Cancer Immunotherapy ‘Uniquely Suppressed’ by Liver Tumors

On October 2, 2020 University of California San Francisco reported that Though cancer immunotherapy has become a promising standard-of-care treatment – and in some cases, perhaps a cure – for a wide variety of different cancers, it doesn’t work for everyone, and researchers have increasingly turned their attention to understanding why (Press release, University of California San Francisco, OCT 2, 2020, View Source [SID1234568068]).

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For example, doctors have noticed that patients who initially respond well to the immunotherapy drugs known as checkpoint inhibitors, such as those that target a protein called PD-1, can develop resistance to these therapies if their cancer has metastasized from its initial location to form additional tumors in the liver – even if their primary cancer is quite distant from the liver.

In a new study published Oct. 2 in Science Immunology, a UC San Francisco research team led by Hematology and Oncology Clinical Fellow James Lee, MD, MHS, used a unique mouse model to figure out how this happens.

Then, the researchers, including senior author Jeffrey Bluestone, PhD, adjunct professor of microbiology and immunology and the A.W. and Mary Margaret Clausen Distinguished Professor of Metabolism and Endocrinology, showed that adding a second type of checkpoint inhibitor in a combination therapy can overcome this resistance, and might significantly increase the effectiveness of immunotherapy in patients with liver metastases.

"The liver actually triggers differences in immune cells at distant sites," Lee said. And what’s more, he added, "the liver can choose its enemy – what it wants to protect or not protect."

Cancers are sometimes able to avoid detection within the body by cloaking themselves from the immune system. They can produce large quantities of proteins like PD-L1, which "switch off" cells called regulatory T cells (Tregs; pronounced "tee-regs"), in turn tamping down the immune response of other T cells that attack cancer. Some checkpoint inhibitors counteract this cloaking process by preventing PD-L1 from binding to the PD-1 off-switches on T cells, allowing a normal defensive immune response against cancer cells.

The liver, which is tasked with filtering large quantities of blood directly from the digestive system and the rest of the body, plays an unexpectedly large role in regulating the immune system – specifically, by signaling which of the scavenged proteins it encounters as it does its job are from hostile invaders and which should be ignored.

In work supported by the Parker Institute for Cancer Immunotherapy, the scientists simulated metastasis by implanting mice with cancer cells in two separate locations, first under the skin and in then either the liver or the lung. They found evidence that when cancer takes hold in the liver it is "uniquely suppressive," said Lee – able to harness the liver’s powers to retrain the immune system and exert its influence on the immune response to related cancers that are distant in the body.

Compared to mice with secondary cancers implanted in the lung, survival rates were significantly worse in mice with secondary liver cancers after anti-PD-1 treatment: the immune system did not learn to recognize the liver tumor or, notably, the related tumor implanted under the skin.

That level of immune-system discernment clued the team in on a possible mechanism, because "only a few types of cells can be that specific in regulating the immune system," Lee said, including Tregs. Bluestone has spent decades studying these cells, and that’s where the researchers looked for an explanation. Could a liver tumor change the response of Tregs, and thus other T cells, to a separate, but related, tumor?

Using single-cell analyses, the team showed that, in mice with liver tumors, T cells associated with the related "primary" tumor were not as highly activated. Finally, the researchers showed that liver tumors change which genes are expressed in Tregs and, through those cells, a host of other immune-system cells as well. "It turned out that there wasn’t a difference in the quantity of Tregs between the skin tumors of mice with liver cancers and the mice without liver cancers. It was a difference in quality," Lee said.

Since liver tumors caused Tregs to suppress the T cell response against tumors, the researchers tested two drugs to see if they could override the effect of the Tregs. The first was a drug that blocks the T cell checkpoint inhibitor CTLA-4, which unleashes these cells to attack cancer; in the 1990s, Bluestone did pioneering research on CTLA-4 that helped lay the foundations for cancer immunotherapy. The second drug, another anti-CTLA-4 compound, targets Tregs directly and depletes their numbers. Both restored the effectiveness of anti-PD-1 therapy, though the anti-CTLA-4 drug that depletes Tregs was more effective.

The researchers hope to apply this combination therapy in the future to patients whom they know ahead of time are less likely to respond to treatment.

"We’ve never had this kind of precision in immunotherapy in the past," Lee said. "What if, right from the start, you could use a drug that depletes Tregs as a complement to immunotherapy in patients with liver metastasis?"

Authors: Joining Lee and Bluestone, all from UCSF, were Sadaf Mehdizadeh, Jennifer Smith, PhD, Arabella Young, PhD, Ilgiz A. Mufazalov, PhD, Cody Mowery, and Adil Daud, MD.

