. For cases in which tissue submission was required if available or optional, 16% and 0%, respectively, had tissue sent. The median interval between consent and treatment was 28 (interquartile range, 11-43) days if tissue was requested and 7 (interquartile range, 6-13) days if tissue was not requested (P < .001). Among cases with requested tissue, the median number of related research staff communications was 3 (range, 0-10). Over time, the number of staff communications increased (P < .001). Location of archival tissue was not associated with number of staff communications or treatment intervals.
CONCLUSION:
Lung cancer clinical trial requirements for tissue acquisition and submission affect the time to treatment initiation and require increasing staff effort. Improved systems to expedite these processes, as well as use of blood- or imaging-based biomarkers, may help address these issues.
https://www.ncbi.nlm.nih.gov/pubmed/28576594
Phosphatidylserine Translocation after Radiosurgery in an Animal Model of Arteriovenous Malformation.
Raoufi Rad N1, McRobb LS1, Zhao Z1, Lee VS1, Patel NJ1, Qureshi AS1, Grace M2, McHattan JJ3, Amal Raj JV1, Duong H1, Kashba SR1,4, Stoodley MA1.
Author information
1a ? Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, New South Wales, Australia.b ? Genesis Cancer Care, Macquarie University Hospital, New South Wales, Australia.d ? Department of Neurosurgery, Misurata Cancer Institute, Misurata University, Misurata, Libya.
Abstract
Phosphatidylserine (PS) is asymmetrically distributed across the plasma membrane, located predominantly on the inner leaflet in healthy cells. Translocation of PS to the outer leaflet makes it available as a target for biological therapies. We examined PS translocation after radiosurgery in an animal model of brain arteriovenous malformation (AVM). An arteriovenous fistula was created by end-to-side anastomosis of the left external jugular vein to the common carotid artery in 6-week-old, male Sprague Dawley rats. Six weeks after AVM creation, 15 rats underwent Gamma Knife stereotactic radiosurgery receiving a single 15 Gy dose to the margin of the fistula; 15 rats received sham treatment. Externalization of PS was examined by intravenous injection of a PS-specific near-infrared probe, PSVue-794, and in vivo fluorescence optical imaging at 1, 7, 21, 42, 63 and 84 days postirradiation. Fluorescent signaling indicative of PS translocation to the luminal cell surface accumulated in the AVM region, in both irradiated and nonirradiated animals, at all time points. Fluorescence was localized specifically to the AVM region and was not present in any other anatomical sites. Translocated PS increased over time in irradiated rats (P < 0.001) but not in sham-irradiated rats and this difference reached statistical significance at day 84 (P < 0.05). In summary, vessels within the mature rat AVM demonstrate elevated PS externalization compared to normal vessels. A single dose of ionizing radiation can increase PS externalization in a time-dependent manner. Strict localization of PS externalization within the AVM region suggests that stereotactic radiosurgery can serve as an effective priming agent and PS may be a suitable candidate for vascular-targeting approaches to AVM treatment.
https://www.ncbi.nlm.nih.gov/pubmed/28414573
Phosphatidylserine-Targeted Nanotheranostics for Brain Tumor Imaging and Therapeutic Potential.
Wang L1, Habib AA2,3, Mintz A4,5, Li KC4,6, Zhao D1,3.
Author information
12 Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.3 North Texas VA Medical Center, Dallas, TX, USA.4 Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Abstract
Phosphatidylserine (PS), the most abundant anionic phospholipid in cell membrane, is strictly confined to the inner leaflet in normal cells. However, this PS asymmetry is found disruptive in many tumor vascular endothelial cells. We discuss the underlying mechanisms for PS asymmetry maintenance in normal cells and its loss in tumor cells. The specificity of PS exposure in tumor vasculature but not normal blood vessels may establish it a useful biomarker for cancer molecular imaging. Indeed, utilizing PS-targeting antibodies, multiple imaging probes have been developed and multimodal imaging data have shown their high tumor-selective targeting in various cancers. There is a critical need for improved diagnosis and therapy for brain tumors. We have recently established PS-targeted nanoplatforms, aiming to enhance delivery of imaging contrast agents across the blood-brain barrier to facilitate imaging of brain tumors. Advantages of using the nanodelivery system, in particular, lipid-based nanocarriers, are discussed here. We also describe our recent research interest in developing PS-targeted nanotheranostics for potential image-guided drug delivery to treat brain tumors.
https://www.ncbi.nlm.nih.gov/pubmed/28654387
T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.
