On April 19, 2016 BioLineRx Ltd. (NASDAQ/TASE: BLRX) reported that detailed results from a study on the underlying mechanism of action of BL-8040, its lead platform for the treatment of multiple cancer and hematological indications, were presented by Prof. Amnon Peled at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) 2016 meeting in New Orleans (Press release, BioLineRx, APR 19, 2016, View Source;p=RssLanding&cat=news&id=2158220 [SID:1234511046]).

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The work presented, entitled "CXCR4 Controls BCL-2 Expression and Function by Regulating miR-15a/16-1 Expression in Tumor Cells," illustrates the mechanism by which the CXCR4 pathway controls malignant cell survival and death in preclinical studies. Specifically, the studies point out how BL-8040 increases the expression and activity of a special class of microRNA precursors termed miR-15a/16-1. These microRNA molecules have been previously linked to cancer, and shown to suppress the activity of several tumor-related pro-survival proteins, specifically BCL2, MCL1 and cyclin D1. The studies presented showed that BL-8040 increases the suppression of these three target proteins through miR-15a/16-1, thereby increasing tumor cell death.

The BL-8040 oncology platform is a short cyclic peptide that functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. CXCR4 is overexpressed in the majority of cancer cells, and its degree of expression often correlates with disease severity.

Dr. Kinneret Savitsky, CEO of BioLineRx, stated, "We recently announced the successful top-line results for BL-8040, in combination with Cytarabine, one of the standard-of-care chemotherapies, in a Phase 2 study in relapsed or refractory AML. In that study, BL-8040 showed a triple effect on the leukemic cells. First, BL-8040 monotherapy triggered robust mobilization of AML cells from the bone marrow to the peripheral blood, thereby sensitizing these cells to the chemotherapy and improving its efficacy. Second, BL-8040 monotherapy showed a 3-4 fold increase in the direct apoptotic effect on the leukemia cells in the bone marrow. Last, BL-8040 monotherapy induced leukemia progenitor cells towards differentiation. As a result of these factors, we reported a 38% complete remission rate in the study, compared to historical remission rates in similar patient populations with similar treatment regimens of approximately 20% for Cytarabine on a stand-alone basis. We look forward to providing the full results of this study at an upcoming scientific conference."

"In this regard, we are pleased to announce the current study results presented at the AACR (Free AACR Whitepaper) meeting, which provide significant clarity regarding BL-8040’s mechanism of action relating to apoptosis. The data suggest that BL-8040 is able to indirectly suppress the activity of several tumor-promoting genes, by increasing the activity of the microRNA molecule miR-15a/16-1. Of note, one of these pro-survival proteins, BCL-2, is a validated anti-cancer target that is recently attracting a lot of interest in the drug development space."

"In order to further expand and enhance the potential of our unique oncology platform, BL-8040 is undergoing multiple clinical studies, including our recently announced immuno-oncology collaboration with Merck on a Phase 2 study to investigate BL-8040 in combination with KEYTRUDA for the treatment of pancreatic cancer," concluded Dr. Savitsky.

Link to AACR (Free AACR Whitepaper) On-Line Abstract

About BL-8040
BL-8040 is a clinical-stage drug candidate for the treatment of acute myeloid leukemia, as well as other hematological indications. It is a short cyclic peptide that functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis (growth of new blood vessels in the tumor), metastasis (spread of the disease to other organs or organ parts) and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a Phase 1/2, open-label, dose escalation, safety and efficacy clinical trial in 18 multiple myeloma patients, BL-8040, when combined with G-CSF, demonstrated an excellent safety profile at all doses tested and was highly effective in the mobilization of hematopoietic stem cells and white blood cells from the bone marrow to the peripheral blood. Additionally, in a Phase 1 stem-cell mobilization study in healthy volunteers, BL-8040 as a single agent was safe and well tolerated at all doses tested and resulted in efficient stem-cell mobilization and collection in all study participants. Importantly, the results of this study support the use of BL-8040 as one-day, single-dose collection regimen, which is a significant improvement upon the current standard of care.