Funding: In addition to the Parker Institute, support for this research came from an A.P. Giannini Postdoctoral Research Fellowship Award to Lee, and from the National Institutes for Health/NIAID (T32 5T32AI007334-28).

The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which serves as UCSF’s primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area.

BrainStorm Cell Therapeutics to Announce Third Quarter Financial Results and Provide a Corporate Update

On October 2, 2020 BrainStorm-Cell Therapeutics Inc. (NASDAQ: BCLI), a leader in developing innovative autologous cellular therapies for highly debilitating neurodegenerative diseases, reported that the Company will hold a conference call to update shareholders on financial results for the third quarter ended September 30, 2020, and provide a corporate update, at 8:00 a.m., Eastern Daylight Time (EDT), on October 15, 2020 (Press release, BrainStorm Cell Therapeutics, OCT 2, 2020, View Source [SID1234568000]).

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BrainStorm’s CEO, Chaim Lebovits, will present a corporate update, after which, participant questions will be answered. Joining Mr. Lebovits to answer investment community questions will be Ralph Kern, MD, MHSc, President and Chief Medical Officer, David Setboun, PharmD, MBA, Executive Vice President and Chief Operating Officer, and Preetam Shah, PhD, MBA, Executive Vice President and Chief Financial Officer.

Participants are encouraged to submit their questions prior to the call by sending them to: [email protected]. Questions should be submitted by 5:00 p.m. EDT, Tuesday, October 13, 2020.

Teleconference Details – BRAINSTORM CELL THERAPEUTICS 3Q 2020

The investment community may participate in the conference call by dialing the following numbers:

Those interested in listening to the conference call live via the internet may do so by visiting the "Investors & Media" page of BrainStorm’s website at www.ir.brainstorm-cell.com and clicking on the conference call link.

Event Link: Webcast URL: https://bit.ly/30pVpNG
Webcast Replay Expiration: Friday, October 15, 2021

Those that wish to listen to the replay of the conference call can do so by dialing the numbers below. The replay will be available for 14 days.

About NurOwn

NurOwn (autologous MSC-NTF) cells represent a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors (NTFs). Autologous MSC-NTF cells can effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression. BrainStorm has fully enrolled a Phase 3 pivotal trial of autologous MSC-NTF cells for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm also recently received acceptance from the U.S. Food and Drug Administration (FDA) to initiate a Phase 2 open-label multicenter trial in progressive multiple sclerosis (MS) and initiated enrollment in March 2019.

CASI Pharmaceuticals Announces Poster Presentation At The 2020 AABB Virtual Annual Meeting

On October 2, 2020 CASI Pharmaceuticals, Inc. (Nasdaq: CASI), a U.S. biopharmaceutical company focused on developing and commercializing innovative therapeutics and pharmaceutical products, reported that research conducted at the New York Blood Center investigating the impact of CID-103 on RBC pretransfusion test methods, will be presented at the American Association of Blood Banks (AABB) Virtual Annual Meeting being held October 3-5, 2020 (Press release, CASI Pharmaceuticals, OCT 2, 2020, View Source [SID1234567997]).

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Session: Plenary Oral Abstract Session
Title: CID-103, an Anti-CD38 Monoclonal Antibody Demonstrates Decreased RBC Binding and Decreased Interference with Pretransfusion Test Methods
Poster Number: P-IG-9
Date/Time: Sunday, Oct. 4 from 1:15-2:15pm ET

About CID-103 (Anti-CD38 Mab)

CID-103 is a fully human IgG1 anti-CD38 monoclonal antibody recognizing a unique epitope. Preclinical data demonstrate CID-103 to have enhanced activity against a broad array of malignancies which express CD38, and potentially better preclinical efficacy and safety profile when compared to other CD38 monoclonal antibodies. CASI has exclusive global rights to CID-103 and expects to initiate Phase 1 trials in early 2021.

Natera Announces Prospective Randomized Clinical Trial to Evaluate Palbociclib in Early Stage Breast Cancer Patients Who Test Positive with Signatera™

On October 2, 2020 Natera, Inc. (NASDAQ: NTRA), a pioneer and global leader in cell-free DNA, reported that its Signatera molecular residual disease (MRD) test will be used in the DARE study, a multi-center clinical trial of palbociclib (IBRANCE), a CDK4/6 inhibitor developed by Pfizer for the treatment of HR-positive, HER2-negative advanced breast cancer when given in combination with an aromatase inhibitor or fulvestrant (Press release, Natera, OCT 2, 2020, View Source [SID1234567995]).

