Phase I/II clinical trial of dendritic-cell based immunotherapy (DCVAC/PCa) combined with chemotherapy in patients with metastatic,castration-resistant prostate cancer

Purpose

We conducted an open-label, single-arm Phase I/II clinical trial in metastatic CRPC (mCRPC) patients eligible for docetaxel combined with treatment with autologous mature dendritic cells (DCs) pulsed with killed LNCaP prostate cancer cells (DCVAC/PCa). The primary and secondary endpoints were safety and immune responses, respectively. Overall survival (OS), followed as a part of the safety evaluation, was compared to the predicted OS according to the Halabi and MSKCC nomograms.

Experimental design

Twenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p.o. DCVAC/PCa treatment consisted of a median twelve doses of 1 × 10⁷ dendritic cells per dose injected s.c. (Aldara creme was applied at the site of injection) during a one-year period. The initial 2 doses of DCVAC/PCa were administered at a 2-week interval, followed by the administration of docetaxel (75 mg/m2) and prednisone (5 mg twice daily) given every 3 weeks until toxicity or intolerance was observed. The DCVAC/PCa was then injected every 6 weeks up to the maximum number of doses manufactured from one leukapheresis.

Results

No serious DCVAC/PCa-related adverse events have been reported. The median OS was 19 months, whereas the predicted median OS was 11.8 months with the Halabi nomogram and 13 months with the MSKCC nomogram. Kaplan-Meier analyses showed that patients had a lower risk of death compared with both MSKCC (Hazard Ratio 0.26, 95% CI: 0.13–0.51) and Halabi (Hazard Ratio 0.33, 95% CI: 0.17–0.63) predictions. We observed a significant decrease in Tregs in the peripheral blood. The long-term administration of DCVAC/PCa led to the induction and maintenance of PSA specific T cells. We did not identify any immunological parameter that significantly correlated with better OS.

Conclusions

In patients with mCRPC, the combined chemoimmunotherapy with DCVAC/PCa and docetaxel was safe and resulted in longer than expected survival. Concomitant chemotherapy did not preclude the induction of specific anti-tumor cytotoxic T cells.     

Microscopic structure of the tongue in the lesser hedgehog tenrec (Echinops telfairi,Afrosoricida) and its relation to phylogenesis

Anatomical Science International - The tongue of the lesser hedgehog tenrec (Echinops telfairi) was evaluated by light and scanning electron microscopy. Dorsal and lateral surfaces of the tongue...     

Degradation Processes of Medieval and Renaissance Glazed Ceramics

Corrosion effects in deposit environments (soil, waste pit, etc.), together with the glaze adherence and fit, could cause severe deterioration accompanied by different types of defects or growth of corrosion products. The aim of this work was to identify the source of surface degradation of the lead-glazed ceramics sets from the Prague area from the Romanesque to the Renaissance period. A combination of X-ray fluorescence (XRF), X-ray diffraction (XRD), optical microscopy (OM), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM/EDS), and simultaneous thermal analysis (STA) techniques along with stress state calculations was used to study the defects. Based on the interpretation of the possible sources of the observed defects, four types of degradation effects were schematically expressed for the archaeological samples. It was shown that the glazes were already appropriately chosen during the production of the Romanesque tiles and that their degradation occurred only due to long-term exposure to unsuitable environmental conditions.     

Advances in Diagnostics and Management of Gestational Trophoblastic Disease

BackgroundGestational trophoblastic disease (GTD) is a heterogeneous group of rare tumours characterised by abnormal proliferation of trophoblastic tissue. It consists of benign or premalignant conditions, such as complete and partial molar pregnancy and variants of malignant diseases. The malignant tumours specifically are commonly referred to as gestational trophoblastic neoplasia (GTN). They consist of invasive mole, choriocarcinoma, placental-site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT).ConclusionsPatients with GTD are often asymptomatic, although vaginal bleeding is a common presenting symptom. With the advances in ultrasound imaging in early pregnancy, the diagnosis of molar pregnancy is most commonly made in the first trimester of pregnancy. Sometimes, additional imaging such as chest X-ray, CT or MRI can help detect metastatic disease. Most women can be cured, and their reproductive function can be preserved. In this review, we focus on the advances in management strategies for gestational trophoblastic disease as well as possible future research directions.Key words: gestational trophoblastic disease, hydatidiform mole, molar pregnancy, gestational trophoblastic neoplasia, human chorionic gonadotropin, invasive mole, choriocarcinoma     

Distinct Immunoregulatory Mechanisms in Mesenchymal Stem Cells: Role of the Cytokine Environment

Mesenchymal stem cells (MSCs) represent a population of cells which have the ability to regulate reactivity of T and B lymphocytes by multiple mechanisms. The immunoregulatory activities of MSCs are strictly influenced by the cytokine environment. Here we show that two functionally distinct cytokines, interleukin-4 (IL-4) and interferon-γ (IFN-γ), significantly potentiate the ability of MSCs to inhibit IL-10 production by activated regulatory B cells (Bregs). However, MSCs in the presence of IL-4 or IFN-γ inhibit the IL-10 production by different mechanisms. Preincubation of MSCs with IFN-γ led to the suppression, but pretreatment with IL-4 of neither MSCs nor B cells resulted in the suppression of IL-10 production. The search for candidate regulatory molecules expressed in cytokine-treated MSCs revealed different patterns of the gene expression. Pretreatment of MSCs with IFN-γ, but not with IL-4, induced expression of indoleamine-2,3-dioxygenase, cyclooxygenase-2 and programmed cell death-ligand 1. To identify the molecule(s) responsible for the suppression of IL-10 production, we used specific inhibitors of the putative regulatory molecules. We found that indomethacine, an inhibitor of cyclooxygenase-2 (Cox-2) activity, completely abrogated the inhibition of IL-10 production in cultures containing MSCs and IFN-γ, but had no effect on the suppression in cell cultures containing MSCs and IL-4. The results show that MSCs can inhibit the response of B cells to one stimulus by different mechanisms in dependence on the cytokine environment and thus support the idea of the complexity of immunoregulatory action of MSCs.     

Modern lipid‐, carbohydrate‐, and peptide‐based delivery systems for peptide,vaccine, and gene products

Research related to peptide, vaccine, and gene delivery has grown exponentially over the last decade. In this review, we discuss the development of delivery systems for peptides, gene and vaccine products. Special focus is given to different lipidation and glycosylation strategies to improve the metabolic stability and membrane permeability of therapeutics, and their targeting to specific sites. The synthetic methods for preparation of the systems are also described. © 2009 Wiley Periodicals, Inc. Med Res Rev, 31, No. 4, 520–547, 2011     

Colon-specific 9-aminocamptothecin-HPMA copolymer conjugates containing a 1,6-elimination spacer.

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-9-aminocamptothecin (9-AC) conjugate for oral colon-specific drug delivery was designed, synthesized, and characterized. The drug, 9-AC, was attached to the polymer carrier via a spacer containing a combination of an aromatic azo bond and a 4-aminobenzylcarbamate group. The design of the spacer ensured a fast and highly efficient release of unmodified 9-AC from the polymer in the colon by azo bond cleavage followed by a 1,6-elimination mechanism. An in vitro degradation study indicated that this conjugate was stable in simulated upper GI tract conditions, including small intestine (SI) contents, SI mucosa suspension, and in PBS (pH 1.5 and 7.4). A fast release of the unmodified drug (85+/-10% of 9-AC in 12 h) was detected in rat cecal contents. This drug delivery system has potential in the treatment of colon cancer.