Immunotherapeutic efficacy of retargeted ohsvs designed for propagation in an ad hoc cell line

Our laboratory has pursued the generation of cancer‐specific oncolytic herpes simplex viruses (oHSVs) which ensure high efficacy while maintaining a high safety profile. Their blueprint included retargeting to a Tumor‐Associated Antigen, e.g., HER2, coupled to detargeting from natural receptors to avoid off‐target and off‐tumor infections and preservation of the full complement of unmodified viral genes. These oHSVs are “fully virulent in their target cancer cells”. The 3rd generation retargeted oHSVs carry two distinct retargeting moieties, which enable infection of a producer cell line and of the target cancer cells, respectively. They can be propagated in an ad hoc Vero cell derivative at about tenfold higher yields than 1st generation recombinants, and more effectively replicate in human cancer cell lines. The R‐335 and R‐337 prototypes were armed with murine IL‐12. Intratumorally‐administered R‐337 conferred almost complete protection from LLC‐ 1‐HER2 primary tumors, unleashed the tumor microenvironment immunosuppression, synergized with the checkpoint blockade and conferred long‐term vaccination against distant challenge tumors. In summary, the problem intrinsic to the propagation of retargeted oHSVs—which strictly require cells positive for targeted receptors—was solved in 3rd generation viruses. They are effective as immunotherapeutic agents against primary tumors and as antigen‐agnostic vaccines

Completing the puzzle of the 2004-2005 outburst in V0332+53: the brightening phase included

Analysis of the data obtained with the RXTE observatory during a powerful outburst of the X-ray pulsar V0332+53 in 2004-2005 is presented. Observational data covering the outburst brightening phase are analysed in detail for the first time. A comparison of source parameters and their evolution during the brightening and fading phases shows no evidence for any hysteresis behaviour. It is found that the dependences of the energy of the cyclotron absorption line on the luminosity during the brightening and fading phases are almost identical. The complete data sequence including the outburst brightening and fading phases makes it possible to impose the more stringent constraints on the magnetic field in the source. The pulse profile and pulsed fraction are studied as functions of the luminosity and photon energy.Comment: 9 pages, 10 figures, accepted for publication in MNRA

Genotype of Immunologically Hot or Cold Tumors Determines the Antitumor Immune Response and Efficacy by Fully Virulent Retargeted oHSV

We report on the efficacy of the non-attenuated HER2-retargeted oHSV named R-337 against the immunologically hot CT26-HER2 tumor, and an insight into the basis of the immune protection. Preliminarily, we conducted an RNA immune profiling and immune cell content characterization of CT26-HER2 tumor in comparison to the immunologically cold LLC1-HER2 tumor. CT26-HER2 tumor was implanted into HER2-transgenic BALB/c mice. Hallmarks of R-337 effects were the protection from primary tumor, long-term adaptive vaccination directed to both HER2 and CT26-wt cell neoantigens. The latter effect differentiated R-337 from OncoVEXGM-CSF. As to the basis of the immune protection, R-337 orchestrated several changes to the tumor immune profile, which cumulatively reversed the immunosuppression typical of this tumor (graphical abstract). Thus, Ido1 (inhibitor of T cell anticancer immunity) levels and T regulatory cell infiltration were decreased; Cd40 and Cd27 co-immunostimulatory markers were increased; the IFNγ cascade was activated. Of note was the dampening of IFN-I response, which we attribute to the fact that R-337 is fully equipped with genes that contrast the host innate response. The IFN-I shut-down likely favored viral replication and the expression of the mIL-12 payload, which, in turn, boosted the antitumor response. The results call for a characterization of tumor immune markers to employ oncolytic herpesviruses more precisely