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The DARE study is a randomized, Phase II trial of ctDNA-guided second line adjuvant therapy for stage II-III, HR-positive, HER2-negative breast cancer. DARE will be conducted in the United States through Criterium, Inc. d/b/a the Academic Breast Cancer Consortium (ABRCC) network, which plans to identify about 100 MRD-positive patients for enrollment in the study. These 100 patients will be randomized to continue their current adjuvant endocrine therapy or start treatment with palbociclib plus fulvestrant for two years. Signatera is to be used for patient enrollment eligibility and continued therapy effectiveness monitoring after randomization.

"Detecting relapse before it becomes clinically symptomatic requires a test with high sensitivity and specificity," said Lajos Pusztai, MD, DPhil, Professor of Medicine (Medical Oncology); Co-Leader, Genetics, Genomics and Epigenetics Research Program, Yale Cancer Center, Yale School of Medicine and Principal Investigator of the trial. "Signatera enables us to confidently identify patients with molecular relapse when the disease burden is so low that it is undetectable with imaging. The trial will test if early intervention at this stage could delay or avert a clinical relapse."

Palbociclib was the first CDK4/6 inhibitor to be approved by the FDA as a therapy for patients with HR-positive, HER2-negative advanced breast cancer when taken in combination with endocrine therapy; however, efficacy has not yet been demonstrated in early stage disease. Each year, approximately 69,000 women are diagnosed with Stage II or III HR-positive breast cancer in the United States.1,2

"We are delighted to collaborate with Yale and Criterium/ABRCC to investigate the efficacy of palbociclib in patients with detectable residual disease based on Signatera," said Alexey Aleshin, MD, MBA, Natera’s Senior Medical Director for Oncology. "This is the second clinical trial using Signatera to evaluate the efficacy of a CDK4/6 inhibitor, and it heralds the significant utility of personalized MRD testing for early relapse detection in patients with breast cancer."

About Signatera

Signatera is a custom-built ctDNA test for treatment monitoring and MRD assessment in patients previously diagnosed with cancer. The test is available for clinical and research use, and it was granted Breakthrough Device Designation by the FDA in 2019 and The Signatera test is personalized and tumor-informed, providing each individual with a customized blood test tailored to fit the unique signature of clonal mutations found in that individual’s tumor. This maximizes accuracy for detecting the presence or absence of residual disease in a blood sample, even at levels down to a single tumor molecule in a tube of blood. Unlike a standard liquid biopsy, Signatera is not intended to match patients with any particular therapy. Rather, it is intended to detect and quantify how much cancer is left in the body, to detect recurrence earlier and to help optimize treatment decisions. Signatera’s test performance has been clinically validated in multiple cancer types including colorectal, non-small cell lung, breast, and bladder cancers. Signatera has been developed and its performance characteristics determined by Natera, the CLIA-certified laboratory performing the test. The test has not been cleared or approved by the US Food and Drug Administration (FDA). CAP accredited, ISO 13485 certified, and CLIA certified.

Benitec Biopharma Announces Pricing of $10.0 Million Public Offering

On October 2, 2020 Benitec Biopharma Inc. (NASDAQ: BNTC) ("Benitec" or "the Company"), a development-stage, gene therapy-focused, biotechnology company developing novel genetic medicines based on the proprietary DNA-directed RNA interference ("ddRNAi") platform, reported the pricing of an underwritten public offering of 3,225,806 shares of its common stock (or common stock equivalents in lieu thereof) at a price to the public of $3.10 per share (Press release, Benitec Biopharma, OCT 2, 2020, View Source [SID1234567994]). The Company expects to receive aggregate gross proceeds of approximately $10.0 million from the offering. The offering is expected to close on or about October 6, 2020, subject to satisfaction of customary closing conditions.

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H.C. Wainwright & Co. is acting as the sole book-running manager for the offering.

The Company has also granted the underwriter a 30-day option to purchase up to 483,870 additional shares of its common stock, at the public offering price, less underwriting discounts and commissions, to cover over-allotments, if any.

The Company intends to use the net proceeds from the offering for the continued advancement of development activities for its product pipeline, general corporate purposes, and strategic growth opportunities.

A registration statement on Form S-1 (File No. 333-246314) relating to these securities was declared effective by the U.S. Securities and Exchange Commission (the "SEC") on October 2, 2020. This offering is being made only by means of a prospectus forming part of the effective registration statement. A preliminary prospectus relating to and describing the terms of the offering has been filed with the SEC. Electronic copies of the preliminary prospectus and, when available, copies of the final prospectus relating to the offering may be obtained for free by visiting the SEC’s website at www.sec.gov or by contacting H.C. Wainwright & Co., LLC, 430 Park Avenue, 3rd Floor, New York, New York 10022, by email at [email protected] or by telephone at 646-975-6996.

This press release shall not constitute an offer to sell or a solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction.