On November 05, 2019 Allogene Therapeutics and Notch Therapeutics reported an exclusive worldwide collaboration and license agreement to research and develop induced pluripotent stem cell (iPSC) AlloCAR therapy products for initial application in non-Hodgkin lymphoma, leukemia and multiple myeloma (Press release, Allogene, NOV 5, 2019, View Source [SID1234618291]). Under the partnership, Allogene and Notch will create allogeneic cell therapy candidates from T cells or natural killer (NK) cells using Notch’s Engineered Thymic Niche (ETN) platform.

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Notch was established in 2018 by Juan Carlos Zúñiga-Pflücker, Ph.D. and Peter Zandstra, Ph.D., recognized pioneers in iPSC and T cell differentiation technology. Notch is developing a next-generation approach to differentiating mature immune cells from iPSCs. The Notch ETN technology platform offers potential flexibility and scalability for the production of stem cell-derived immune cell therapies. iPSCs may provide renewable starting material for AlloCAR T therapies that could allow for improved efficiency of gene editing, greater scalability of supply, product homogeneity and more streamlined manufacturing.

"This collaboration exemplifies Allogene’s long-term commitment to advancing the field of cancer treatment as we continue to expand and progress our innovative pipeline of off-the-shelf AlloCAR candidates," said David Chang, M.D., Ph.D., President, CEO and Co-Founder of Allogene Therapeutics. "The scientific founders of Notch Therapeutics are among the most respected experts in the field of stem cell biology and its applications to generating T cells and other functional immune cells. We are confident that their technology and expertise, combined with Allogene’s leadership in AlloCAR therapies, has the potential to unlock future generations of cell therapy treatments for patients."

"Renewable-source, off-the-shelf cell therapies that may produce cells with greater consistency and at industrial scale have long been the dream for people working in this field," said Ulrik Nielsen, Ph.D., Executive Chairman of Notch. "We are delighted to spring into the research collaboration for iPSC-based AlloCAR therapies with Allogene, a leader in the allogeneic CAR T field, with the goal of expanding options for patients."

Under the terms of the agreement, Notch will be responsible for preclinical research of next-generation iPSC AlloCAR T cells. Allogene will clinically develop the product candidates and holds exclusive worldwide rights to commercialize resulting products. Allogene will provide to Notch an upfront payment of $10 million. Notch will be eligible to receive up to $7.25 million upon achieving certain agreed research milestones, up to $4.0 million per exclusive target upon achieving certain pre-clinical development milestones, and up to $283 million per exclusive target and cell type upon achieving certain clinical, regulatory and commercial milestones as well as tiered royalties on net sales in the mid to high single digits. In addition to this collaboration and license agreement, Allogene has acquired a 25 percent equity position in Notch and will assume a seat on Notch’s Board of Directors.

"Master cell banks of genetically modified, induced pluripotent stem cells could provide an inexhaustible source of cell therapies that may improve outcomes and expand applicability to new areas," said Notch Co-Founder Juan Carlos Zúñiga-Pflücker, Ph.D., a senior scientist at Sunnybrook Research Institute and a Professor and Chair of the Department of Immunology at the University of Toronto.

"This work with Allogene may also pave the way for additional off-the-shelf cell therapeutics that are custom-designed to treat other immunity-related diseases such as infectious diseases, autoimmune diseases and aging," said Notch Co-Founder and Chief Scientific Officer Peter Zandstra, Ph.D., a Professor at the University of British Columbia and University of Toronto.

On November 5, 2019 eFFECTOR Therapeutics, Inc., a leader in the development of selective translation regulators (STRs) for the treatment of cancer, reported the dosing of the first subject in the phase 1/2 study of zotatifin (eFT226) being developed for advanced solid tumor malignancies (Press release, eFFECTOR Therapeutics, NOV 5, 2019, View Source [SID1234553137]). Zotatifin is a novel, potent and selective small molecule inhibitor of eukaryotic initiation factor 4A (eIF4A).

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The study will enroll patients with activating mutations, amplifications or fusions in HER2, ERBB3, FGFR1, or FGFR2 receptor tyrosine kinases, or any KRAS mutation subtype. It will also include pancreatic adenocarcinoma with no molecular typing since the large majority of those patients harbor a KRAS mutation.

