An epithelial to mesenchymal transition (EMT) enables epithelial tumor cells to break out of the primary tumor mass and to metastasize. Understanding the molecular mechanisms driving EMT in more detail will provide important tools to interfere with the metastatic process. To identify pharmacological modulators and druggable targets of EMT, we have established a novel multi-parameter, high-content, microscopy-based assay and screened chemical compounds with activities against known targets. Out of 3423 compounds, we have identified 19 drugs that block transforming growth factor beta (TGFβ)-induced EMT in normal murine mammary gland epithelial cells (NMuMG). The active compounds include inhibitors against TGFβ receptors (TGFBR), Rho-associated protein kinases (ROCK), myosin II, SRC kinase and uridine analogues. Among the EMT-repressing compounds, we identified a group of inhibitors targeting multiple receptor tyrosine kinases, and biochemical profiling of these multi-kinase inhibitors reveals TGFBR as a thus far unknown target of their inhibitory spectrum. These findings demonstrate the feasibility of a multi-parameter, high-content microscopy screen to identify modulators and druggable targets of EMT. Moreover, the newly discovered "off-target" effects of several receptor tyrosine kinase inhibitors have important consequences for in vitro and in vivo studies and might beneficially contribute to the therapeutic effects observed in vivo.

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Deoxycytidine kinase (dCK), a rate-limiting enzyme in the cytosolic deoxyribonucleoside (dN) salvage pathway, is an important therapeutic and positron emission tomography (PET) imaging target in cancer. PET probes for dCK have been developed and are effective in mice but have suboptimal specificity and sensitivity in humans. To identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds-[(18)F]Clofarabine; 2-chloro-2′-deoxy-2′-[(18)F]fluoro-9-β-d-arabinofuranosyl-adenine ([(18)F]CFA) and 2′-deoxy-2′-[(18)F]fluoro-9-β-d-arabinofuranosyl-guanine ([(18)F]F-AraG)-for dCK and deoxyguanosine kinase (dGK), a dCK-related mitochondrial enzyme. We demonstrate that, in the tracer concentration range used for PET imaging, [(18)F]CFA is primarily a substrate for dCK, with minimal cross-reactivity. In contrast, [(18)F]F-AraG is a better substrate for dGK than for dCK. [(18)F]CFA accumulation in leukemia cells correlated with dCK expression and was abrogated by treatment with a dCK inhibitor. Although [(18)F]CFA uptake was reduced by deoxycytidine (dC) competition, this inhibition required high dC concentrations present in murine, but not human, plasma. Expression of cytidine deaminase, a dC-catabolizing enzyme, in leukemia cells both in cell culture and in mice reduced the competition between dC and [(18)F]CFA, leading to increased dCK-dependent probe accumulation. First-in-human, to our knowledge, [(18)F]CFA PET/CT studies showed probe accumulation in tissues with high dCK expression: e.g., hematopoietic bone marrow and secondary lymphoid organs. The selectivity of [(18)F]CFA for dCK and its favorable biodistribution in humans justify further studies to validate [(18)F]CFA PET as a new cancer biomarker for treatment stratification and monitoring.

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On April 1, 2016 CEL-SCI Corporation (NYSE MKT: CVM) ("CEL SCI" or the "Company") reported that during the month of March it has enrolled 32 patients in its ongoing Phase 3 trial of its investigational immunotherapy Multikine* (Leukocyte Interleukin, Injection) in patients with advanced primary head and neck cancer (Press release, Cel-Sci, APR 1, 2016, View Source [SID:1234510296]). Total patient enrollment for the trial is now 756 as of March 31, 2016.

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"We continue to enroll patients into our Phase 3 trial at a rate of about one patient per day in the world’s largest Phase 3 trial in head and neck cancer," stated CEL-SCI CEO Geert Kersten.

The current study goal is to enroll 880 patients through approximately 100 clinical centers in over 20 countries.

About the Multikine Phase 3 Study

The Multikine Phase 3 study is enrolling patients with advanced primary squamous cell carcinoma of the head and neck. The objective of the study is to demonstrate a statistically significant improvement in the overall survival of enrolled patients who are treated with the Multikine treatment regimen plus standard of care ("SOC") vs. subjects who are treated with SOC only.

About Multikine

Multikine (Leukocyte Interleukin, Injection) is an investigational immunotherapeutic agent that is being tested in an open-label, randomized, controlled, global pivotal Phase 3 clinical trial as a potential first-line treatment for advanced primary squamous cell carcinoma of the head and neck. Multikine is designed to be a different type of therapy in the fight against cancer: one that appears to have the potential to work with the body’s natural immune system in the fight against tumors.

