Adoptive T-cell immunotherapy of chronic lymphocytic leukaemia

Immunotherapy for B-cell chronic lymphocytic leukaemia (B-CLL) and other haematological malignancies may consist of passive antibody, active immunization or adoptive T-cell transfer. This chapter will focus on T-lymphocyte immunotherapy; an approach supported by earlier observations that the beneficial effects of allogeneic stem cell transplantation depend, in part, on the graft-versus-leukaemia effects mediated by these cells. One promising strategy consists of the genetic manipulation of effector T lymphocytes to express tumour-specific T-cell receptors or chimeric antigen receptors directed against surface antigens on the B-CLL cells. This methodology is now being integrated with the concept that tumour recurrence may be due to the persistence of a reservoir of more primitive and chemoresistant tumour cells, dubbed 'cancer stem cells', with self-renewal capacity. Identification and characterization of these cancer stem cells in B-CLL is crucial for the development of new anti-tumour agents, and for the identification of target antigens for cellular immunotherapy. This chapter will describe how immunotherapy may be directed to a more primitive side population of B-CLL cells

Investigations of the pi N total cross sections at high energies using new FESR: log nu or (log nu)^2

We propose to use rich informations on pi p total cross sections below N= 10 GeV in addition to high-energy data in order to discriminate whether these cross sections increase like log nu or (log nu)^2 at high energies, since it is difficult to discriminate between asymptotic log nu and (log nu)^2 fits from high-energy data alone. A finite-energy sum rule (FESR) which is derived in the spirit of the P' sum rule as well as the n=1 moment FESR have been required to constrain the high-energy parameters. We then searched for the best fit of pi p total cross sections above 70 GeV in terms of high-energy parameters constrained by these two FESR. We can show from this analysis that the (log nu)^2 behaviours is preferred to the log nu behaviours.Comment: to be published in Phys. Rev. D 5 pages, 2 eps figure

Testing the Meson Cloud Model in Inclusive Meson Production

We have applied the Meson Cloud Model to calculate inclusive momentum spectra of pions and kaons produced in high energy proton-proton and proton-nucleus collisions. For the first time these data are used to constrain the cloud cut-off parameters. We show that it is possible to obtain a reasonable description of data, especially the large $x_F$ ($x_F \geq 0.2$) part of the spectrum and at the same time describe (partially) the E866 data on $\bar d - \bar u$ and $\bar d / \bar u$. We also discuss the relative strength of the $\pi N$ and $\pi \Delta$ vertices. We find out that the corresponding cut-off parameters should be both soft and should not differ by more than 200 MeV from each other. An additional source (other than the meson cloud) of sea antiquark asymmetry, seems to be necessary to completely explain the data. A first extension of the MCM to proton nucleus collisions is discussed.Comment: 14 pages, Latex, 6 ps figures. Submitted to Phys. Rev.

Validation of Multiplex Serology detecting human herpesviruses 1-5

Human herpesviruses (HHV) cause a variety of clinically relevant conditions upon primary infection of typically young and immunocompetent hosts. Both primary infection and reactivation after latency can lead to more severe disease, such as encephalitis, congenital defects and cancer. Infections with HHV are also associated with cardiovascular and neuro-degenerative disease. However, most of the associations are based on retrospective case-control analyses and well-powered prospective cohort studies are needed for assessing temporality and causality. To enable comprehensive investigations of HHV-related disease etiology in large prospective population-based cohort studies, we developed HHV Multiplex Serology. This methodology represents a low-cost, high-throughput technology that allows simultaneous measurement of specific antibodies against five HHV species: Herpes simplex viruses 1 and 2, Varicella zoster virus, Epstein-Barr virus, and Cytomegalovirus. The newly developed HHV species-specific (‘Monoplex’) assays were validated against established gold-standard reference assays. The specificity and sensitivity of the HHV species-specific Monoplex Serology assays ranged from 92.3% to 100.0% (median 97.4%) and 91.8% to 98.7% (median 96.6%), respectively. Concordance with reference assays was very high with kappa values ranging from 0.86 to 0.96 (median kappa 0.93). Multiplexing the Monoplex Serology assays resulted in no loss of performance and allows simultaneous detection of antibodies against the 5 HHV species in a high-throughput manner

Systematics of Leading Particle Production

Using a QCD inspired model developed by our group for particle production, the Interacting Gluon Model (IGM), we have made a systematic analysis of all available data on leading particle spectra. These data include diffractive collisions and photoproduction at HERA. With a small number of parameters (essentially only the non-perturbative gluon-gluon cross section and the fraction of diffractive events) good agreement with data is found. We show that the difference between pion and proton leading spectra is due to their different gluon distributions. We predict a universality in the diffractive leading particle spectra in the large momentum region, which turns out to be independent of the incident energy and of the projectile type.Comment: 13 pages, Latex, 4 ps figures. To appear in Phys. Rev.