Hard X-ray emission from the galaxy cluster A3667

We report the results of a long BeppoSAX observation of Abell 3667, one of the most spectacular galaxy cluster in the southern sky. A clear detection of hard X-ray radiation up to ~ 35 keV is reported, while a hard excess above the thermal gas emission is present at a marginal level that should be considered as an upper limit to the presence of nonthermal radiation. The strong hard excesses reported by BeppoSAX in Coma and A2256 and the only marginal detection of nonthermal emission in A3667 can be explained in the framework of the inverse Compton model. We argue that the nonthermal X-ray detections in the PDS energy range are related to the radio index structure of halos and relics present in the observed clusters of galaxie.Comment: 15 pages, 1 figure, ApJL in pres

Insights into Thymus Development and Viral Thymic Infections

T-cell development in the thymus is a complex and highly regulated process, involving a wide variety of cells and molecules which orchestrate thymocyte maturation into either CD4+ or CD8+ single-positive (SP) T cells. Here, we briefly review the process regulating T-cell differentiation, which includes the latest advances in this field. In particular, we highlight how, starting from a pool of hematopoietic stem cells in the bone marrow, the sequential action of transcriptional factors and cytokines dictates the proliferation, restriction of lineage potential, T-cell antigen receptors (TCR) gene rearrangements, and selection events on the T-cell progenitors, ultimately leading to the generation of mature T cells. Moreover, this review discusses paradigmatic examples of viral infections affecting the thymus that, by inducing functional changes within this lymphoid gland, consequently influence the behavior of peripheral mature T-lymphocytes

BeppoSAX Detection and Follow-up of GRB980425

We present BeppoSAX GRBM and WFC light curves of GRB980425 and NFI follow-up data taken in 1998 April, May, and November. The first NFI observation has detected within the 8' radius error box of the GRB an X-ray source positionally consistent with the supernova SN 1998bw, exploded within a day of GRB980425, and a fainter X-ray source, not consistent with the position of the supernova. The former source is detected in the following NFI pointings and exhibits a decline of a factor of two in six months. If it is associated with SN 1998bw, this is the first detection of hard X-ray emission from a Type I supernova. The latter source exhibits only marginally significant variability. Based on these data, it is not possible to select either source as a firm candidate for the GRB counterpart.Comment: 2 pages, 1 PostScript figure, submitted to A&AS, Proc. of the Conference "Gamma-Ray Bursts in the Afterglow Era", held in Rome, 1998 November 3-6. Results concerning 'Source 2' have been update

On-ground performance tests of the SAX/PDS detector

The Phoswich Detection System (PDS) is one of the four narrow field experiments on board the SAX satellite. The PDS will be dedicated to deep temporal and spectral studies of celestial X-ray sources in the 15–300 keV energy band. It also includes a gamma-ray burst monitor. The PDS detector is composed of 4 actively shielded NaI(Tl)/CsI(Na) phoswich scintillators with a total geometric area of 795 cm2 and a field of view of 1:4 (FWHM). The performance of the detector, before its integration with its flight electronic, was tested using standard instrumentation. Here we present results of these tests. The measured energy resolution of the phoswich units is better than 15% at 60 keV, confirming the expectations. Also test results of the anticoincidence shield of CsI(Na) and collimator are discussed

The very red afterglow of GRB 000418 - further evidence for dust extinction in a GRB host galaxy

We report near-infrared and optical follow-up observations of the afterglow of the Gamma-Ray Burst 000418 starting 2.5 days after the occurrence of the burst and extending over nearly seven weeks. GRB 000418 represents the second case for which the afterglow was initially identified by observations in the near-infrared. During the first 10 days its R-band afterglow was well characterized by a single power-law decay with a slope of 0.86. However, at later times the temporal evolution of the afterglow flattens with respect to a simple power-law decay. Attributing this to an underlying host galaxy we find its magnitude to be R=23.9 and an intrinsic afterglow decay slope of 1.22. The afterglow was very red with R-K=4 mag. The observations can be explained by an adiabatic, spherical fireball solution and a heavy reddening due to dust extinction in the host galaxy. This supports the picture that (long) bursts are associated with events in star-forming regions.Comment: Accepted for publication in The Astrophysical Journal. 12 pages; citations & references updated; minor textual change