BL-8040 also mobilizes cancer cells from the bone marrow and may therefore sensitize these cells to chemo- and bio-based anti-cancer therapy. Importantly, BL-8040 has also demonstrated a direct anti-cancer effect by inducing apoptosis. Pre-clinical studies show that BL-8040 inhibits the growth of various tumor types including multiple myeloma, non-Hodgkin’s lymphoma, leukemia, non-small cell lung carcinoma, neuroblastoma and melanoma. BL-8040 also significantly and preferentially stimulated apoptotic cell death of malignant cells (multiple myeloma, non-Hodgkin’s lymphoma and leukemia). Significant synergistic and/or additive tumor cell killing activity has been observed in-vitro and in-vivo when tumor cells were treated with BL-8040 together with Rituximab, Bortezomib, Imatinib, Cytarabine and the FLT-3 inhibitor AC-220 (in NHL, MM, CML, AML, and AML-FLT3-ITD models, respectively). In addition, the recently completed Phase 2 clinical trial in AML patients has demonstrated robust mobilization and apoptosis of cancer cells, along with a clinically meaningful response rate. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.

Arthralgia is a common toxicity among women taking aromatase inhibitors (AIs) and can lead to premature discontinuation of therapy. We evaluated the association between arthralgia, co-morbid fatigue and/or insomnia, and inflammatory biomarkers among women taking AIs.
Women taking AIs for early-stage breast cancer completed a modified version of the Brief Pain Inventory, the Brief Fatigue Inventory, and the Insomnia Severity Index and provided blood samples for simultaneous assessment of 34 inflammatory biomarkers with a Luminex kit. Two-sided t tests were used to compare inflammatory biomarker concentrations for patients with or without moderate to severe arthralgia. Multivariate linear regression analyses were performed to evaluate the relationship between comorbid arthralgia, fatigue, and insomnia with identified biomarker concentrations.
Among 203 participants, the severity of arthralgia, fatigue, and insomnia were significantly correlated with each other (p < 0.001 for all comparisons). After controlling for race, chemotherapy history, non-steroidal anti-inflammatory drug use, age, and body mass index, the coexistence of arthralgia, fatigue, and insomnia was associated with elevated C-reactive protein (CRP) (β = 93.1; 95 % confidence interval (CI): 25.1-161.1; p = 0.008), eotaxin (β = 79.9; 95 % CI: 32.5-127.2; p = 0.001), monocyte chemoattractant protein (MCP)-1 (β = 151.2; 95 % CI: 32.7-269.8; p = 0.013), and vitamin D-binding protein (VDBP) (β = 19,422; 95 % CI: 5500.5-33,344; p = 0.006).
Among women taking AIs, the coexistence of arthralgia, fatigue, and insomnia was associated with increased levels of inflammatory biomarkers (elevated CRP, eotaxin, MCP-1, and VDBP). These findings suggest a possible shared inflammatory mechanism underlying these common symptoms.

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On April 19, 2016 Euclises Pharmaceuticals, Inc., a biopharmaceutical company focused on the discovery and development of novel COX-2 inhibitors for the treatment of cancer, reported that its Late-Breaking Abstract has been accepted for presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans on April 19, 2016 (Press release, Euclises, APR 19, 2016, View Source [SID:1234511093]).

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Entitled, "Anti-tumor effects of ECP-1014 in combination with erlotinib in HT-29 xenograft murine colon carcinoma model," the presentation will report the results of key preclinical experiments using Euclises’ COX-2 inhibitor candidate, ECP-1014. The study, conducted in collaboration with Guangzhou Institute of BioMedicine and Health, builds upon recent research demonstrating a role for overactive COX-2 in maintaining an immunosuppressive microenvironment for a variety of tumors, including colorectal and non-small cell lung cancers.

"The epidermal growth factor (EGFR) inhibitor erlotinib is the current standard of care for advanced colorectal cancer," said Dr. Bobby W. Sandage, Jr., Ph.D., CEO of Euclises. "In this preclinical study, we demonstrate a substantial additional benefit in tumor suppression from combining erlotinib with our third-generation COX-2 inhibitor."

"The research to be presented at AACR (Free AACR Whitepaper) strongly validates Euclises’ approach," added Rick Ryan, Ph.D., chairman of Euclises’ board. "These results comprise an important step towards the clinical translation and commercialization of effective COX-2 inhibitors for colorectal cancer patients."

Dr. Sandage will present the research on Tuesday morning, April 19, in Section 11 of the Late-Breaking Research: Experimental and Molecular Therapeutics 3 poster session.

On April 19, 2016 Kite Pharma, Inc. (Nasdaq:KITE) ("Kite") reported updated clinical results from the phase 1 portion of Kite’s ZUMA-1 trial of its lead product candidate, KTE-C19, in patients with chemorefractory, aggressive non-Hodgkin lymphoma (NHL) (Press release, Kite Pharma, APR 19, 2016, View Source [SID:1234511121]). KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a chimeric antigen receptor (CAR) that is designed to target the antigen CD19, a protein expressed on the cell surface of B cell lymphomas and leukemias.

