On April 16, 2018 Biological Dynamics, a molecular diagnostics company dedicated to improving global health outcomes by empowering global communities with low-cost, accessible cancer diagnostics, reported that new data on the company’s novel technology (ACE) will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2018 Annual Meeting, at McCormick Place Convention Center on April 13 – 18 in Chicago (Press release, Biological Dynamics, APR 16, 2018, View Source [SID1234525413]).

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Abstracts from two studies examining the application of the company’s technology as an isolation platform for a novel class of biomarkers, such as extracellular vesicles (EVs), and as a cell-free DNA (cfDNA)-based diagnostic assay, will be presented:

Novel AC Electrokinetic Platform for Rapid Isolation and Characterization of Extracellular Vesicles from NSCLC Patients
Presented by Raj Krishnan, Ph.D., CEO of Biological Dynamics, on April 16 at 1:00 p.m. CT in Section 44. (Late-breaking abstract # LB-174)
Diagnostic Application of Novel ACE Technology: Treatment Response Monitoring via Quantification of Cell-Free DNA (cfDNA) in Plasma from Late-Stage Cancer Patients
Presented by Robert Kovelman, Ph.D., Biological Dynamics’ Sr. Director of Assay Development and Clinical Affairs, on April 17 at 8:00 a.m. CT in Section 27. (Abstract # 3666)
Biological Dynamics announced on Friday, April 13, the addition of two new members to its Board of Directors. Irwin Jacobs, founding Chairman and CEO Emeritus of Qualcomm and Chairman Emeritus of the Salk Institute for Biological Studies, and Martin J. Wygod, founder of Medco Containment Services Inc. and former Chairman of WebMD Health Corp., have joined Biological Dynamics’ Board of Directors. (Read more here.)

On April 16, 2018 Innovation Pharmaceuticals (OTCQB:IPIX) ("the Company"), a clinical stage biopharmaceutical company, is pleased to report additional information from the Company’s successfully completed Phase 2 clinical trial of Brilacidin-OM (see NCT02324335) for the indication of decreasing the incidence of Severe Oral Mucositis (SOM) (WHO Grade ≥3) in Head and Neck Cancer (HNC) patients receiving chemoradiation (Press release, CellCeutix, APR 16, 2018, View Source [SID1234525812]).

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These additional data align with previously released Brilacidin-OM results showing a risk reduction in the incidence of SOM, including up to an 80.3% risk reduction in the incidence of SOM among patients receiving more aggressive chemotherapy. Other previously released results indicate Brilacidin-OM also delayed onset of SOM. The Company is developing Brilacidin-OM under FDA Fast Track designation as a convenient, and clearly differentiated, therapy aimed to decrease incidence of SOM.
Initial Instance Duration of SOM was defined as the number of days from initial WHO Grade ≥3 during radiation therapy to the first WHO Grade 2 or lower OM Grade. Overall Duration of SOM was defined as the number of days from initial WHO Grade ≥3 during radiation therapy to the day prior to the next OM assessment after the last WHO Grade ≥3 during/after radiation therapy. Note: 50th percentiles are from Kaplan-Meier analysis. Patients who did not experience SOM have duration set to 0.

Previously, the Company reported statistically significant results showing Brilacidin-OM reduced the incidence of SOM in HNC patients receiving cisplatin administered in a high-dose regimen (80-100 mg/m2), approximately every 21 days. For the Modified Intent-to-Treat (mITT) population, Brilacidin-OM in the high-dose chemotherapy regimen reduced the incidence of SOM by 65.0% ([incidence control- incidence active]/incidence control) as compared with placebo (Brilacidin: 25.0%; placebo: 71.4%; p=0.0480). For the Per Protocol (PP) population, Brilacidin-OM in the high-dose chemotherapy regimen similarly reduced the incidence of SOM by 80.3% as compared with placebo (Brilacidin: 14.3%; placebo: 72.7%; p=0.0249).