"There is an immediate need for more effective treatment options in patients with advanced cancers unable to respond to alternative therapies," said Steve Worland, Ph.D., president and chief executive officer of eFFECTOR. "Tumors treated with agents targeting specific RTKs frequently become resistant, and there are no available therapies targeting multiple KRAS mutation subtypes. The antitumor response observed in preclinical studies demonstrates the potential for zotatifin in the treatment of solid tumors with genetic modifications associated with aggressive disease, including RTK alterations such as FGFR1/2 and HER2 and KRAS, and provides direction for patient selection in our clinical trial."

In the open label, dose escalation and cohort expansion study, subjects will be assigned sequentially to increasing zotatifin doses until the maximum tolerated dose is reached. Zotatifin will be administered as a monotherapy in weekly intravenous infusions in subjects with advanced solid tumor malignancies. Treatment and study subject evaluations will be performed in 21-day cycles.

The primary endpoints of the study include safety and tolerability of zotatifin as monotherapy. Secondary endpoints include antitumor activity and survival, as well as pharmacokinetics of the drug. Exploratory endpoints include pharmacodynamics of zotatifin.

Scientists from eFFECTOR recently presented preclinical data at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) – also known as the Triple Meeting. The data demonstrated that solid tumor cell lines driven by alterations in FGFR1, FGFR2 and HER2 treated with zotatifin showed decreased MAPK and AKT signaling, potent inhibition of cell proliferation and apoptosis and strong in vivo anti-tumor activity, indicating potential for zotatifin to treat FGFR1/2 or HER2-driven cancers.

About Zotatifin (eFT226)

Zotatifin (eFT226) is a potent and selective inhibitor of eukaryotic translation initiation factor 4A (eIF4A). eIF4A is located downstream from key oncogenic mutations and their common resistance mechanisms. Zotatifin inhibits the translation of mRNA encoding several important oncogenes and survival factors, including several RTKS, KRAS, Cyclin D, MCL1 and BCL-2 resulting in potent in vivo efficacy in multiple tumor models dependent on these factors, including colorectal cancer, non-small cell lung cancer, breast cancer, hepatocellular carcinoma and B cell lymphomas. Since Zotatifin inhibits the translation of mRNA encoding KRAS and RTK, it is not limited to any mutation subtypes. The drug is currently being evaluated in a Phase 1/2 clinical trial in patients with solid tumors.

On November 5, 2019 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies for the treatment of cancer, reported that the United States Food and Drug Administration (FDA) has granted AUTO1 orphan drug designation for treatment of acute lymphoblastic leukemia (ALL) patients (Press release, Autolus, NOV 5, 2019, View Source [SID1234550683]).

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According to the National Institute of Health’s National Cancer Institute, in the United States, there will be an estimated 5,930 new cases of ALL and an estimated 1,500 related deaths in 2019. Patients are predominantly children; approximately 60% of cases occur at age < 20 years. ALL occurs when the bone marrow makes too many immature lymphocytes, which are a type of white blood cell. Despite a high rate of response to induction chemotherapy, only 30–40% of adult patients with ALL will achieve long-term remission. Similarly, pediatric patients typically respond well to first-line treatment (combination chemotherapy) but 10 to 20% of total patients relapse with chemotherapy-resistant disease, leading to a significant unmet need in pediatric patients with high-risk relapsed or refractory ALL.

"We are pleased to receive orphan drug designation for AUTO1 for acute lymphoblastic leukemia," said Dr. Christian Itin, chairman and chief executive officer of Autolus. "From the data reported in our ongoing studies, we have seen strong remission rates and excellent CAR T cell expansion and persistence without inducing high-grade CRS, a serious adverse event affecting a significant number of patients on currently available CAR T treatments. We look forward to presenting data on AUTO1 at ASH (Free ASH Whitepaper) at the end of the year."

Orphan drug designation is granted by the FDA Office of Orphan Products Development to drugs and biologics which are intended for the treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S. Under the Orphan Drug Act, the FDA may provide grant funding toward clinical trial costs, tax advantages, FDA user-fee benefits, and seven years of market exclusivity in the United States following marketing approval by the FDA. For more information about orphan designation, please visit the FDA website at www.fda.gov.