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David Chang, M.D., Ph.D., Kite’s Executive Vice President, Research and Development, and Chief Medical Officer, commented, "Today’s report affirms the early safety and efficacy profile of KTE-C19 in chemorefractory, aggressive NHL. We are encouraged by the ongoing complete remissions in patients with significant unmet need for new therapies. We remain on track to provide interim data from the pivotal phase 2 portion of the study later this year and to submit the KTE-C19 registration filing to the U.S. Food and Drug Administration (FDA) by the end of 2016."

"The data reported today are important because refractory DLBCL is incurable. Median survival for these patients is short and there is no standard therapy," noted Ronald Levy, M.D., Robert K. Summy and Helen K. Summy Professor of Medicine and Director of the Lymphoma Program at Stanford University School of Medicine and Associate Director of Translational Science for the Stanford Cancer Institute. "A rate of complete response and durability of response in the ranges of those reported today would be of profound clinical importance if replicated in the phase 2 portion of the ZUMA-1 study. Adoptive transfer of engineered T cells has the potential to become standard of care for patients with refractory NHL in the near future."

Updated Phase 1 Results from ZUMA-1: A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 (Anti-CD19 CAR T Cells) in Subjects with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

Session: Early Clinical Trials Evaluating Cell-based, Checkpoint Inhibitors, and Novel Immunotherapeutics; Abstract Number: CT135; Presenter: Armin Ghobadi, M.D., Washington University, St. Louis, MO

Phase 1 of ZUMA-1 treated a total of 7 patients with chemorefractory, diffuse large B cell lymphoma (DLBCL)
KTE-C19 related adverse events consisted predominantly of cytokine release syndrome (CRS) and neurotoxicity which were generally reversible
Grade 3 or higher CRS was observed in 14% and neurotoxicity in 57%; all were reversible except in one patient with dose-limiting toxicity
KTE-C19 achieved rapid and durable responses in patients with chemorefractory disease (objective response rate 71%, complete response rate 57%)
Ongoing complete response (CR) observed in 3 of 7 patients. One ongoing CR as of 9-month study follow-up and 2 ongoing CRs as of 6-month study follow-up.
In addition, two posters on KTE-C19 engineered cell manufacturing and characteristics were presented at AACR (Free AACR Whitepaper) on April 18, 2016.

Manufacturing and Characterization of KTE-C19 in a Multicenter Trial of Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) (ZUMA-1)

Session: Adoptive Cell Therapy; Abstract Number: 2308; Presenter: John Rossi, M.S., Kite Pharma

The optimized GMP-manufacturing process generated anti-CD19 CAR T cells rapidly and without the need for pre-selection of a defined composition of T cells
Biologically active anti-CD19 CAR T cells were manufactured for all patients enrolled in the multicenter phase 1 ZUMA-1 trial.
Comparative Evaluation of Peripheral Blood T Cells and Resultant Engineered Anti-CD19 CAR T Cell Products from Relapsed/Refractory Non-Hodgkin’s Lymphoma (NHL) Patients

Session: Adoptive Cell Therapy; Abstract Number: 2305; Presenter: Timothy J. Langer, Kite Pharma

CAR T cells were successfully manufactured for all patients enrolled in the study at the National Cancer Institute, Surgery Branch
CAR T cell products were composed of both CD4+ and CD8+ T cells with a less differentiated phenotype than the starting leukapheresis products
CAR T cells were polyfunctional and produced a wide range of immune homeostatic, modulating and effector cytokines/chemokines in response to antigen-positive target cells.

On April 19, 2016 Corvus Pharmaceuticals, Inc. (NASDAQ:CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of novel immuno-oncology therapies, reported results of three preclinical studies of CPI-444, the Company’s lead oral checkpoint inhibitor (Press release, Corvus Pharmaceuticals, APR 19, 2016, View Source;p=irol-newsArticle&ID=2158492 [SID:1234512141]). The studies demonstrated that CPI-444, a selective and potent inhibitor of the adenosine A2A receptor, was effective in stimulating various immune cells, generating anti-tumor immunity, suppressing tumor growth and delaying tumor progression in animal models of cancer. The data were presented in oral and poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans.

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"These preclinical studies demonstrate that CPI-444 enhances the immune response to various tumors in animal models of melanoma, breast and colon cancer. Enhancement of T-cell function was also corroborated with adoptively transferred T-cells and with tumor vaccines, indicating that this agent may have broad applications in immuno-oncology," said Richard A. Miller, M.D., an oncologist and co-founder, president and chief executive officer of Corvus. "These studies support our commitment to advancing the clinical development of CPI-444 as an immuno-oncology therapy for many types of cancer. Based on these study findings and others, we have begun enrolling patients in a Phase 1/1b clinical trial to evaluate the safety, tolerability and preliminary efficacy of CPI-444 as a single agent and in combination with an anti-PD-L1 in patients with solid tumors."