Exploratory Endpoint: Unplanned Office Visits, Emergency Department Visits, and/or Hospital Admissions Due to OM

Positive OM assessment endpoints are additionally supported by zero (0) of the patients in the Brilacidin-OM group having unplanned office visits, ED visits, or hospital admissions due to OM, compared to four (4) patients in the placebo group.

Other Study Observations

Regardless of the oral sites irradiated (at least two sites from: buccal mucosa, floor of mouth, ventral/lateral tongue, and soft palate), the incidence by patient of Severe OM on Brilacidin-OM relative to placebo was consistently reduced.

Across cumulative radiation dose intervals, patients in the Brilacidin-OM group consistently reported less often feeling the sensation "swollen" (approximately half of that reported for the placebo group). "Burning" sensation also was reported consistently less frequently in the Brilacidin treatment group.

Patients in the Brilacidin-OM group appeared to trend more favorably over the course of chemoradiation treatment according to Eastern Cooperative Oncology Group (ECOG) Performance Status—a common set of criteria used in oncology trials to assess debility.

Management Comments

"Drug makers, the world-over, have spent decades and enormous sums in both money and resources trying to develop an effective OM drug in a bid to address dire patient needs as well as capture a tremendous market opportunity," commented Leo Ehrlich, Chief Executive Officer at Innovation Pharmaceuticals. "Yet, there is currently no drug approved to treat, let alone prevent, severe OM in patients with Head and Neck Cancer. Most Pharmas currently conducting OM trials target shortening the duration of severe OM as their primary endpoint, not reduction of incidence, like we did. The Brilacidin-OM Phase 2 trial met its primary objective and its key secondary objectives. As we continue to analyze subset data, we are extremely enthusiastic about observed trends. Hundreds of thousands of patients would benefit from a preventative OM treatment and we’re excited that Brilacidin-OM may one day provide these patients a much-needed breakthrough treatment option."

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On April 16, 2018 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported that it presented two posters summarizing preclinical research with its MAGE-A4 and MAGE-A10 SPEAR T-cells at the annual AACR (Free AACR Whitepaper) meeting at McCormick Place in Chicago, Illinois (Press release, Adaptimmune, APR 16, 2018, View Source;p=RssLanding&cat=news&id=2342743 [SID1234525326]).

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The MAGE-A4 poster presented the discovery process and extensive preclinical validation work performed by Adaptimmune to characterize the specificity, affinity, and potency of MAGE-A4 SPEAR T-cells. The T-cell receptor (TCR) engineered to target MAGE-A4 was found to be specific for MAGE-A4 with an appropriate affinity and avidity, and there were no safety concerns identified preclinically. Further, the examination of more than 500 non-small lung cancer (NSCLC) tumor samples stained by MD Anderson Cancer Center scientists through its strategic collaboration with Adaptimmune revealed that the MAGE-A4 antigen is expressed in approximately 51% of squamous cell carcinomas of the lung, 8% of adenocarcinomas, and in 24% of all NSCLC cases. In addition, numerous other tumors express MAGE-A4 at variable levels. Details about the selection and affinity enhancement of MAGE-A10 SPEAR T‑cells were also presented. The refined methods used to test this SPEAR T-cell candidate are expected to further mitigate risk of unexpected off-target toxicities.

"Our proprietary preclinical development and validation program for our SPEAR T-cells, developed over more than 10 years, enables us to generate TCRs that have the right level of specificity, affinity, and overall avidity for cancer cells expressing specific targets, while minimizing the risk of off-target toxicity," said Rafael Amado, Adaptimmune’s Chief Medical Officer. "MAGE-A4 and MAGE-A10 are in clinical trials in a variety of solid tumors, and we expect to deliver data on the benefit:risk profile of these products throughout the second half of 2018."