About AUTO1
AUTO1 is a CD19 CAR T cell investigational therapy designed to overcome the limitations in safety – while maintaining similar levels of efficacy – compared to current CD19 CAR T cell therapies. Designed to have a fast target binding off-rate to minimize excessive activation of the programmed T cells, AUTO1 may reduce toxicity and be less prone to T cell exhaustion, which could enhance persistence and improve the T cells’ abilities to engage in serial killing of target cancer cells. In 2018, Autolus signed a license agreement under which Autolus acquired global rights from UCL Business plc (UCLB), the technology-transfer company of UCL, to develop and commercialize AUTO1 for the treatment of B cell malignancies. AUTO1 is currently being evaluated in two Phase 1 studies, one in pediatric ALL and one in adult ALL.

On November 5, 2019 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies for the treatment of cancer, announced today pre-clinical data on AUTO6NG, the company’s next generation GD2-targeting CAR T cell therapy, at the 34th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) being held November 6-10, 2019, in Washington, D.C (Press release, Autolus, NOV 5, 2019, View Source [SID1234550682]). SITC (Free SITC Whitepaper) published the abstract today, which can be found at:

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View Source;ABSID=12038&CONF=SITC19&ssoOverride=OFF&CKEY=

"AUTO6NG builds on the clinically active AUTO6 GD2-targeting CAR and adds cell programming modules to improve persistence and render the product insensitive to several tumor defense mechanisms," said Dr Christian Itin, chairman and chief executive officer of Autolus. "This is the first program presentation illustrating our suite of advanced cell programming technologies."

Poster Presentation
Abstract #: P146
Abstract Title: "AUTO6NG: Next generation GD2-targeting CAR T-cell therapy with improved persistence and insensitivity to TGFBeta and checkpoint inhibition for relapsed/refractory neuroblastoma", Achkova, D., et al.
Session Date: Saturday, November 9
Session Time: Posters on display 7:00 am – 8:30 pm Eastern Time; author(s) will be at poster 12:35 – 2:05 p.m. and also during the poster reception 7 – 8:30 p.m.

About AUTO6NG
AUTO6NG is a next generation programmed T cell product candidate in pre-clinical development. AUTO6NG builds on preliminary proof of concept data from AUTO6, a CAR in clinical development for the treatment of neuroblastoma, which can target GD2-expressing cancers with a chimeric antigen receptor (CAR). AUTO6NG incorporates additional cell programming modules to augment its functions by extending persistence and rendering modified T-cells resistant to immune inhibition. With the enhanced properties of AUTO6NG, it may be suitable for the treatment of GD2-expressing solid tumors, including neuroblastoma, osteosarcoma, melanoma, small cell lung cancer, and soft tissue sarcoma.

AUTO6 is currently in a Phase 1 clinical trial for pediatric neuroblastoma conducted by Cancer Research UK in collaboration with University College London. Autolus has worldwide commercial rights to the GD2-targeting programmed T cell product candidate.

On November 5, 2019 Ambry Genetics (Ambry), a leading clinical genetic testing company, reported that it will present at this week’s National Society of Genetic Counselors Annual Conference in Salt Lake City, Utah, data from the first 2,500 patients that received +RNAinsight, paired RNA and DNA genetic testing for hereditary cancer risk (Press release, Ambry Genetics, NOV 5, 2019, View Source [SID1234550595]). Data revealed that +RNAinsight resulted in a substantial increase in diagnostic yield, identifying more patients with genetic mutations (disease-causing errors in our DNA) compared to DNA testing alone. This is the first major increase in diagnostic yield for hereditary cancer risk in over 10 years, since the adoption of deletion/duplication testing. Through +RNAinsight, Ambry is the first and only lab to offer paired RNA and DNA genetic testing for hereditary cancer as a commercially available clinical test.

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Standard DNA testing for hereditary cancer risk excludes large portions of DNA, thereby missing some mutations. In addition, DNA testing can produce inconclusive results and fail to determine that an error in our DNA increases cancer risk. These limitations impact patients and their families because doctors may not have the information needed to recommend appropriate preventive, early detection, or therapeutic steps. Additionally, relatives may not be referred for genetic testing and obtain the care they would otherwise have gotten if they had learned they had mutations.

Adding RNA to DNA testing overcomes these limitations for a substantial number of patients as it provides considerably more evidence than DNA testing alone about whether our DNA has mutations. Ambry will present data showing that paired testing with +RNAinsight both (1) identified new mutations that would have been missed with DNA testing alone, and (2) clarified inconclusive results as disease-causing. DNA testing alone would have found these latter results as inconclusive and left doctors without this crucial information.

