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...     

Magnetic and Electrical Behaviors of the Homo- and Heterometallic 1D and 3D Coordination Polymers Based on the Partial Decomposition of the [Cr(C2O4)3]3− Building Block

One-dimensional (1D) oxalate-bridged homometallic {[Mn(bpy)(C₂O₄)]·1.5H₂O}_n (1) (bpy = 2,2’-bipyridine) and heterodimetallic {[CrCu₃(bpy)₃(CH₃OH)(H₂O)(C₂O₄)₄][Cu(bpy)Cr(C₂O₄)₃]·CH₂Cl₂·CH₃OH·H₂O}_n (2) coordination polymers, as well as the three-dimensional (3D) heterotrimetallic {[CaCr₂Cu₂(phen)₄(C₂O₄)₆]·4CH₃CN·2H₂O}_n (3) (1,10-phenanthroline) network, have been synthesized by a building block approach using a layering technique, and characterized by single-crystal X-ray diffraction, infrared (IR) and impedance spectroscopies and magnetization measurements. During the crystallization process partial decomposition of the tris(oxalato)chromate(III) happened and 1D polymers 1 and 2 were formed. The antiferromagnetic interactions between the manganese(II) ions were mediated by oxalate ligands in the chain [Mn(bpy)(C₂O₄)]_n of 1, with intra-chain super-exchange interaction 𝐽 = (−3.134 ± 0.004) K; magnetic interaction between neighbouring chains is negligible making this system closer than other known Mn-chains to the ideal 1D Heisenberg antiferromagnet. Compound 2 comprises a 1D coordination anion [Cu(bpy)Cr(C₂O₄)₃]_nⁿ⁻ (Cr2–Cu4) with alternating [Cr(C₂O₄)₃]³⁻ and [Cu(bpy)]²⁺ units mutually bridged through the oxalate group. Another chain (Cr1–Cu3) is similar, but involves a homodinuclear unit [Cu(bpy)(H₂O)(µ-C₂O₄)Cu(bpy)(CH₃OH)]²⁺ (Cu1–Cu2) coordinated as a pendant group to a terminal oxalate oxygen. Magnetic measurements showed that the Cu1−Cu2 cationic unit is a strongly coupled antiferromagnetic dimer, independent from the other magnetic ions within ferromagnetic chains Cr1–Cu3 and Cr2–Cu4. A 3D polymer {[CaCr₂Cu₂(phen)₄(C₂O₄)₆]·4CH₃CN·2H₂O}_n (3) comprising three different metal centers (Ca²⁺, Cr³⁺ and Cu²⁺) oxalate-bridged, contains Ca²⁺ atoms as nodes connected with four Cr³⁺ atoms through oxalate ligands. The network thus formed can be reduced to an underlying graph of diamondoid (dia) or (6⁶) topology. Magnetization of 3 shows the ferromagnetic oxalate-bridged dimers [Cu^IICr^III], whose mutual interaction could possibly originate through the spin polarization of Ca²⁺ orbitals. Compounds 1 and 3 exhibit lower electrical conductivity at room temperature (RT) in comparison to compound 2.     

Normal bone turnover in transient hyperphosphatasemia

Transient hyperphosphatasemia of infancy and early childhood (THI) is characterized by a temporary isolated elevation of serum alkaline phosphatase activity (ALP), predominantly its bone or liver isoform, in either sick or healthy children under 5 years of age. Return to normal ALP levels usually occurs within four months. Spontaneous rise of ALP might concern the physician, especially when treating seriously ill children. However, THI is considered a benign biochemical disorder with no clinical consequences. Some existing reports support the hypothesis that THI is a result of increased bone turnover. We present evidence of normal bone turnover in two children with THI. In a one-year-old girl and a boy of the same age, high ALP levels (31 and 109 μkat/L, respectively) were accidentally detected. The children had no signs of metabolic bone disease or of liver disease. The high ALP levels returned to normal in two months, thus fulfilling the diagnosis of THI. In both patients, serum parathyroid hormone and bone turnover markers, serum CrossLaps, and serum osteocalcin were neither elevated, nor did these markers follow the ALP dynamics, thus reflecting normal bone turnover in THI. Children with THI should be spared from extensive investigations and unnecessary vitamin D treatment.     

