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SOT101 is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain, representing a promising clinical candidate for the treatment of cancer. SOT101 among other immune cells specifically stimulates natural killer (NK) cells and memory CD8+ T cells with no significant expansion or activation of the regulatory T cell compartment. In this study, we showed that SOT101 induced expression of cytotoxic receptors NKp30, DNAM-1 and NKG2D on human NK cells. SOT101 stimulated dose-dependent proliferation and the relative expansion of both major subsets of human NK cells, CD56brightCD16- and CD56dimCD16+, and these displayed an enhanced cytotoxicity in vitro. Using human PBMCs and isolated NK cells, we showed that SOT101 added concomitantly or used for immune cell pre-stimulation potentiated clinically approved monoclonal antibodies Cetuximab, Daratumumab and Obinutuzumab in killing of tumor cells in vitro. The anti-tumor efficacy of SOT101 in combination with Daratumumab was assessed in a solid multiple myeloma xenograft in CB17 SCID mouse model testing several combination schedules of administration in the early and late therapeutic setting of established tumors in vivo. SOT101 and Daratumumab monotherapies decreased with various efficacy tumor growth in vivo in dependence on the advancement of the tumor development. The combination of both drugs showed the strongest anti-tumor efficacy. Specifically, the sequencing of both drugs did not matter in the early therapeutic setting where a complete tumor regression was observed in all animals. In the late therapeutic treatment of established tumors Daratumumab followed by SOT101 administration or a concomitant administration of both drugs showed a significant anti-tumor efficacy over the respective monotherapies. These results suggest that SOT101 might significantly augment the anti-tumor activity of therapeutic antibodies by increasing NK cell-mediated activity in patients. These results support the evaluation of SOT101 in combination with Daratumumab in clinical studies and present a rationale for an optimal clinical dosing schedule selection.

The article announces several appointments including Melynda Geurts and Roy Fleischmann as the newest members of D.L. Anderson's Board of Directors, Ulrich Moebius as the head of preclinical development and project management at MorphoSys, and James Knapp as the business development director at Penn Pharma's.

The article announces the appointment of several executives including Ulrich Moebius as head of pre-clinical development and project management of MorphoSys, Sarah Faihurst as chairman of the British Protected Ornamental Association (BPOA) and Julie Downsborough as sales manager of NanoSight.

Rewetting can strongly affect the matter balance of peatlands. Owing to evidence of increasing CH emissions and P mobilisation after rewetting, the effects of peatland restoration on climate, eutrophication risks and related controversies are discussed. Our study focuses on the role of helophytes in the carbon and nutrient balance of rewetted fen grasslands of NE Germany. We hypothesise that the helophytes Carex riparia, Glyceria maxima, Phalaris arundinacea, Phragmites australis and Typha latifolia differ in biomass production and nutrient standing stock according to site conditions and harvest time. We analysed the helophyte biomass three times a year and continuously measured water levels and quality. Biomass production, nutrient standing stock and litter accumulation were highly species specific and depended on nutrient availability, mean water levels and harvesting time. We conclude that helophytes store considerable amounts of carbon and temporarily improve the water quality by withdrawing high amounts of nutrients from the top soil during the growing season, and by reducing nutrient discharges. Restoring peatlands as effective nutrient and carbon sinks in the landscape should favour highly productive potentially peat-forming helophytes as Phragmites australis by establishing adequate water levels. If nutrients are to be removed from the degraded peatland, then management can combine the restoration of helophyte stands by rewetting with harvesting measures. [ABSTRACT FROM AUTHOR]