Selective elimination of a chemoresistant side population of B-CLL cells by cytotoxic T lymphocytes in subjects receiving an autologous hCD40L/IL-2 tumor vaccine

Side-population (SP) analysis identifies precursor cells in normal and malignant tissues. Cells with this phenotype have increased resistance to many cytotoxic agents, and may represent a primary drug-resistant population in malignant diseases. To discover whether drug-resistant malignant SP cells are nonetheless sensitive to immune-mediated killing, we first established the presence of a malignant CD5+ CD19+ SP subset in the blood of 18/21 subjects with B-cell chronic lymphocytic leukemia (B-CLL). We examined the fate of these cells in six of these individuals who received autologous human CD40 ligand and interleukin-2 (hCD40L/IL-2) gene-modified tumor cells as part of a tumor vaccine study. Vaccinated patients showed an increase in B-CLL-reactive T cells followed by a corresponding decline in circulating CD5+ CD19+ SP cells. T-cell lines and clones generated from vaccinated patients specifically recognized B-CLL SP tumor cells. Elimination of SP cells is likely triggered by their increased expression of target antigens, such as receptor for hyaluronan-mediated motility (RHAMM), after stimulation of the malignant cells by hCD40L, as CD8+ RHAMM-specific T cells could be detected in the peripheral blood of immunized patients and were associated with the decline in B-CLL SP cells. Hence, malignant B cells with a primary drug-resistant phenotype can be targeted by T-cell-mediated effector activity after immunization of human subjects

Meson Cloud of the Nucleon in Polarized Semi-Inclusive Deep-Inelastic Scattering

We investigate the possibility of identifying an explicit pionic component of the nucleon through measurements of polarized $\Delta^{++}$ baryon fragments produced in deep-inelastic leptoproduction off polarized protons, which may help to identify the physical mechanism responsible for the breaking of the Gottfried sum rule. The pion-exchange model predicts highly correlated polarizations of the $\Delta^{++}$ and target proton, in marked contrast with the competing diquark fragmentation process. Measurement of asymmetries in polarized $\Lambda$ production may also reveal the presence of a kaon cloud in the nucleon.Comment: 23 pages REVTeX, 7 uuencoded figures, accepted for publication in Zeit. Phys.

Selective depletion of a minor subpopulation of B-chronic lymphocytic leukemia cells is followed by a delayed but progressive loss of bulk tumor cells and disease regression

Cancer precursor/progenitor cells may initiate and sustain the growth of tumors, but evidence for their existence in human disease is indirect, relying on their it in vitro it properties and animal models. More directly, specific elimination of these rare cells from cancer patients should produce a delayed but progressive disappearance of differentiated malignant progeny. Here, we describe selective eradication of a putative precursor population in a patient with B-cell chronic lymphocytic leukemia, followed 6 months later by a progressive loss of mature tumor cells without further treatment. This outcome supports the presence of a rare population of precursor/progenitor cells in human malignancies, and suggests benefit from their removal

Inclusive production of charged pions in p+C collisions at 158 GeV/c beam momentum

The production of charged pions in minimum bias p+C interactions is studied using a sample of 377000 inelastic events obtained with the NA49 detector at the CERN SPS at 158 GeV/c beam momentum. The data cover a phase space area ranging from 0 to 1.8 GeV/c in transverse momentum and from -0.1 to 0.5 in Feynman x. Inclusive invariant cross sections are given on a grid of 270 bins per charge thus offering for the first time a dense coverage of the projectile hemisphere and of the cross-over region into the target fragmentation zone.Comment: 31 pages, 30 figures, submitted to European Journal of Physic

Magnetoluminescence

Pulsar Wind Nebulae, Blazars, Gamma Ray Bursts and Magnetars all contain regions where the electromagnetic energy density greatly exceeds the plasma energy density. These sources exhibit dramatic flaring activity where the electromagnetic energy distributed over large volumes, appears to be converted efficiently into high energy particles and gamma-rays. We call this general process magnetoluminescence. Global requirements on the underlying, extreme particle acceleration processes are described and the likely importance of relativistic beaming in enhancing the observed radiation from a flare is emphasized. Recent research on fluid descriptions of unstable electromagnetic configurations are summarized and progress on the associated kinetic simulations that are needed to account for the acceleration and radiation is discussed. Future observational, simulation and experimental opportunities are briefly summarized.Comment: To appear in "Jets and Winds in Pulsar Wind Nebulae, Gamma-ray Bursts and Blazars: Physics of Extreme Energy Release" of the Space Science Reviews serie