Huang AC1,2,3,4, Postow MA5,6, Orlowski RJ1,2,3,4, Mick R3,4,7, Bengsch B2,4,8, Manne S2,8, Xu W1,3, Harmon S1,3, Giles JR2,4,8, Wenz B1,3, Adamow M9, Kuk D10, Panageas KS10, Carrera C5,11, Wong P9,12, Quagliarello F2,8, Wubbenhorst B1,3, D'Andrea K1,3, Pauken KE2,8, Herati RS1,2,3, Staupe RP2,8, Schenkel JM13, McGettigan S1,3, Kothari S1, George SM2,4,8, Vonderheide RH1,2,3,4, Amaravadi RK1,3, Karakousis GC3,14, Schuchter LM1,3, Xu X3,15, Nathanson KL1,3,4, Wolchok JD5,12, Gangadhar TC1,3, Wherry EJ2,3,4,8.
Author information
Abstract
Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.
https://www.ncbi.nlm.nih.gov/pubmed/28397821
Efficacy and Safety Outcomes in Patients With Advanced Melanoma Who Discontinued Treatment With Nivolumab and Ipilimumab Because of Adverse Events: A Pooled Analysis of Randomized Phase II and III Trials.
Schadendorf D1, Wolchok JD1, Hodi FS1, Chiarion-Sileni V1, Gonzalez R1, Rutkowski P1, Grob JJ1, Cowey CL1, Lao CD1, Chesney J1,Robert C1, Grossmann K1, McDermott D1, Walker D1, Bhore R1, Larkin J1, Postow MA1.
Author information
1Dirk Schadendorf, University Hospital Essen and the German Cancer Consortium, Essen, Germany; Jedd D. Wolchok and Michael A. Postow, Memorial Sloan Kettering Cancer Center; Michael A. Postow, Weill Cornell Medical College, New York, NY; F. Stephen Hodi, Dana-Farber Cancer Institute; David McDermott, Beth Israel Deaconess Medical Center, Boston, MA; Vanna Chiarion-Sileni, Istituto Oncologico Veneto, Veneto, Italy; Rene Gonzalez, University of Colorado Denver, Aurora, CO; Piotr Rutkowski, Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Jean-Jacques Grob, Aix-Marseille Université, Assistance Publique Hôpitaux de Marseille Timone, Marseille; Caroline Robert, Gustave Roussy and Université Paris-Sud, Paris, France; C. Lance Cowey, Texas Oncology-Baylor Cancer Center, Dallas, TX; Christopher D. Lao, University of Michigan, Ann Arbor, MI; Jason Chesney, University of Louisville, Louisville, KY; Kenneth Grossmann, Huntsman Cancer Institute, Salt Lake City, UT; Dana Walker and Rafia Bhore, Bristol-Myers Squibb, Princeton, NJ; and James Larkin, Royal Marsden Hospital, London, United Kingdom.
Abstract
Purpose Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409). Efficacy was assessed in all randomly assigned patients who discontinued because of AEs during the induction phase (n = 96) and in those who did not discontinue because of AEs (n = 233). Safety was assessed in treated patients who discontinued because of AEs (n = 176) at any time and in those who did not discontinue because of AEs (n = 231). Results At a minimum follow-up of 18 months, median progression-free survival was 8.4 months for patients who discontinued treatment because of AEs during the induction phase and 10.8 months for patients who did not discontinue because of AEs ( P = .97). Median overall survival had not been reached in either group ( P = .23). The objective response rate was 58.3% for patients who discontinued because of AEs during the induction phase and 50.2% for patients who did not discontinue. The vast majority of grade 3 or 4 AEs occurred during the induction phase, with most resolving after appropriate management. Conclusion Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy.
https://www.ncbi.nlm.nih.gov/pubmed/28841387
Heterogeneous Tumor-Immune Microenvironments among Differentially Growing Metastases in an Ovarian Cancer Patient.
Jiménez-Sánchez A1, Memon D2, Pourpe S3, Veeraraghavan H4, Li Y5, Vargas HA6, Gill MB1, Park KJ7, Zivanovic O8, Konner J9,Ricca J5, Zamarin D10, Walther T3, Aghajanian C9, Wolchok JD11, Sala E6, Merghoub T5, Snyder A12, Miller ML13.
Author information
Abstract
We present an exceptional case of a patient with high-grade serous ovarian cancer, treated with multiple chemotherapy regimens, who exhibited regression of some metastatic lesions with concomitant progression of other lesions during a treatment-free period. Using immunogenomic approaches, we found that progressing metastases were characterized by immune cell exclusion, whereas regressing and stable metastases were infiltrated by CD8+ and CD4+ T cells and exhibited oligoclonal expansion of specific T cell subsets. We also detected CD8+ T cell reactivity against predicted neoepitopes after isolation of cells from a blood sample taken almost 3 years after the tumors were resected. These findings suggest that multiple distinct tumor immune microenvironments co-exist within a single individual and may explain in part the heterogeneous fates of metastatic lesions often observed in the clinic post-therapy. VIDEO ABSTRACT.
https://www.ncbi.nlm.nih.gov/pubmed/28841418