On April 16, 2018 X4 Pharmaceuticals, a clinical stage biotechnology company developing novel CXCR4 inhibitor drugs to improve immune cell trafficking to treat cancer and rare diseases, reported data from a presentation at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, X4 Pharmaceuticals, APR 16, 2018, View Source [SID1234525412]) The data, generated from serial tumor biopsies and blood draws taken from melanoma patients, demonstrated dramatic infiltration and activation of cytotoxic CD8+ T cells and increased inflammatory status in the tumor microenvironment (TME) following once-daily oral administration of X4P-001-IO. X4P-001-IO is an investigational CXCR4 allosteric antagonist. Findings highlight single agent X4P-001-IO has the ability to help restore immunity within the TME and has the potential to enhance the anti-tumor activity of agents such as checkpoint inhibitors.

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Results from the tumor biopsies taken from melanoma patients before and after receiving single agent X4P-001-IO treatment for 3 weeks, were analyzed and presented. Single agent X4P-001-IO showed evidence of enhanced immune cell infiltration and activation in the tumor microenvironment, including:

Increases in proliferating CD8+ cells, indicative of cytotoxic T cell activation,
Increases in Granzyme B, a marker of immune-mediated cell killing,
Decreases in distance between CD8+ T cells and the nearest tumor cells, indicative of increased CD8+ T cell infiltration,
Increases in antigen presentation/processing gene expression, suggesting enhanced antigen priming and activation, and
Increases in the Tumor Inflammation Signature (TIS), indicative of increased inflammation status in the TME.
After single agent X4P-001-IO treatment, patients received X4P-001-IO in combination with Keytruda (pembrolizumab) for an additional 6 weeks. Continued signs of positive immune cell changes in the tumor microenvironment were seen. The combination of X4P-001-IO alone and in combination with Keytruda was well tolerated.

"These results demonstrate that CXCR4 inhibition substantially alters the tumor microenvironment in a way that is consistent with the emerging understanding of tumor immunity and inflammatory response," said Robert Andtbacka, MD, CM, a surgeon and investigator with the Huntsman Cancer Institute of the University of Utah, Associate Professor in the Division of Surgical Oncology at the University of Utah School of Medicine, and Principle Investigator of the X4P-001-IO study in melanoma.

In a separate poster presentation, preclinical findings showed that CXCR4 inhibition increases CD8+ T cells in the tumor microenvironment and has potent anti-tumor activity in the syngenic B16-OVA murine melanoma model. The anti-tumor activities were associated with the increase in immunostimulatory CD8+/Perforin+ cells and the reduction of immunosuppressive myeloid derived suppressor cells (MDSCs) and Treg populations in the tumor microenvironment.

"Results from these posters demonstrate the unique mechanism of X4P-001-IO, as it impacts critical aspects of immune cell trafficking, infiltration and activation – playing a positive role in tumor immunity," said Sudha Parasuraman, MD, X4’s Chief Medical Officer. "These data, together with X4P-001-IO’s favorable safety and tolerability profile, support the potential for X4P-001-IO to improve outcomes for patients with tumors that are less responsive to checkpoint inhibitors."

The posters were presented in the Immune Response to Therapy Session at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 14-18, 2018 in Chicago, IL.

About X4P-001-IO in Cancer

X4P-001-IO is an investigational selective, oral, small molecule inhibitor of CXCR4 (C-X-C receptor type 4) that regulates the tumor microenvironment thereby enhancing endogenous anti-tumor responses. CXCR4 is a chemokine receptor that modulates immune function and angiogenesis through the trafficking of key immune cells such as T- cells, dendritic cells, and myeloid derived suppressor cells. CXCR4 signaling is disrupted in a broad range of cancers, facilitating tumor growth by allowing cancer cells to evade immune detection and creating a pro-tumor microenvironment. X4P-001-IO is being investigated in three separate clinical studies in solid tumors.

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 Taiho Pharmaceutical Co., Ltd., a Japanese R&D-driven specialty pharma focused on oncology and Helsinn, a Swiss pharmaceutical group focused on building quality cancer care products, reproted that they are collaborating on the development of an investigational highly-selective RET inhibitor TAS0286/HM05, being evaluated in non-small cell lung cancer and other carcinomas (Press release, Helsinn, APR 16, 2018, View Source [SID1234561171]). Preliminary data regarding TAS0286/HM05 is being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) meeting in Chicago, Illinois, U.S.A. Abstracts of the presentations are available at: View Source!/4562/presentation/6785

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In in-vitro preclinical studies, TAS0286/HM05 inhibited the proliferation of various RET fusions and RET-activating mutations positive cells as well as in in-vivo preclinical studies, TAS0286/HM05 was shown to significantly inhibit the growth of tumors harboring various RET fusions and activating mutations at a range of 20 to 100 mg/kg/day without any body weight loss. The antitumor efficacy of TAS0286/HM05 was more potent than pre-existing multikinase inhibitors at their maximum tolerated dose. Primary data in mice studies has shown an effect in tumor growth, providing an induced tumor regression of 40% within 15 days. This study is being presented as a poster on Tuesday, April 17 from 1:00 PM to 5:00 PM CST in Poster Section 36, Poster Board Number 13 (Abstract No. 4784).

"Preliminary data for TAS0286/HM05 suggests it may be a potential agent for future clinical development in patients with RET gene abnormalities," Sergio Cantoreggi, Helsinn Group Chief Scientific Officer commented. "Helsinn and Taiho Pharmaceutical have collaborated over many years on a number of programs and we are delighted to be able to present this promising preclinical data, and we look forward to further collaboration."

"Over the years, Taiho Pharmaceutical has collaborated with Helsinn as an excellent partner in the development and marketing of new drugs. I am excited about the new collaboration with Helsinn on the selective RET inhibitor that was discovered by the Taiho Tsukuba Research Center. I look forward to the success of the program and the strengthening of our partnership." Teruhiro Utsugi, Taiho Managing Director commented.

TAS0286/HM05 was discovered by Taiho Pharmaceutical and it will now be jointly developed by Helsinn and Taiho Pharmaceutical. TAS0286/HM05 is an investigational agent and is not approved for commercial use in any country.

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.