How can Cytokine-induced killer cells overcome CAR-T cell limits

The successful treatment of patients affected by B-cell malignancies with Chimeric Antigen Receptor (CAR)-T cells represented a breakthrough in the field of adoptive cell therapy (ACT). However, CAR-T therapy is not an option for every patient, and several needs remain unmet. In particular, the production of CAR-T cells is expensive, labor-intensive and logistically challenging; additionally, the toxicities deriving from CAR-T cells infusion, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), have been documented extensively. Alternative cellular therapy products such as Cytokine-induced killer (CIK) cells have the potential to overcome some of these obstacles. CIK cells are a heterogeneous population of polyclonal CD3+CD56+ T cells with phenotypic and functional properties of NK cells. CIK cell cytotoxicity is exerted in a major histocompatibility complex (MHC)-unrestricted manner through the engagement of natural killer group 2 member D (NKG2D) molecules, against a wide range of hematological and solid tumors without the need for prior antigen exposure or priming. The foremost potential of CIK cells lies in the very limited ability to induce graft-versus-host disease (GvHD) reactions in the allogeneic setting. CIK cells are produced with a simple and extremely efficient expansion protocol, which leads to a massive expansion of effector cells and requires a lower financial commitment compared to CAR-T cells. Indeed, CAR-T manufacturing involves the engineering with expensive GMP-grade viral vectors in centralized manufacturing facilities, whereas CIK cell production is successfully performed in local academic GMP facilities, and CIK cell treatment is now licensed in many countries. Moreover, the toxicities observed for CAR-T cells are not present in CIK cell-treated patients, thus further reducing the costs associated with hospitalization and post-infusion monitoring of patients, and ultimately encouraging the delivery of cell therapies in the outpatient setting. This review aims to give an overview of the limitations of CAR-T cell therapy and outline how the use of CIK cells could overcome such drawbacks thanks to their unique features. We highlight the undeniable advantages of using CIK cells as a therapeutic product, underlying the opportunity for further research on the topic

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe

Tubular Epithelial NF-κB Activity Regulates Ischemic AKI

NF-κB is a key regulator of innate and adaptive immunity and is implicated in the pathogenesis of AKI. The cell type–specific functions of NF-κB in the kidney are unknown; however, the pathway serves distinct functions in immune and tissue parenchymal cells. We analyzed tubular epithelial-specific NF-κB signaling in a mouse model of ischemia-reperfusion injury (IRI)–induced AKI. NF-κB reporter activity and nuclear localization of phosphorylated NF-κB subunit p65 analyses in mice revealed that IRI induced widespread NF-κB activation in renal tubular epithelia and in interstitial cells that peaked 2–3 days after injury. To genetically antagonize tubular epithelial NF-κB activity, we generated mice expressing the human NF-κB super-repressor IκBαΔN in renal proximal, distal, and collecting duct epithelial cells. Compared with control mice, these mice exhibited improved renal function, reduced tubular apoptosis, and attenuated neutrophil and macrophage infiltration after IRI-induced AKI. Furthermore, tubular NF-κB–dependent gene expression profiles revealed temporally distinct functional gene clusters for apoptosis, chemotaxis, and morphogenesis. Primary proximal tubular cells isolated from IκBαΔN-expressing mice and exposed to hypoxia-mimetic agent cobalt chloride exhibited less apoptosis and expressed lower levels of chemokines than cells from control mice did. Our results indicate that postischemic NF-κB activation in renal tubular epithelia aggravates tubular injury and exacerbates a maladaptive inflammatory response

Measuring KS0^0_{\rm S}K±^{\rm \pm} interactions using Pb-Pb collisions at sNN=2.76{\sqrt{s_{\rm NN}}=2.76} TeV

We present the first ever measurements of femtoscopic correlations between the KS0 and K ± particles. The analysis was performed on the data from Pb–Pb collisions at sNN=2.76 TeV measured by the ALICE experiment. The observed femtoscopic correlations are consistent with final-state interactions proceeding via the a0(980) resonance. The extracted kaon source radius and correlation strength parameters for KS0K− are found to be equal within the experimental uncertainties to those for KS0K+ . Comparing the results of the present study with those from published identical-kaon femtoscopic studies by ALICE, mass and coupling parameters for the a0 resonance are tested. Our results are also compatible with the interpretation of the a0 having a tetraquark structure instead of that of a diquark