"These findings further demonstrate that hereditary cancer panels should include both RNA and DNA genetic testing," said Rachid Karam, MD, PhD, lead study author and Director of the Translational Genomics Lab at Ambry Genetics. "By looking at regions of the gene that other tests don’t, +RNAinsight reduces false negatives, maximizing the number of patients who learn they have higher risks for hereditary cancer."

The data show an overall relative increase in diagnostic yield of 6.7 percent compared to DNA testing alone, increasing by as much as 19 percent for specific genes. For example, for BRCA1, 14 percent more patients learned they had a mutation that increased their cancer risks than would have if they had only received DNA testing. Moreover, by analyzing regions of DNA known as introns that standard DNA testing alone does not assess, paired RNA and DNA testing found completely new mutations that DNA-only testing would not have found or identified as disease-causing. Thus, patients who learn they have mutations from paired testing can get the appropriate medical treatment while those who undergo standard DNA testing alone might not because they may never learn they have those mutations.

RNA genetic testing also resulted in an overall 4.5 percent relative decrease in the number of patients that would have received inconclusive results with DNA testing alone, reducing inconclusive results by as much as 9 percent in specific genes. As with identifying entirely new mutations, clarifying results can let more patients with mutations learn they have them.

+RNAinsight is now available through doctors and genetic counselors around the country. For more information on RNA genetic testing, please go to www.ambrygen.com/RNAinsight.

In addition to this paired RNA and DNA testing data, Holly LaDuca, Senior Manager, Clinical Affairs Research at Ambry, will present data from a survey sent to clinicians assessing how genetic testing results inform patient care.

Since January 2018, Ambry Genetics has provided surveys to all clinicians ordering hereditary cancer testing through Ambry both before and after they receive their patients’ genetic test results. In the first few months of offering the survey, 131 providers completed pre-and post-test surveys for 469 patients who received genetic testing. When genetic testing found mutations, changes to preventive screening recommendations were made for 62.1 percent of patients and surgical recommendations were made for 37.9 percent of patients. In addition, 40.9 percent of clinicians recommended genetic counseling changes, such as the testing of family members and discussions of reproductive risks.

"Management guidelines have been developed for numerous cancer-predisposition genes. However, data is limited on how these guidelines and genetic testing results impact patient care in the real world," said Ms. LaDuca. "Preliminary data from this ongoing survey demonstrate that positive genetic test results frequently lead to changes in medical management."

For the full list of studies that will be presented at NSGC, please see below:

Featured Oral Presentations at 2019 NSGC

Date & Time

Presentation

Presenter

Session

Tues., Nov. 5,
2019

8:30 AM – 2:30
PM

Clarity in Chaos: Using somatic
genetic testing to inform germline
interpretation

Pia
Summerour

Session #A03: Pre-
Conference
Symposium

Wed., Nov. 6,
2019

12:30 PM

Unparalleled Clarity and Mutations:
Clinical RNA Testing Provides
Answers Beyond DNA

Rachid Karam

Level 2,

Room 250

Lunch Presentation

Thurs., Nov. 7,
2019

3:10 PM- 4:40
PM

The New GC in Town: Demystifying
the Role of Gene Curation in Variant
Interpretation, Clinical Reporting and
Case Reanalysis

Kelly Radtke

Session #C16:
Educational Breakout
Session

Featured Poster Presentations at 2019 NSGC

Date & Time

Presentation

Lead Author

Poster

Wed., Nov. 6,
2019

6:15 PM – 7:30
PM

A Nationwide Multi-Center Study Provides Insight
into the Increase in Clinically Actionable Results
from Concurrent DNA and RNA Genetic Testing

Rachid Karam

B-131

Investigating Variants of Uncertain Significance:
Reclassification Triggers and Drivers in Breast
Cancer Predisposition Genes

Kirsten Kelly

B-233

Thurs., Nov. 7,
2019

1:20 PM – 2:35
PM

Better than Guidelines? Pre & Post Genetic Testing
Data Suggests Change in Management Trends

Zöe Powis

C-132

What Should I Order? Genetic Testing Ordering
Trends for Autism Spectrum Disorder

Catherine
Schultz

C-294