Session, date, time, and location (for both posters):

• Date: Monday, Apr 16, 2018
• Time: 1:00 PM – 5:00 PM (CDT)
• Location: McCormick Place South, Exhibit Hall A, Poster Section 24
Poster 1 – MAGE-A4
• Title: Affinity-enhanced T-cell receptor (TCR) for adoptive T-cell therapy targeting MAGE-A4
• Poster Board Number: 21
• Permanent Abstract Number: 2562
• Objectives:
Determine the frequency of MAGE-A4 expression in non-small cell lung cancer (NSCLC) to identify patients most likely to benefit from SPEAR T-cell therapy
Perform preclinical testing for specificity, potency, and safety of MAGE-A4 SPEAR T-cells

• Methods:
MAGE-A4 expression in NSCLC: 534 resected NSCLC cases (stage I to IV) with clinicopathological information including overall survival and recurrence were analyzed for MAGE-A4 expression by immunohistochemistry (IHC)
Preclinical testing for specificity, potency, and safety of MAGE-A4 SPEAR T-cells:
− Potency/efficacy testing of MAGE-A4 SPEAR T-cells by antigen driven proliferation, cytokine release, and cytotoxicity assays
− In vitro testing against panels of primary normal cells from multiple organ systems in 2-D, 3-D, and induced pluripotent stem cell culture formats to identify cross-reactivities in more physiologically relevant cultures
− Molecular mapping of the TCR peptide-major histocompatibility complex (MHC) binding preferences to identify potential cross-reactive peptides, verification of identified peptides by loading candidates on antigen-presenting cells, and expression of source proteins in antigen-presenting cells to confirm lack of candidate peptide processing and presentation

• Conclusions:
MAGE-A4 expression was observed in ~24% of all NSCLC cases, with higher frequency observed in squamous cell carcinoma (SCC) (51%) versus adenocarcinoma (8%)
Extensive in vitro preclinical safety assessment and identified no major safety concerns for MAGE-A4 SPEAR T-cell reactivity
This MAGE-A4 SPEAR T-cell is being evaluated in a clinical trial in patients with in bladder, melanoma, head & neck, ovarian, NSCLC, esophageal, and gastric cancers
Poster 2 – MAGE-A10
• Title: Selection of affinity-enhanced T-cell receptors for adoptive T-cell therapy targeting MAGE‑A10
• Poster Board Number: 23
• Permanent Abstract Number: 2564
• Objectives: Generate and systematically test affinity-enhanced TCRs that recognize an HLA-A*02 restricted epitope from MAGE-A10 cancer/testis antigens
• Develop an extensive in vitro testing strategy to characterize and reduce the risk of TCR cross-reactivity, including a novel approach for generating peptide specificity profiles for candidate TCRs – the peptide X-scan
• Methods:
Twenty-one parental TCRs recognizing the HLA-A*0201-restricted MAGE-A10 peptide GLYDGMEHL254-262 (MAGE-A10254-262) epitope were characterized using surface plasmon resonance (SPR)
Ten parental TCRs were cloned into a lentiviral vector and transduced into primary human T-cells, and screened for recognition of natively processed antigen using MAGE-A10–positive and –negative cell lines and primary cells as targets
Three parental TCRs selected for affinity enhancement, and the complementarity-determining regions (CDRs) of their α- and β‑chains were mutated, and resulting TCRs tested for affinity and specificity

• Conclusions:
Adaptimmune developed an affinity-enhanced TCR with high specificity and potency against cells expressing HLA-A*0201 and the cancer antigen MAGE-A10
− After generating TCR mutants with diverse germline and CDR loop sequences, the optimal candidate for preclinical testing was identified by applying a novel comprehensive specificity screen (X-scan)
− Together with other key developments in preclinical safety and potency assessments, this strategy is expected to mitigate the risk of unexpected off-target crossreactivity and resulting clinical toxicities
The MAGE-A10 SPEAR T-cell that was selected is being evaluated in clinical trials in NSCLC, and a triple tumor study in bladder, melanoma, and head & neck cancers

On April 16, 2018 Fate Therapeutics, Inc. (NASDAQ:FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported that the Company is presenting new preclinical data on FT819, its off-the-shelf CAR T-cell product candidate, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held from April 14-18, 2018 in Chicago, Illinois (Press release, Fate Therapeutics, APR 16, 2018, View Source [SID1234525343]).

