On April 16, 2018 Exicure, Inc., the pioneer in gene regulatory and immunotherapeutic drugs utilizing three-dimensional, spherical nucleic acid (SNA) constructs, reported that it will present preclinical data in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2018 Annual Meeting in Chicago, Illinois from April 14-18, 2018 (Press release, Exicure, APR 16, 2018, View Source;p=RssLanding&cat=news&id=2342684 [SID1234525342]). The poster titled "TLR9 agonist SNA-induced innate and adaptive immune responses in tumor microenvironment enhance checkpoint inhibitor antitumor activity in mouse tumor models" supports the ongoing clinical development of the company’s proprietary SNA technology and highlights its potential impact in the tumor microenvironment in potentiating antitumor effects of anti-PD-1.

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The data presented in the poster, in combination with many other preclinical studies, provided the basis for advancing Exicure’s drug candidate, AST-008, into its Phase 1 clinical trial. We began subject dosing in our Phase 1 clinical trial for AST-008 in the fourth quarter of 2017 and expect this trial to be completed in mid-2018.

AST-008 utilizes Exicure’s proprietary spherical nucleic acid (SNA) technology designed in this case to agonize toll-like receptor 9, or TLR9, for application in immuno-oncology. Exicure has observed that administration of AST-008 as a monotherapy can have anti-tumor activity in colon cancer, breast cancer, lymphoma and melanoma mouse models. The company has also observed that, in preclinical studies in a variety of tumor models, AST-008 applied in combination with certain checkpoint inhibitors exhibited anti-tumor responses and survival rates that were greater than those demonstrated by checkpoint inhibitors alone.

Details on the poster presentation are as follows:

Title: TLR9 agonist SNA-induced innate and adaptive immune responses in tumor micro-environment enhance checkpoint inhibitor antitumor activity in mouse tumor models
Abstract No: 3758
Session Title: Immunomodulatory Agents and Interventions 1
Date/Time: April 17, 2018; 8:00 AM – 12:00 PM CT
Location: McCormick Place South, Exhibit Hall A, Poster Section 32

Full abstracts are available on the AACR (Free AACR Whitepaper) conference website at View Source

On April 16, 2018 A proprietary,precision cancer therapy platform from SRI International has reported that identified new molecular targets for the treatment and prevention of an aggressive and difficult-to-treat type of breast cancer (Press release, SRI International, APR 16, 2018, View Source [SID1234525359]). Subarna Sinha, Ph.D., bioinformatics program leader at SRI, presented new data describing the platform and the validated target today during a minisymposium at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting.

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Identification of new molecular targets for drug therapy is an area of active investigation and continued need in oncology. The Mining Synthetic Lethals (MiSL) platform offered by SRI may accelerate the discovery of new targeted oncology drugs by integrating a computational approach that mines patterns from primary tumor data with pre-clinical validation of potential targets.

The MiSL platform works by "looking" for synthetic lethal (SL) partners among primary tumor data and then validating them in vivo. Synthetic lethality offers a new approach to finding targeted therapies for previously "undruggable" tumor mutations. In SL interactions, a diseased cell with a mutation is dependent on a second gene for cell survival. Inhibiting activity of the second gene in these cells leads to cell death.

"If you can inhibit the SL partner, you can very exquisitely kill cancer cells," said Dr. Sinha. "MiSL overcomes the limitations of cell line screening methods such as shRNA and CRISPR, and has previously demonstrated ability to identify valid SL partners in multiple tumor types, including acute myeloid leukemia and kidney cancer. Today we presented the first data demonstrating the platform’s ability to identify new targets in triple-negative breast cancer."
BRCA1 is mutated in 15 to 20 percent of triple negative breast cancer (TNBC). SRI researchers used MiSL to identify and predict 22 SL partners of the BRCA1 mutation in TNBC, including XRCC6. To test the prediction that XRCC6 is an SL partner of BRCA1 in TNBC, SRI researchers examined the effect of inhibiting XRCC6 in a BRCA1-mutated TNBC cell line. The researchers found that this XRCC6 "knockdown" significantly increased cell death (37.3 percent) and reduced viability (50 percent reduction, p < 0.0001) as compared to controls. SRI researchers are testing the remaining SL partners identified by MiSL in an effort to expand the set of available molecular targets that may become the focus of new drug discovery projects.

"This platform opens the door for discovering new options to treat BRCA1-mutated breast cancers and could lead to new chemo-prevention strategies for individuals carrying germline BRCA1 mutations," added Dr. Sinha.

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 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.