The objective of the present study was to evaluate the cellular effects of the oncolytic HSV-1 based vector, G207, on the tumor microenvironment. We established progressively growing intracerebral xenografts in athymic nude rats generated from three different human GBM surgical specimens. The lesions were identified by MRI and subsequently injected with a concentrated vector stock. The animals were killed 10 or 30 days after G207 injection and the tumors were quantitatively evaluated for virus-induced changes in proliferation, apoptosis and vascularity. Moreover, we assessed vector spread as well as the infiltration pattern of CD68-positive inflammatory cells. In all G207-injected lesions, immunostaining identified widespread regions of viral infection and replication (plaques). Proliferation indices were significantly lower, whereas apoptotic counts were significantly elevated in plaques as compared with that in non-infected areas of the same lesions, as well as in corresponding control xenografts. Furthermore, there was a significant decline in the number of blood vessels in the plaques and the vascular area fractions were reduced. CD68-positive inflammatory cells accumulated in the plaques. The present study highlights the favorable cellular responses to G207 treatment seen from a clinical viewpoint, such as reduced tumor cell proliferation, more frequent events of tumor cell death and a strongly attenuated tumor vascular compartment. However, our results suggest that transduction of a significant volume of tumor tissue is essential, as these beneficial changes were only observed in areas of active viral replication, leaving non-transduced tumor tissues unaffected. [ABSTRACT FROM AUTHOR]

Tumor cells, including renal cell carcinoma (RCC) cells, do not effectively stimulate T lymphocyte responses against specific antigens presented on their surface. Reasons for this low immunogenicity may include low or absent expression of MHC class I and/or class II molecules, as well as accessory and costimulatory molecules. We used tumor cell pretreatment with cytokines, together with monoclonal antibodies (mAbs) directed at receptors for costimulatory molecules, to render RCC cells immunostimulatory. Interferon-γ or tumor necrosis factor-α pretreatment enhanced expression of MHC class I and class II molecules, as well as CD54, but had only minimal effects on T cell activation. A CD28 mAb, or an even more effective combination of CD28 and CD5 mAb, induced strong primary proliferative responses of allogeneic resting T lymphocytes. Cytokine pretreatment further augmented this T cell response in vitro and allowed T cell expansion and establishment of T cell lines. Stimulation of T cells with autologous RCC cells resulted in a similar T cell activation but with the expansion of cytolytic T cells directed at autologous MHC class II molecules. These experiments demonstrate that cytokines combined with costimulatory mAbs are useful for increasing the immunogenicity of tumor cells. They also indicate, however, that autologous MHC class II expression on tumor cells, together with strong costimulation, may lead to the activation of autoreactive T cells. [ABSTRACT FROM AUTHOR]

Colorectal cancer is considered a non-immunogenic malignany. One strategy to augment the immunogenicity of such tumours is represented by the expression of costimulatory molecules by gene transfer. Using transfected variants of the human colorectal cancer cell line SW480 we tested various costimulatory molecules (CD80, CD86, CD54) and a class II major histocompatibility complex (MHC) allele (HLA-DR3) alone or in combination on their ability to support primary T-lymphocyte activation in vitro. Expression of CD80 or CD86 similarly as the combination of both was not sufficient to induce proliferation of human allogeneic T cells. Expression of CD54 together with CD80 strongly augmented the costimulatory function of CD80, as observed in the presence of a CD3 monoclonal antibody (mAb), but did not lead directly to a T-cell response against modified tumour cells. Importantly, SW480 cells coexpressing CD54, CD80 and the HLA-DR3 allele effectively promoted T-lymphocyte proliferation. Moreover, the use of such CD54+/CD80+/HLA-DR3+ SW480 variants for repetitive stimulations resulted in the generation of T-cell lines predominantly composed of CD8+ T cells exhibiting class I MHC restricted cytolytic activity towards untransfected SW480 tumour cells. This demonstrates that the generation of immunogenic tumour cell variants, i.e. for the use as cellular vaccines, requires multiple genetic alterations in the case of non-immunogenic human tumours cells, such as colorectal cancer cells. [ABSTRACT FROM AUTHOR]

The article lists patents of several studies related to anatomy which includes "Compositions and Methods for Cell Dedifferentiation and Tissue Regeneration," by Mark T. Keating, Shannon J. Odelberg, and Kenneth D. Poss, "Method of Constructing Three-Dimensional Structure of Transmembrane Protein," by Hideaki Umeyama and Mitsuo Iwadate, and "Secreted and Transmembrane Polypeptides and Nucleic Acids Encoding the Same," by Kevin P. Baker and colleagues.