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The presentation of FT819 was accepted by AACR (Free AACR Whitepaper) as a late-breaking abstract, and was subsequently selected by AACR (Free AACR Whitepaper) to be featured at the AACR (Free AACR Whitepaper) Annual Meeting press program being held today at 8:30 a.m. CT.
FT819 is an off-the-shelf CAR T-cell product candidate produced from a master induced pluripotent stem cell (iPSC) line. FT819 has two targeting receptors, a chimeric antigen receptor (CAR) targeting CD19-positive tumor cells and a CD16 Fc receptor that can engage other proven cancer therapies, such as tumor antigen-targeting monoclonal antibody (mAb)-based treatments, to overcome antigen escape. Fate Therapeutics is developing FT819 as part of a research collaboration being led by Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering, Memorial Sloan Kettering Cancer Center.

In preclinical studies, FT819 exhibited an efficient cytotoxic T-cell response in vitro when challenged with CD19-positive tumor cells, displaying robust production of effector cytokines, including INF-gamma and TNF-alpha, and cytolytic proteins, including perforin and granzyme B. The product candidate’s activity was also found to be target-specific in vitro, attacking only CD19-positive tumor cells and sparing CD19-negative tumor cells. Additionally, when combined with a mAb-based treatment targeting CD20, FT819 was shown to elicit antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro against CD19-negative, CD20-positive tumor cells through CD16 engagement.
The master iPSC line used for the production of FT819 is engineered in a one-time event to insert CAR19 into the T-cell receptor α constant (TRAC) locus for enhanced safety and potency and to completely eliminate T-cell receptor (TCR) expression. The line serves as a renewable source for consistently and repeatedly manufacturing homogeneous cell products in quantities that support the treatment of many thousands of patients in an off-the-shelf manner. This approach eliminates the need to create a personalized therapy from a patient’s own cells, enables mass production at scale and significantly reduces the cost of, and time to, patient treatment.
The data is also being presented by the Company in a poster session.

Presentation: Generation of off-the-shelf TCR-less CAR-targeted cytotoxic T cells from renewable pluripotent cells for cancer immunotherapy

Session: Late-Breaking Poster Session – Immunology
Time and Date:8:00 a.m. – 12:00 p.m. CT, Monday, April 16, 2018
Location:McCormick Place South (Level 3), Exhibit Hall A, Section 45, Poster LB-108 / 5
Following presentation at the meeting, the AACR (Free AACR Whitepaper) press program and poster presentations will be available on the Company’s website at www.fatetherapeutics.com.

On April 16, 2018 Synlogic, Inc. (Nasdaq: SYBX), a clinical-stage drug discovery and development company applying synthetic biology to probiotics to develop novel living medicines, reported that preclinical data from its immuno-oncology (IO) program were featured in two presentations at the annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Synlogic, APR 16, 2018, View Source [SID1234525360]). The data demonstrate that, in mouse models, Synlogic’s Synthetic Biotic medicines were shown to stimulate an antitumor response and robustly reprogram the tumor microenvironment potentially enabling the treatment of a variety of cancers.

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"Our IO program highlights the potential of our Synthetic Biotic platform for the design and engineering of novel living medicines with multiple mechanisms of action to treat a broad range of diseases, including cancer," said J.C. Gutiérrez-Ramos, Ph.D., Synlogic’s president and chief executive officer. "Our approach enables us, in a single treatment, to locally deliver multiple, regulatable activities that stimulate an immune response and modulate the tumor environment in order to mobilize the immune system against the tumor and its metastases. We intend to advance our first IO program into IND enabling studies this year."