Multikine is also being tested in a Phase 1 study under a Cooperative Research and Development Agreement ("CRADA") with the U.S. Naval Medical Center, San Diego, and at University of California, San Francisco (UCSF), as a potential treatment for peri-anal warts in HIV/HPV co-infected men and women. Dr. Joel Palefsky, a world-renowned scientist and Key Opinion Leader (KOL) in human papilloma virus (HPV) research and the prevention of anal cancer, is the Principal Investigator at UCSF, which was added to the study in July 2015.

CEL-SCI has also entered into two additional co-development agreements for up to $3 million each with Ergomed Clinical Research Limited to further the development of Multikine for cervical dysplasia/neoplasia in women who are co-infected with HIV and HPV and for peri-anal warts in men and women who are co-infected with HIV and HPV.

On April 1, 2016. Medigene AG (MDG1, Frankfurt, Prime Standard), a clinical stage immune-oncology company, reported the treatment start of the first phase II-patient in its dendritic cell (DC) vaccine clinical phase I/II trial in acute myeloid leukaemia (AML) (Press release, MediGene, APR 1, 2016, View Source [SID:1234510295]). This triggers a milestone payment in the amount of approx. 3.2 m EUR to be made by Medigene AG to former contributing shareholders of Medigene Immunotherapies GmbH (formerly: Trianta Immunotherapies GmbH) within the next five months. Medigene intends to settle this payment through the issuance of new shares from authorised capital. The milestone payment was an agreed part of the purchase price in the acquisition of Trianta in January 2014.

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Prof. Dolores J. Schendel, CEO of Medigene AG, comments: "We are glad to announce the start of the clinical phase II trial of our DC vaccines shortly after the successful completion of patient recruitment for the phase I part of this trial and the Data and Safety Monitoring Board’s recommendation to continue clinical development in this project. This demonstrates the steady progress of our clinical programs and the further validation of our immunotherapies."

Study design: Medigene’s Phase I/II trial (NCT02405338) will include 20 AML patients who show complete remission after standard chemotherapy but are not eligible for stem cell transplantation that would reduce the risk of a relapse. Patients will be vaccinated with Medigene’s DC vaccines for 50 weeks with a follow-up period of one year or until progression of the disease. The primary objective is to prove feasibility and safety of active immunotherapy with Medigene’s dendritic cells. Secondary objectives of the study are induction of tumour-specific immune response, control of minimal residual disease (MRD), and clinical response/time to progression (TTP).

About Medigene’s DC vaccines: The platform for the development of antigen-tailored DC vaccines is the most advanced of Medigene’s highly innovative and complementary immunotherapy platforms. Currently Medigene evaluates its DC vaccines in a company-sponsored Phase I/II clinical trial in acute myeloid leukaemia (AML). Further studies utilising Medigene’s DC vaccine technology include two ongoing clinical investigator-initiated trials (IITs), i.e. a clinical Phase I/II trial for the treatment of acute myeloid leukaemia (AML) at Ludwig Maximilians University Hospital Grosshadern, Munich, and a clinical Phase II trial for prostate cancer treatment at Oslo University Hospital. Moreover, compassionate use[1] patients are treated with DC vaccines at the Department of Cellular Therapy at Oslo University Hospital.

Dendritic cells (DCs) are the most potent antigen-presenting cells of our immune system. Their task is to take up, process and present antigens on their cell surface, which enables them to activate antigen-specific T cells for maturation and proliferation. This way T cells can recognise and eliminate antigen-bearing tumour cells. Dendritic cells can also induce natural killer cells (NK cells) to attack tumour cells. The team of Medigene Immunotherapies scientists has developed new, fast and effective methods for generating dendritic cells ex-vivo, which are able to activate both T cells and NK cells. The DC vaccines are developed from autologous (patient-derived) precursor cells, isolated from the patient’s blood, and can be loaded with tumour-specific antigens to treat different types of cancer. Medigene’s DC vaccines are in development for the treatment of minimal residual disease or for the use in combination therapies.

Further audio-visual information about Medigene’s DC vaccines at:
View Source

About acute myeloid leukaemia (AML)

Acute myeloid leukaemia is a malignant disease of the hematopoietic system, affecting mainly adults above 60 years of age. In Germany, about 3,600 incidences are registered annually.

