On February 17, 2020 A Ludwig Cancer Research reported that study has identified a mechanism by which regulatory T cells, which suppress immune responses, adapt their metabolism to thrive in the harsh microenvironment of the tumor (Press release, Ludwig Institute For Cancer Research, FEB 17, 2020, View Source [SID1234554428]). This mechanism, the study finds, is exclusively engaged by regulatory T cells (Tregs) that reside in tumors and could be disrupted to selectively target such Tregs and boost the effects of cancer immunotherapy.

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"It has long been known that the Tregs found in tumors protect cancer cells from immune attack, so countering Tregs would be an important strategy for cancer immunotherapy," says Ping-Chih Ho, associate member of the Lausanne Branch of the Ludwig Institute for Cancer Research, who led the study. "But a major hurdle to such interventions is that the systemic suppression of Treg activity can cause severe autoimmune reactions. We have discovered a potential approach to overcoming that problem, one that selectively targets Tregs in tumors and could therefore prevent such adverse effects."

Tregs play a critical role in healthy tissues, where they prevent autoimmune disease and aid wound-healing. But, when recruited into tumors, Tregs also thwart anti-cancer immune responses—and immunotherapy. The current study, published in Nature Immunology, identifies a protein that drives the metabolic adaptations of intratumoral Tregs. The researchers show in a mouse model of melanoma that targeting that protein with an antibody significantly boosts the efficacy of immunotherapy without causing autoimmune side effects.

The cores of tumors are often acidic and starved of oxygen and vital nutrients, which forces resident cells to adapt their metabolism to survive. Ho and graduate student Haiping Wang suspected those adaptations might also reveal vulnerabilities unique to intratumoral Tregs. To find those vulnerabilities, they analyzed a dataset of Treg gene expression in breast tumors and blood compiled a few years ago by the laboratory of Ludwig MSK Director Alexander Rudensky.

They found that those and other intratumoral Tregs expressed high levels of genes involved in lipid uptake and metabolism—particularly CD36, a receptor involved in lipid import. An analysis of Tregs from human melanoma patients conducted by Ludwig Memorial Sloan Kettering (MSK) researchers Taha Merghoub and Jedd Wolchok yielded similar results.

To explore the role of CD36 in intratumoral Tregs, the researchers generated mice that lacked the CD36 gene only in their Treg cells and engrafted them with melanoma. "We found that the tumor burden was reduced in CD36-deficient mice," says Wang, "and the number and functionality of Tregs declined only within tumors, not in the other, healthy tissues of the mice."

CD36 deficiency induced in intratumoral Tregs a form of cell suicide known as apoptosis that was driven by a decline in the health and number of mitochondria—the power generators of cells. Further study revealed that CD36 fuels the activity of PPARβ, a protein essential to the genesis and function of mitochondria.

Treating mice bearing melanoma tumors with an antibody to CD36 resulted in a decline of intratumoral Tregs that was not seen in genetically identical control mice. When this antibody was combined with an immunotherapy known as PD-1 blockade, which stimulates a T cell attack on cancer cells, tumor growth slowed significantly, prolonging the survival of the mice.

"By targeting CD36 with an antibody, we don’t just create trouble for intratumoral Tregs, we also create trouble for the tumor’s ability to maintain an immunosuppressive microenvironment and hamper immunotherapy," says Ho.

Ho’s lab is now working to translate these findings into a potential cancer therapy while exploring how CD36-targeting might be combined with other interventions to more extensively disable Tregs selectively within tumors. They are also exploring which other types of solid tumors harbor Tregs that are dependent on CD36 for survival.

This study was supported by Ludwig Cancer Research, the Swiss Cancer Foundation, the Swiss Institute for Experimental Cancer Research, the European Research Council, the Cancer Research Institute, the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper), the US National Institutes of Health, the Research Foundation—Flanders, the Swiss Cancer Research Foundation, Swim Across America, the Parker Institute for Cancer Immunotherapy and the Breast Cancer Research Foundation.

On February 17, 2020 NRG Oncology reported that result of clinical study NRG-CC001 concluded that lowering radiotherapy dose to hippocampal stem cells improves cognitive and patient-reported outcomes for patients with brain metastases (Press release, NRG Oncology, FEB 17, 2020, View Source [SID1234554427]). These findings were presented at Plenary Sessions at the 2018 Society for Neuro-Oncology (SNO) and the 2019 American Academy of Neurology (AAN) Annual Meetings and are now published in the Journal of Clinical Oncology.