Anomalous evolution of the near-side jet peak shape in Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

The measurement of two-particle angular correlations is a powerful tool to study jet quenching in a pT region inaccessible by direct jet identification. In these measurements pseudorapidity (Δη) and azimuthal (Δφ) differences are used to extract the shape of the near-side peak formed by particles associated with a higher pT trigger particle (1<pT,trig<8 GeV/c). A combined fit of the near-side peak and long-range correlations is applied to the data allowing the extraction of the centrality evolution of the peak shape in Pb-Pb collisions at sNN=2.76 TeV. A significant broadening of the peak in the Δη direction at low pT is found from peripheral to central collisions, which vanishes above 4 GeV/c, while in the Δφ direction the peak is almost independent of centrality. For the 10% most central collisions and 1<pT,assoc<2 GeV/c, 1<pT,trig<3 GeV/c a novel feature is observed: a depletion develops around the center of the peak. The results are compared to pp collisions at the same center of mass energy and ampt model simulations. The comparison to the investigated models suggests that the broadening and the development of the depletion is connected to the strength of radial and longitudinal flow

Evolution of the longitudinal and azimuthal structure of the near-side jet peak in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}} = 2.76 TeV

In two-particle angular correlation measurements, jets give rise to a near-side peak, formed by particles associated to a higher-pT trigger particle. Measurements of these correlations as a function of pseudorapidity (Δη) and azimuthal (Δφ) differences are used to extract the centrality and pT dependence of the shape of the near-side peak in the pT range 1<pT<8 GeV/c in Pb-Pb and pp collisions at sNN = 2.76 TeV. A combined fit of the near-side peak and long-range correlations is applied to the data and the peak shape is quantified by the variance of the distributions. While the width of the peak in the Δφ direction is almost independent of centrality, a significant broadening in the Δη direction is found from peripheral to central collisions. This feature is prominent for the low-pT region and vanishes above 4 GeV/c. The widths measured in peripheral collisions are equal to those in pp collisions in the Δφ direction and above 3 GeV/c in the Δη direction. Furthermore, for the 10% most central collisions and 1<pT,assoc< 2 GeV/c, 1<pT,trig< 3 GeV/c, a departure from a Gaussian shape is found: a depletion develops around the center of the peak. The results are compared to A Multi-Phase Transport (AMPT) model simulation as well as other theoretical calculations indicating that the broadening and the development of the depletion are connected to the strength of radial and longitudinal flow

Measurement of electrons from beauty-hadron decays in p-Pb collisions at sNN=5.02 \sqrt{s_{\mathrm{NN}}}=5.02 TeV and Pb-Pb collisions at sNN=2.76 \sqrt{s_{\mathrm{NN}}}=2.76 TeV

The production of beauty hadrons was measured via semi-leptonic decays at mid-rapidity with the ALICE detector at the LHC in the transverse momentum interval 1<p$_{T}$ < 8 GeV/c in minimum-bias p-Pb collisions at $\sqrt{s_{\mathrm{NN}}}=5.02$ TeV and in 1.3 < p$_{T}$ < 8 GeV/c in the 20% most central Pb-Pb collisions at $\sqrt{s_{\mathrm{NN}}}=2.76$ TeV. The pp reference spectra at $\sqrt{s_{\mathrm{NN}}}=5.02$ TeV and $\sqrt{s}=2.76$ TeV, needed for the calculation of the nuclear modification factors R$_{pPb}$ and R$_{PbPb}$, were obtained by a pQCD-driven scaling of the cross section of electrons from beauty-hadron decays measured at $\sqrt{s}=7$ TeV. In the p$_{T}$ interval 3 < p$_{T}$ < 8 GeV/c, a suppression of the yield of electrons from beauty-hadron decays is observed in Pb-Pb compared to pp collisions. Towards lower p$_{T}$, the R$_{PbPb}$ values increase with large systematic uncertainties. The R$_{pPb}$ is consistent with unity within systematic uncertainties and is well described by theoretical calculations that include cold nuclear matter effects in p-Pb collisions. The measured R$_{pPb}$ and these calculations indicate that cold nuclear matter effects are small at high transverse momentum also in Pb-Pb collisions. Therefore, the observed reduction of R$_{PbPb}$ below unity at high p$_{T}$ may be ascribed to an effect of the hot and dense medium formed in Pb-Pb collisions