AML is caused by uncontrolled growth of dysfunctional hematopoietic precursor cells in the bone marrow. These cells prevent the generation of normal blood cells, causing a drop in erythrocytes and platelets, for example. Typical symptoms of AML include anaemia, fever, increased risk of infection, and blood coagulation disorder. AML progresses rapidly and may be fatal within a few weeks if untreated.

AML is treated initially with intensive chemotherapy. Another treatment option is allogeneic hematopoietic stem cell transplantation. Unfortunately the majority of patients suffer a relapse. Only about 15 – 20 % of the patients show long-term remission after conventional chemotherapy. Allogeneic hematopoietic stem cell transplantation is the only treatment option that offers a more positive prognosis.

On April 1, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending the grant of a conditional marketing authorization for DARZALEX (daratumumab) in the European Union (Press release, Genmab, APR 1, 2016, View Source [SID:1234510294]). The recommendation is for the use of DARZALEX as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

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The positive opinion of the CHMP was predominantly based on data from the Phase II study (SIRIUS MMY2002, published in The Lancet in January 2016) of daratumumab in multiple myeloma patients who have received at least three prior lines of therapy including both a PI and an immunomodulatory agent, or who are double refractory to a PI and an immunomodulatory agent.
Additional data from four other studies, including the Phase I/II GEN501 monotherapy study (published in The New England Journal of Medicine in August 2015) support the opinion. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize daratumumab.

"We are very pleased to receive the positive opinion from the CHMP for the use of DARZALEX as monotherapy in patients with relapsed and refractory multiple myeloma. The CHMP opinion brings Genmab and its partner Janssen one step closer towards offering a fundamentally new treatment option to patients with multiple myeloma in Europe, and we look forward to the decision of the European Commission," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

A CHMP opinion is one of the final steps in the regulatory process of the European Medicines Agency. The CHMP reviewed DARZALEX under the EMA’s accelerated assessment program. A final decision by the European Commission is anticipated in 60 — 90 days.

In November 2015, DARZALEX was approved by the U.S. FDA under a Breakthrough Therapy Designation and Priority Review for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.

Safety and Efficacy Data from the Phase II MMY2002 (SIRIUS) Study

Results from the pivotal Phase II SIRIUS study showed that treatment with single-agent DARZALEX resulted in an overall response rate (ORR) of 29.2% in patients who had received a median of five prior lines of therapy, including a PI and an immunomodulatory agent. Stringent complete response (sCR) was reported in 2.8% of patients, very good partial response (VGPR) was reported in 9.4% of patients, and partial response (PR) was reported in 17% of patients.1

For responders, the median duration of response was 7.4 months. At baseline, 97% of patients were refractory to their last line of therapy, 95% were refractory to both a PI and an immunomodulatory agent, and 77% were refractory to alkylating agents.1
The warnings and precautions for DARZALEX include infusion-related reactions (IRRs) and interference with serological testing.1 The most commonly occurring adverse reactions (in 20 percent or more of patients in three pooled clinical studies) were IRRs, fatigue, nausea, back pain, anemia, neutropenia (abnormally low levels of neutrophils, a type of white blood cell) and thrombocytopenia (abnormally low levels of platelets in the blood).1

In data from three pooled clinical studies including a total of 156 patients, four percent of patients discontinued treatment due to adverse reactions, none of which were considered drug-related. IRRs were reported in approximately half of all patients treated with DARZALEX, the majority of which (91 percent) occurred during the first infusion. Seven percent of patients had an IRR at more than one infusion. Common (≥5 percent) symptoms of IRRs included nasal congestion, chills, cough, allergic rhinitis, throat irritation, dyspnea, and nausea, and these were mild to moderate in severity.1 Severe IRRs (4 percent), including bronchospasm (1.3 percent), hypertension (1.3 percent), and hypoxia, or decreased oxygen supply to the tissues (0.6 percent), were also reported.1

About multiple myeloma

Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.2 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.3 Approximately 26,850 new patients were estimated to be diagnosed with multiple myeloma and approximately 11,240 people would die from the disease in the U.S. in 2015.4 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would die from the disease in 2015.5 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.6 Patients who relapse after treatment with standard therapies, including proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.7

About DARZALEX (daratumumab)

DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,1,8 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,1,8 antibody-dependent cellular phagocytosis9,10 and antibody-dependent cellular cytotoxicity.1,8 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were paralleled by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.1

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin’s lymphoma.