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"NRG-CC001 provides physicians with the information needed to offer patients a safer alternative to standard whole-brain radiotherapy. Hippocampal avoidance whole-brain radiotherapy with memantine should be a standard of care that providers offer for patients with brain metastases who are seeking whole-brain radiotherapy," stated Paul D. Brown, MD, of Mayo Clinic and co-lead author of the NRG-CC001 manuscript.

The NRG-C001 phase III trial enrolled 518 patients, which were randomly assigned to either receive whole-brain radiotherapy plus memantine with hippocampal avoidance or standard whole-brain radiotherapy plus memantine. The primary endpoint of the trial was cognitive function failure and the trial looked at secondary endpoints including overall survival, intracranial progression-free survival, toxicity, and patient-reported neurologic symptoms.

"Hippocampal avoidance during whole-brain radiotherapy in NRG-CC001 leads to a 26% relative reduction in cognitive toxicity risk following treatment. This is the first definitive and most important clinical evidence that the hippocampus is important in determining the negative effects that radiotherapy can have on cognitive function," added Vinai Gondi, MD, the Director of Research at the Northwestern Medicine Chicago Proton Center, Co-Director of the Brain Tumor Center at the Northwestern Medicine Cancer Center Warrenville, and co-lead author of the NRG-CC001 manuscript.

With a median follow up of 7.9 months, the risk of cognitive function failure was lower following hippocampal avoidance whole-brain radiotherapy versus standard whole-brain radiotherapy (adjusted hazard ratio, 0.74, 95% confidence interval:0.58-0.95, p=0.02).The difference was attributable to less deterioration in executive function at 4 months (23.3% vs. 40.4%, p=0.01) and learning and memory at 6 months (11.5% vs. 24.7%, p=0.049, and 16.4% vs. 33.3%, p=0.02, respectively). At 6 months, patients who received whole-brain radiotherapy with hippocampal avoidance reported less fatigue (p=0.04), less difficulty remembering things (p=0.01), and less difficulty speaking (p=0.0049), in addition to fewer cognitive symptoms (p=0.01) and less interference of neurologic symptoms in daily activities (p=0.008). There was no statistically significant difference between overall survival, intracranial progression-free survival, or toxicity between treatment arms.

NRG-CC001 was supported by grants UG1CA189867 (NRG Oncology NCORP) and U24CA180803 (IROC) from the National Cancer Institute (NCI). Clinicaltrials.gov identifier: NCT02360215.

Citation
Brown PD, Gondi V, Pugh SL, Tome WA, Wefel JS, Armstrong TS, Bovi JA, Robinson C, Konski A, Khuntia D, Grosshans D, Benzinger TLS, Bruner D, Gilbert MR, Roberge D, Kundapur V, Devisetty K, Shah S, Usuki K, Anderson BM, Stea B, Yoon H, Li J, Laack NN, Kruser TJ, Chmura SJ, Shi W, Deshmukh S, Mehta MP, Kachnic LA. Hippocampal Avoidance during Whole-Brain Radiotherapy plus Memantine for Patients with Brain Metastases: Phase III Trial NRG Oncology CC001. J Clin Oncol. Feb. 14, 2020. doi: 10.1200/JCO.19.02767. [Epub ahead of print] PubMed PMID: 32058845

On February 17, 2020 Cancer Research UK reported Scientists have created one of the most detailed maps of breast cancer ever achieved, revealing how genetic changes shape the physical tumour landscape (Press release, Cancer Research UK, FEB 17, 2020, View Source [SID1234554417]).

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‘At the moment, doctors only look for a few key markers to understand what type of breast cancer someone has. But as we enter an era of personalised medicine, the more information we have about a patient’s tumour, the more targeted and effective we can make their treatment’ – Dr Raza Ali
An international team of scientists*, brought together by an ambitious £20 million Grand Challenge award from Cancer Research UK, has developed intricate maps of breast tumour samples, with a resolution smaller than a single cell.

These maps show how the complex cancer landscape, made up of cancer cells, immune cells and connective tissue, varies between and within tumours, depending on their genetic makeup.

This technique could one day provide doctors with an unparalleled wealth of information about each patient’s tumour upon diagnosis, allowing them to match each patient with the best course of treatment for them.

In the future, it could also be used to analyse tumours during treatment, allowing doctors to see in unprecedented detail how tumours are responding to drugs or radiotherapy. They could then modify treatments accordingly, to give each patient the best chance of beating the disease.

Dr Raza Ali, lead author of the study and junior group leader at the Cancer Research UK Cambridge Institute, said: "At the moment, doctors only look for a few key markers to understand what type of breast cancer someone has. But as we enter an era of personalised medicine, the more information we have about a patient’s tumour, the more targeted and effective we can make their treatment."

