On April 19 2016 Medigene AG (MDG1, Frankfurt, Prime Standard), a clinical stage immune-oncology company focusing on the development of T cell immuno-therapies for the treatment of cancer, reported that clinical data of a dendritic cell (DC) vaccine trial for the treatment of prostate cancer were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA, USA (Press release, MediGene, APR 19, 2016, View Source [SID:1234511089]).

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The clinical data were collected, utilising Medigene’s DC vaccine technology in part, in an ongoing clinical phase I/II study on dendritic cell (DC) vaccines for the treatment of prostate cancer at the Department of Cellular Therapy at the Oslo University Hospital, Norway, under the responsibility of Prof. Gunnar Kvalheim. The poster presented was entitled "Clinical results of a Phase I/II trial of adjuvant therapeutic vaccination in high risk resected prostate cancer patients using autologous dendritic cells loaded with mRNA from primary prostate cancer tissue, hTERT and survivin".

More than 50% of high risk prostate cancer patients will develop an early biochemical relapse, with no curative therapy presently available. Therefore, Prof. Gunnar Kvalheim and his team have chosen this patient population for their ongoing Phase I/II dendritic cell (DC) vaccine study. Dendritic cells from each of the 20 enrolled patients were differentiated from enriched monocytes and matured with one of two different maturation cocktails. The DCs were then transfected with mRNA from primary prostate cancer tissue, hTERT and Survivin and then frozen and stored until use. Based on encouraging clinical results with a new type of DCs in patients with different types of tumours treated in a compassionate use[1] programme, the DC vaccine protocol was changed to the use of new generation DCs. The last five of 20 treated patients received DCs that were matured with a new TLR7/8-agonist maturation cocktail developed by Medigene. Three of 15 patients given DC vaccines derived with the old (standard) maturation cocktail have experienced a biochemical relapse (raised levels of prostate-specific antigen, PSA) during the vaccination period of 3 years. None of the patients given the new type of DC vaccines has so far experienced a rise in PSA levels.

Prof. Gunnar Kvalheim, Head of Department of Cellular Therapy, Oslo University Hospital concluded on the results: "To our knowledge this is the first adjuvant DC vaccine study in high risk prostate cancer and we conclude that the study is feasible, safe and utmost promising."

Prof. Dolores J. Schendel, CEO/CSO of Medigene AG added: "We feel very encouraged by these preliminary data. The advanced method of making DC vaccines is identical with the method Medigene is also using in its own ongoing DC vaccine study in acute myeloid leukaemia."

More detailed information on the presented data can be found under the following link: View Source;sKey=ac456e79-efd5-416e-a7de-67382c67723a&cKey=2ab5cd11-b3d8-40a8-8087-b0c57f2e8034&mKey=1d10d749-4b6a-4ab3-bcd4-f80fb1922267

The Oslo University Hospital has an agreement with Medigene for use of Medigene`s new generation DC vaccines for their ongoing academic clinical studies.

About Medigene’s DC vaccines: The platform for the development of antigen-tailored DC vaccines is the most advanced platform of the highly innovative and complementary immunotherapy platforms of Medigene Immunotherapies. 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): a clinical phase I/II trial for treating acute myeloid leukaemia (AML) at Ludwig Maximilians University Hospital Grosshadern, Munich, and a clinical phase II trial of a treatment for prostate cancer at Oslo University Hospital. Moreover, compassionate use 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 GmbH’s scientists has developed new, fast and efficient methods for generating dendritic cells ex-vivo, which have relevant characteristics 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 use in combination therapies.

On April 19, 2016 Innate Pharma and OREGA Biotech today presented preclinical data on IPH52, a new CD39 checkpoint inhibitor program, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana, USA (Press release, Innate Pharma, APR 19, 2016, View Source [SID:1234511088]).

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Poster #3222 presents IPH52, Innate’s humanized anti-CD39 blocking antibody. This novel antibody exhibits high affinity and specificity for CD39 and potently inhibits ATPase activity in in vitro assays and ex vivo models with patient biopsies. In a murine tumor model, treatment with anti-CD39 antibody results in a significant decrease in tumor volume, and improved survival.

