Iomab-B for Hematopoietic Stem Cells Transplantation:

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Iomab-B (BC8-I-131 construct) has already been successfully used as a myeloconditioning/myeloablative agent in over 250 patients with incurable blood cancers (Company Pipeline, Actinium Pharmaceuticals, APR 19, 2016, View Source [SID:1234511053]). In both Phase I and Phase II trials Iomab-B has led to effective cures in patients with no options left. The only potentially curative treatment option for those patients is bone marrow transplantation (BMT), also known as a hematopoietic stem cell transplant (HSCT), but vast majority of patients over the age of 50 are either ineligible for myeloablative conditioning due to concomitant conditions or have a high burden and/or very resistant disease that makes reduced dose conditioning futile.

BC8-I-131 has demonstrated ability to successfully prepare such patients for bone marrow transplants when no other treatment was indicated. ATNM intends to develop Iomab-B through a regulatory approval via a pivotal registration trial in AML refractory/relapsing patients. That would allow for a relatively quick path to the market and provide a potentially curative treatment to patients who currently have little or no chance of achieving even a temporary remission, let alone a cure.

The targeting part of the Iomab-B construct is a monoclonal antibody that targets CD45, an antigen widely expressed on hematopoietic cells but not other tissues. Due to this broad expression, Iomab-B has demonstrated utility in other groups of patients and other indications as well, including Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia, Hodgkin’s Disease and Non-Hodgkin Lymphoma. These are follow-on indications which could be pursued simultaneously or delayed, for cash conservation, and financed from commercial revenues.

The company is already preparing a program for replacing iodine 131 with Actinium 225 to create a second generation drug that would enable a significant expansion of use, described below as Actimab-B, Iomab-B was invented by researchers at the Fred Hutchinson Cancer Research Center (FHCRC), ATNM’s key collaborator on this program from whom ATNM obtained rights for all the commercial uses. FHCRC played a pivotal role in developing the entire field of bone marrow transplantation and the lead Hutchinson researcher, Dr. E. Donnall Thomas received the 1990 Nobel Prize in physiology/medicine for work in this area.

Several antibody-maytansinoid conjugates (AMCs) are in clinical trials for the treatment of various cancers. Each of these conjugates can be metabolized by tumor cells to give cytotoxic maytansinoid metabolites that can kill targeted cells. In preclinical studies in mice, the cytotoxic metabolites initially formed in vivo are further processed in the mouse liver to give several oxidized metabolic species. In this work, the primary AMC metabolites were synthesized and incubated with human liver microsomes (HLMs) to determine if human liver would likely give the same metabolites as those formed in mouse liver. The results of these HLM metabolism studies as well as the subsequent syntheses of the resulting HLM oxidation products are presented. Syntheses of the minor impurities formed during the conjugation of AMCs were also conducted to determine their cytotoxicities and to establish how these impurities would be metabolized by HLM.

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As key negative regulator of the p53 tumour suppressor, Mdm2 is an attractive therapeutic target. Small molecules such as Nutlin have been developed to antagonise Mdm2, resulting in p53-dependent death of tumour cells. We have recently described a mutation in Mdm2 (M62A), which precludes binding of Nutlin, but not p53. This Nutlin-resistant variant is not, however, refractory to binding and inhibition by stapled peptide antagonists targeting the same region of Mdm2. A detailed understanding of how stapled peptides are recalcitrant to Mdm2 mutations conferring Nutlin-resistance will aid in the further development of potent Mdm2 antagonists. Here, we report the 2.00 Å crystal structure of a stapled peptide antagonist bound to Nutlin resistant Mdm2. The stapled peptide relies on an extended network of interactions along the hydrophobic binding cleft of Mdm2 for high affinity binding. Additionally, as seen in other stapled peptide structures, the hydrocarbon staple itself contributes to binding through favourable interactions with Mdm2. The structure highlights the intrinsic plasticity present in both Mdm2 and the hydrocarbon staple moiety, and can be used to guide future iterations of both small molecules and stapled peptides for improved antagonists of Mdm2.

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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.

On April 19, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies, hosted a Research Reception on Monday, April 18, 2016 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana (Press release, Advaxis, APR 19, 2016, View Source [SID:1234511045]).