Synlogic is focused initially on developing Synthetic Biotic medicines to treat so-called "cold tumors," which lack infiltrating anti-tumor T-cells by first stimulating an innate anti-tumor response to make the tumor "hot" and then modifying the tumor microenvironment (TME) to enable T cell expansion and the development of memory, using a single agent to both prime T-cells to mount an immune response and sustain the response. Recent studies have demonstrated that activation of the stimulator of interferon genes (STING) pathway can play a critical role in the initiation of an anti-tumor immune response via activation of antigen presenting cells (APCs) and presentation of tumor antigens. The TME has long been understood to have a role in preventing or interrupting this process. Certain metabolites produced within the tumor such as kynurenine or adenosine can lead to T cell dysfunction and exhaustion, significantly blunting anti-tumor immune responses. Data presented at AACR (Free AACR Whitepaper) demonstrate the potential of Synlogic’s Synthetic Biotic medicines to manipulate both pathways to enable efficient anti-tumor activity in mouse models.

In a presentation in the late-breaking research immunology session, Activation of Innate and Adaptive Immunity via Combinatorial Immunotherapy using Synthetic Biotic Medicines,Synlogic described two new genetic circuits engineered into E. coli Nissle, an immune "initiator" STING activating circuit (SYN-STING) and an immune "sustainer" kynurenine consuming circuit (SYN-Kyn). SYN-STING can be delivered directly into the tumor enabling its localized site of action. The approach of using intra-tumoral injection elicits innate responses in the tumor but not in the circulation, potentially decreasing the risk of adverse events that may arise from the production of systemic type I interferon. In contrast to other therapeutic approaches in development, SYN-Kyn lowers levels of the kynurenine metabolite by degrading it, a mechanism that is independent of the enzyme(s) used by both immune and tumor cells to produce kynurenine (IDO1/2 and/or TDO).

In preclinical studies, Synlogic has demonstrated that:
In vitro, SYN-STING produces biologically-relevant levels of ci-di-AMP, activating APCs, while SYN-Kyn consumes kynurenine at concentrations comparable to those found in patients’ tumors;
SYN-STING treatment of either B16.F10 or A20 tumors results in robust tumor rejection or control, which correlates with an early rise in innate-immune cytokines and later results in T cell activation in tumors and tumor-draining lymph nodes;
Combining SYN-Kyn with a checkpoint inhibitor led to profound anti-tumor activity in the CT26 immunocompetent tumor model; and
A strain engineered to combine both genetic circuits (SYN-STING:Kyn) demonstrates equivalent production of ci-di-AMP and consumption of kynurenine in vitro compared to the individual strains SYN-STING and SYN-Kyn, respectively.
A second presentation entitled Metabolic Modulation of the Tumor Microenvironment using Synthetic Biotic Medicines demonstrated that engineered bacterial strains designed to consume either kynurenine (SYN-Kyn) or adenosine (SYN-Ade) effectively relieved TME immunosuppression and promoted anti-tumor activity.
In summary:
Invitro SYN-Kyn and SYN-Ade can deplete kynurenine and adenosine, respectively, at concentrations that are clinically relevant;
SYN-Kyn demonstrated rapid and near-complete reductions in tumor kynurenine levels in vivo;
A combination of either SYN-Kyn or SYN-Ade with checkpoint inhibition led to superior anti-tumor activity in the MC38 immunocompetent tumor model compared with checkpoint inhibitors alone.
About Synthetic Biotic Medicines
Synlogic’s innovative new class of Synthetic Biotic medicines leverages the tools and principles of synthetic biology to genetically engineer probiotic microbes to perform or deliver critical functions missing or damaged due to disease. The company’s two lead programs, SYNB1020 and SYNB1618, target hyperammonemia as a result of liver damage or genetic disease, and phenylketonuria, respectively. Patients with these diseases are unable to break down commonly occurring by-products of digestion that then accumulate to toxic levels and cause serious health consequences. When delivered orally, these medicines can act from the gut to compensate for the dysfunctional metabolic pathway and have a systemic effect, with the potential to significantly improve symptoms of disease for affected patient. Synlogic has earlier-stage programs that apply the broad potential of its Synthetic Biotic platform in other disease areas, from inflammatory and immune disorders to cancer.