Poster #3218 presents for the first time the impact of CD39 disruption on the efficacy of other cancer therapeutics by comparing their effects in wildtype versus CD39 knock-out mice. The results revealed that CD39 deficiency sensitized to anti-PD1 treatment in animals that failed to respond to anti-PD-1 treatment. The antitumor efficacy of CD39 disruption is further improved when combined with an immunogenic chemotherapy. In animals bearing PD-1 insensitive tumors, combination of immunogenic chemotherapy, anti-PD1 antibody and CD39 disruption led to complete tumor eradication and long term protection (specific anti-tumor immunity) in most animals. The efficacy of an ADCC-inducing cytotoxic antibody was also improved in CD39 knock-out mice compared to wildtype.

Nicolai Wagtmann, CSO of Innate Pharma, said: "Taken together, the data presented by Innate and our partner OREGA Biotech form a very promising body of evidence supporting the development of this new, first-in-class checkpoint inhibitor antibody. The results presented today raise exciting perspectives for the development of IPH52, both as single-agent and in combination with other checkpoint inhibitors, and we are eager to now take this first-in-class candidate forward into the preclinical development phases".

Jeremy Bastid, COO of OREGA Biotech, further commented: "CD39 mediates immunosuppression through a different mechanism than other immune checkpoints and may broadly impede the efficacy of cancer therapies. The exciting data released today using both antibody blockade and genetic CD39 deficiency shed light on the capacity of CD39 disruption to drive antitumor immune responses, either alone or in combination with PD-1 checkpoint blockers, ADCC antibodies and immunogenic chemotherapy, suggesting broad development potential".

The cohesin complex consists of multiple core subunits that play critical roles in mitosis and transcriptional regulation. The cohesin-associated protein Wapal plays a central role in off-loading cohesin to facilitate sister chromatid separation, but its role in regulating mammalian gene expression is not understood. We used embryonic stem cells as a model, given that the well-defined transcriptional regulatory circuits were established through master transcription factors and epigenetic pathways that regulate their ability to maintain a pluripotent state.
RNAi-mediated depletion of Wapal causes a loss of pluripotency, phenocopying loss of core cohesin subunits. Using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq), we determine that Wapal occupies genomic sites distal to genes in combination with CTCF and core cohesin subunits such as Rad21. Interestingly, genomic sites occupied by Wapal appear enriched for cohesin, implying that Wapal does not off-load cohesin at regions it occupies. Wapal depletion induces derepression of Polycomb group (PcG) target genes without altering total levels of Polycomb-mediated histone modifications, implying that PcG enzymatic activity is preserved. By integrating ChIP-seq and gene expression changes data, we identify that Wapal binding is enriched at the promoters of PcG-silenced genes and is required for proper Polycomb repressive complex 2 (PRC2) recruitment. Lastly, we demonstrate that Wapal is required for the interaction of a distal cis-regulatory element (CRE) with the c-Fos promoter.
Collectively, this work indicates that Wapal plays a critical role in silencing of PcG target genes through the interaction of distal CREs with promoters.

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Ultrasound-induced cavitation has found many applications in the field of cancer therapy. One of its beneficial effects is the enhancement of drug intake by tumor cells. Our group has developed a device that can create and control unseeded cavitation in tissue using ultrasound. We conducted experiments on tumor-bearing mice using our device to assess the impact of sonication on the penetration of fluorescent probes into tumor cells. We studied the influence of pressure level, timing of sonication and sonication duration on treatment efficiency. Our results indicate that fluorescent probes penetrate better into tumors exposed to ultrasound. The best results revealed an increase in penetration of 61% and were obtained when sonicating the tumor in presence of the probes with a peak negative pressure at focus of 19 MPa. At this pressure level, the treatment generated only minor skin damage. Treatments could be significantly accelerated as equivalent enhanced penetration of probes was achieved when multiplying the initial raster scan speed by a factor of four.
Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

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Dolastatin 10 is a powerful antineoplastic agent and microtubule inhibitor that was discovered by Pettit et al. and published in 1987. Since then, many research groups have engaged in SAR studies of synthetic analogues, termed "auristatins". It was eventually discovered that auristatins are of great value as payloads in antibody drug conjugates (ADCs), which led to the FDA-approved ADC brentuximab vedotin (Seattle Genetics). Currently, over 30 ADCs in clinical trials employ auristatins as payloads, and there is a great interest in the research community, both on academic and industrial sides, to further study these analogues. This review will provide an overview of the recent advancements in auristatin development spanning a time frame of about the past ten years. The main focus will be to describe structural changes made to the auristatin peptide and their resulting biological activities in tumor cell proliferation assays. Selected ADC examples will also be described.

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