Expression of heat shock protein receptors on fibroblast-like synovial cells derived from rheumatoid arthritis-affected joints

We examined the membrane expression of inducible Hsp70 and HSP receptors like TLR2, TLR4, CD14, CD36, CD40 and CD91 on fibroblast-like synovial cells (SC) derived from synovial tissue in 23 patients with rheumatoid arthritis (RA), who underwent synovectomy by using flow cytometric analysis. For comparison, autologous skin fibroblasts (SF) derived from the operation wound were tested. Significantly higher Hsp70 expression was found on synovial cells than on skin fibroblasts (median SC 21.4% x SF 5.0%, P < 0.001). Both synovial cells and skin fibroblasts expressed high levels of cell surface CD91 (median SC 80.2% x SF 79.2%), however, no or low levels of CD14, CD40, TLR2, TLR4 and CD36. Further, we observed high co-expression of CD91 and Hsp70 on RA synovial cells (median 18.6%), while skin fibroblasts showed only background Hsp70 expression (median 3.9%, P < 0.001). Since we demonstrated the high prevalence of inducible Hsp70 in RA synovial fluids, we speculate that Hsp70 might be captured onto the membrane of synovial cells from the extracellular space via the CD91 receptor. The significance of the Hsp70 interaction with synovial cells via CD91 remains undefined, but may mediate other non-immune purposes.     

SB203580, a pharmacological inhibitor of p38 MAP kinase transduction pathway activates ERK and JNK MAP kinases in primary cultures of human hepatocytes

Mitogen-activated protein kinases (MAPKs) were extensively studied in cancer-derived cell lines; however, studies in non-transformed human cells are scarce. In the current paper, we studied the effect of SB203580, a pharmacological inhibitor of p38 MAPK, on activation and inhibition of p38 MAPK transduction partway in primary human hepatocytes (in vitro model of differentiated cells) in comparison with several tumor cell lines (proliferating non-differentiated in vitro model). In addition, we analyzed the effect of SB203580 on extracellular-regulated protein kinase (ERK) and c-jun-N-terminal kinase (JNK) pathways both in primary human hepatocytes and tumor cell lines employing primary antibodies detecting phosphorylated kinases. We show that SB203580 activates ERK and JNK in primary cultures of human hepatocytes. The levels of ERK-P(Thr202/Tyr204), JNK-P(Thr183/Tyr185) and c-Jun-P(Ser63/73), a target down-stream protein of JNK, were increased by SB203580. In contrast, SB203580 activated ERK but not JNK in HepG2, HL-60, Saos-2 and HaCaT human cancer cell lines. We tested, whether the effects of SB203580 are due to metabolism. Using liquid chromatography/mass spectrometry, we found one minor metabolite in human liver microsomes but not in HepG2 cells. These data imply that biotransformation could be responsible for the effects of SB203580 in human hepatocytes. This study is the first report on the effects of MAPK activators (sorbitol, anisomycin, EGF) and MAPK inhibitors in primary human hepatocytes. We observed differential effects of these compounds in primary human hepatocytes and in cancer cells, implying the cell-type specificity and the essential differences between the role and function of MAPKs in normal and cancer cells.     

Glycol porphyrin derivatives as potent photodynamic inducers of apoptosis in tumor cells

The design and synthesis of glycol-functionalized porphyrins that contain one to four low molecular weight glycol chains that are linked via ether bonds to the meta-phenyl positions of meso-tetraphenylporphyrin and the comparison of fluorinated and nonfluorinated para derivatives are reported. The cellular uptake and photodynamic activity significantly depend on terminal groups of the glycol substituent. Hydroxy glycol porphyrins, in contrast with methoxy glycol porphyrins, show efficient intracellular transport and a high induction of apoptosis in tumor cell lines in vitro . Furthermore, the ethylene glycol chain at the meta position exhibits a superior efficacy that leads to the permanent ablation of human breast carcinoma (MDA-MB-231) in nude mice. In addition, fluorination enhanced the photosensitizing potential of para-phenyl derivatives. The analysis of the cell-death mechanism revealed that glycol-functionalized porphyrins represent novel nonmitochondrially localized photosensitizers that have a profound ability to induce apoptosis in tumor cells that act upstream of caspase activation. The strong interaction with a tumor marker (sialic acid) indicates the preferential association of these compounds with tumor cells.