The researchers studied 483 different tumour samples, collected as part of the Cancer Research UK funded METABRIC study, a project that has already revolutionised our understanding of the disease by revealing that there are at least 11 different subtypes of breast cancer.

The team looked within the samples for the presence of 37 key proteins, indicative of the characteristics and behaviour of cancer cells. Using a technique called imaging mass cytometry, they produced detailed images, which revealed precisely how each of the 37 proteins were distributed across the tumour.

The researchers then combined this information with vast amounts of genetic data from each patient’s sample to further enhance the image resolution. This is the first time imaging mass cytometry has been paired with genomic data.

These tumour ‘blueprints’ expose the distribution of different types of cells, their individual characteristics and the interactions between them.

By matching these pictures of tumours to clinical information from each patient, the team also found that the technique could be used to predict how someone’s cancer might progress and respond to different treatments.

Professor Carlos Caldas, co-author of the study from the Cancer Research UK Cambridge Institute, said: "We’ve shown that the effects of mutations in cancer are far more wide-ranging than first thought.

"They affect how cancer cells interact with their neighbours and other types of cell, influencing the entire structure of the tumour."

The research was funded by Cancer Research UK’s Grand Challenge initiative. By providing international, multidisciplinary teams with £20 million grants, this initiative aims to solve the biggest challenges in cancer.

Dr David Scott, director of Grand Challenge at Cancer Research UK said: "This team is making incredible advances, helping us to peer into a future when breast cancer treatments are truly personalised.

"There’s still a long way to go before this technology reaches patients, but with further research and clinical trials, we hope to unlock its powerful potential."

On February 17, 2020 Arix Bioscience plc (LSE: ARIX) ("Arix Bioscience"), a global venture capital company focused on investing in and building breakthrough biotech companies, reported that one of its portfolio companies, Imara Inc., ("Imara"), has filed a registration statement on Form S-1 with the U.S. Securities and Exchange Commission (the "SEC") for a proposed initial public offering ("IPO") in the United States of shares of its common stock (Press release, Arix Bioscience, FEB 17, 2020, View Source;imara-files-for-proposed-initial-public-offering-in-the-united-states-301005809.html [SID1234554400]). All shares to be sold in the offering will be offered by Imara. Imara has applied to list its common stock on the Nasdaq Global Market under the ticker symbol "IMRA". The offering is subject to market conditions, and there can be no assurance as to whether or when the offering may be completed, or as to the actual size or terms of the offering. A further announcement will be made in due course.

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A registration statement relating to these securities has been filed with the SEC but has not yet become effective. These securities may not be sold, nor may offers to buy be accepted, prior to the time the registration statement becomes effective. This announcement does not constitute an offer to sell or the solicitation of an offer to buy securities, and shall not constitute an offer, solicitation or sale in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of that jurisdiction. Any offers, solicitations or offers to buy, or any sales of securities will be made in accordance with the registration requirements of the Securities Act of 1933, as amended.

The securities referred to in this release are to be offered only by means of a prospectus. When available, copies of the preliminary prospectus can be obtained from Morgan Stanley, 180 Varick Street, 2nd Floor, New York, New York 10014, Attention: Prospectus Dept.; Citigroup, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, New York, 11717 or by telephone at (800) 831-9146; or SVB Leerink, One Federal Street, 37th Floor, Boston, Massachusetts, 02110, Attention: Syndicate Department, by telephone at (800) 808-7525, ext. 6132, or by email at [email protected].

This announcement includes information that is inside information as defined in Article 7 of the Market Abuse Regulation (EU) No.596/2014.The person responsible for arranging for the release of this announcement on behalf of Arix Bioscience plc is Robert Lyne, General Counsel.

On February 17, 2020 PTC Therapeutics, Inc. (NASDAQ: PTCT) reported that the Company will host a webcast conference call to report its fourth quarter and year-end 2019 financial results and provide an update on the company’s business and outlook on Monday, March 2, 2020 at 4:30 p.m. (ET) after the closing of the market (Press release, PTC Therapeutics, FEB 17, 2020, https://www.prnewswire.com/news-releases/ptc-therapeutics-to-host-conference-call-to-discuss-fourth-quarter-and-year-end-2019-financial-results-301006141.html [SID1234554399]).

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The call can be accessed by dialing (877) 303-9216 (domestic) or (973) 935-8152 (international) five minutes prior to the start of the call and providing the passcode 1732477. A live, listen-only webcast of the conference call can be accessed on the investor relations section of the PTC website at www.ptcbio.com. A webcast replay of the call will be available approximately two hours after completion of the call and will be archived on the company’s website for 30 days following the call.