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The Research Reception featured Rosemarie Krupar, M.D., of Baylor College of Medicine, presenting "Immunogenicity of Axalimogene Filolisbac in Head and Neck Cancer," a review of the late-breaking poster presentation (Abstract #LB-095). The phase 2 trial leveraged a 5-6 week window between diagnosis and trans-oral robotic surgery, administering two doses of treatment with Advaxis’ lead immunotherapy candidate, axalimogene filolisbac (AXAL), two weeks apart to eight patients with late-stage HPV-associated oropharyngeal cancer (HPVOPC). The study observed changes to the tumor immune microenvironment (TME), including cytotoxic T cell infiltration into the post-resection tumor, increased immune activation, a reduction of regulatory T cells, infiltration of cytotoxic T cells, and increased expression of inflammatory activation markers, suggesting that AXAL has the potential to cause positive immunologic responses for patients with HPV+ head and neck cancers.

Nicola Mason, Ph.D., BVetMed, Assistant Professor of Medicine at the University of Pennsylvania, presented "Immune Therapy with ADXS31-164 Prevents Metastatic Disease and Prolongs Overall Survival in Spontaneous Canine Osteosarcoma." In her presentation, Dr. Mason reviewed her experiences with ADXS31-164 in dogs with spontaneous osteosarcoma. In two separate studies, repeat administrations of up to 3.3 x 109 CFUs were well tolerated with transient low-grade side effects. Immune responses to HER2/neu were detected within 6 months in 15 of 18 dogs with minimal residual disease. In these dogs, metastatic disease was delayed or prevented. Radiographic progression of primary osteosarcoma lesions was prevented in a subset of dogs who were treated after palliative radiotherapy. Treated animals had tumor-specific T-cell responses in the tumor site and reduced numbers of Tregs and MDSCs in the tumor microenvironment.

Robert Petit, Ph.D., Chief Scientific Officer and EVP of Advaxis, presented "Effect of Advaxis’ Lm Immunotherapy on the STING Pathway." In his presentation, Dr. Petit discussed the potent triggering of STING (STimulator of Interferon Genes) built into every Advaxis vector and triggered by DNA, including 80-100 copies of DNA plasmids, that code for tumor target antigens. Advaxis Lm-LLO vectors escape into the cytosol of antigen-presenting cells (APCs) where the human STING receptor is triggered preferentially by DNA. Triggering STING results in the secretion of type I interferons and pro-inflammatory cytokines and has been linked to immune sensing of tumors, clinical responses to melanoma, and inflammation of the tumor microenvironment. Experiments in STING knock-out models demonstrate that triggering of STING contributes to part, but not all, of the ability of ADXS11-001 to control HPV+ tumors.

The Research Reception concluded with a final presentation by Robert Petit, "Cancer Neoepitope Immunotherapy: An Update on ADXS-NEO." Advaxis’ Lm Technology is being used to develop novel ADXS-NEO immunotherapies personalized to the specific and unique neo-epitopes found in an individual patient’s tumor. ADXS-NEO is projected to be available for patients in 6-8 weeks from biopsy to infusion. This platform is able to decrease Tregs and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and can be used to combine tumor driver targets along with neoepitope targets. Data was presented from a mouse model, demonstrating the ability of ADXS-NEO to express multiple tumor neoantigens which were capable of controlling tumor growth. The data developed in this model confirms that ADXS-NEO can be successfully executed and administered and has the ability to control the tumors that were the source of the neoantigens. Advaxis is currently developing an Investigational New Drug Application for ADXS-NEO and is planning for upcoming clinical trials.

Advaxis is actively building collaborations in academia and industry to drive ADXS-NEO forward, including the MINE (My Immunotherapy Neo-Epitopes) collaboration with Memorial Sloan Kettering Cancer Center, focusing on preclinical and clinical development of neoepitope-based Lm treatments. The goal of MINE is to develop neo-epitope immunotherapies based on the specific and unique neo-epitopes found in an individual patient’s tumor. Advaxis is currently partnering with SGI-DNA for DNA synthesis and bioinformatics.

To view the presentation slides and to listen to the presenters, visit www.advaxis.com.

About Axalimogene Filolisbac

Axalimogene filolisbac (AXAL) is Advaxis’ lead Lm Technology immunotherapy candidate for the treatment of HPV-associated cancers and is in clinical trials for three potential indications: invasive cervical cancer, head and neck cancer, and anal cancer. In a completed randomized Phase 2 study in recurrent/refractory cervical cancer, axalimogene filolisbac showed apparent prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy, supporting further development of the company’s Lm Technology. Axalimogene filolisbac has Orphan Drug Designation in the U.S. for the treatment of anal cancer.