The Adenosine A2A Receptor Antagonist, CPI-444, Blocks Adenosine-Mediated T-Cell Suppression and Exhibits Anti-Tumor Activity Alone and in Combination with Anti-PD-1 and Anti-PD-L1 (abstract #2337)
Data from this preclinical study were presented in a poster session by Stephen Willingham, Ph.D., senior scientist at Corvus Pharmaceuticals. Results showed that CPI-444 restored T-cell activation in vitro in T-cells that were treated with immuno-suppressive levels of adenosine. CPI-444 demonstrated single-agent anti-tumor activity and synergized with either anti-PD-1 or anti-PD-L1 in multiple animal tumor models, resulting in a significant number of cured animals. CPI-444 combined with anti-PD-L1 treatment resulted in increased CD8+ T-cell infiltrates in tumors, indicating a heightened anti-tumor immune response. In tumor-bearing mice cured by treatment with CPI-444, long-term anti-tumor immunity was demonstrated by showing that all these mice were protected from tumor re-challenge.

Inhibition of Adenosine A2A Receptor (A2AR) by CPI-444 Enhances CD8+ T-Cell Killing of a HER-2/neu Expressing Murine Tumor (abstract #320)
Data from this preclinical study were presented by Blake Scott, a member of the lab of Elizabeth Jaffee, M.D., in The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine. Jaffee also is associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins. Results showed that CPI-444 enhanced the activity of adoptively transferred, cancer-specific CD8+ T-cells when administered with a T-cell-inducing tumor vaccine.

Adenosine A2A Receptor (A2AR) Antagonist as a Means of Enhancing the Efficacy of Checkpoint Blockade and Adoptive T-Cell Therapy (abstract #4364)
Data from this preclinical study were presented in an oral session by Robert D. Leone, M.D., Ph.D., of The Sidney Kimmel Comprehensive Cancer Research Center at Johns Hopkins University School of Medicine. Treatment of animals with CPI-444 enhanced tumor immunity by lowering the expression of other inhibitory checkpoint receptors on tumor infiltrating immune cells (e.g., Lag 3, Tim 3 and PD-1). CPI-444 also enhanced the efficacy of adoptively transferred T-cells, leading to suppressed tumor growth and increased survival compared with controls. CPI-444 increased the expansion of antigen-specific T-cells in vitro and synergized with anti-PD-1 antibody treatment and glutamine metabolism inhibitors in animal models of colon tumors. A co-author of the study is Jonathan Powell, M.D., Ph.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center and associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins.

ABOUT ADENOSINE A2A RECEPTOR ANTAGONISTS
Over the last several years, significant progress has been made in developing immunotherapies for the treatment of cancer, in part due to the development of checkpoint inhibitors — antibodies that block immuno-suppressive mechanisms.

Tumors evade immune attack by usurping pathways that negatively regulate immune responses. Adenosine in the tumor microenvironment leads to the activation of the A2A receptor and has been shown to represent one such negative immune regulatory mechanism. Because the tumor microenvironment produces relatively high concentrations of adenosine, blocking A2A receptor activation has the potential to enhance anti-tumor immunity. Data have demonstrated the ability of A2A receptor blockade to enhance anti-tumor immunity, checkpoint blockade and adoptive T-cell therapy. Studies to date support the development of A2A receptor antagonists as novel immunotherapy treatments.

ABOUT CPI-444
CPI-444, Corvus’s lead checkpoint inhibitor, is an adenosine A2A receptor antagonist. It is designed to disable a tumor’s ability to subvert attack by the immune system by inhibiting adenosine in the tumor microenvironment. CPI-444 is a small molecule that is taken orally. It is in development as an immuno-oncology therapy for the treatment of patients with solid tumors.

Corvus is currently evaluating CPI-444 in a multicenter Phase 1/1b clinical trial in patients with various solid tumors. This successive expansion cohort trial is examining the activity of CPI-444 both as a single agent and in combination with atezolizumab (MPDL3280A), Genentech’s investigational cancer immunotherapy. Atezolizumab is a fully humanized monoclonal antibody targeting protein programmed cell death ligand 1 (PDL-1). Corvus is conducting the trial with Genentech, a member of the Roche Group, under a clinical trial collaboration the two companies entered into in October 2015.