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During the 2018 proton run, a new radio-frequency beam manipulation has been studied and successfully implemented at the CERN Proton Synchrotron (PS) for the first time. This technique is used to deplete a well-defined fraction of a continuous longitudinal beam distribution by creating a so-called barrier bucket. We propose a new application of the barrier bucket gymnastics in the multiturn extraction scheme used at CERN. These two exotic techniques are combined into a highly sophisticated procedure that dramatically reduces the beam losses at PS extraction, thus paving the way to high-intensity proton beams for future fixed-target experiments at the CERN Super Proton Synchrotron (SPS). In this paper, the expected performance of the PS and SPS is analyzed in detail to define a road map for making this novel extraction scheme operational.

A barrier bucket scheme is being considered to reduce losses during the Multi-Turn Extraction from the CERN Proton Synchrotron to the Super Proton Synchrotron for the fixed- target physics programme. For effective loss reduction, the extraction kicker has to be triggered during the gap at the time of the longitudinal barrier. Initial beam studies at injection energy and with low intensity beams allowed to fully qualify an existing wide-band cavity to generate one or multiple beam synchronous pulses per turn. Bunch-length stretching and shortening have been exercised with barriers moving in azimuth with respect to the beam. The encouraging results obtained at injection energy guided the implementation of a de-bunching manipulation at higher energy to move all bunches into a single barrier bucket. Beam measurements at a momentum of 14GeV/c, varying intensity and the width of the barrier, demonstrate that a quasi-constant longitudinal line density and an almost fully depleted gap can be achieved at highest intensities. The contribution summarises the results of the beam studies at high energy together with some observations related to the Multi-Turn Extraction.

For the future intensity increase of the fixed-target beams in the CERN accelerator complex, a barrier-bucket scheme has been developed to reduce the beam loss during the 5-turn extraction from the PS towards the SPS, the so-called Multi-Turn Extraction. The low-level RF system must synchronise the barrier phase with the PS extraction and SPS injection kickers to minimise the number of particles lost during the rise times of their fields. As the RF voltage of the wide-band cavity generating the barrier bucket would be too low for a conventional synchronisation, a combination of a feedforward cogging manipulation and the real-time control of the barrier phase has been developed and tested. A deterministic frequency bump has been added to compensate for the imperfect circumference ratio between PS and SPS. This contribution presents the concept and implementation of the synchronised barrier-bucket transfer. Measurements with high-intensity beam demonstrate the feasibility of the proposed transfer scheme.

The cure of micrometastases following surgery is the major goal of cancer immunotherapy. We have recently isolated tumour-associated antigen (TAA) peptides, MUT 1 and MUT 2, derived from a mutated connexin 37 gap-junction protein, from the malignant 3LL-D122 murine lung carcinoma. We now report that synthetic MUT 1 or MUT 2 induces effective antitumour cytoxic T lymphocytes. Peptide vaccines protect mice from spontaneous metastases of 3LL-D122 tumours. Moreover, peptide vaccines reduce metastatic loads in mice carrying pre-established micrometastases. Tumour-specific immunity was primarily mediated by CD8 + T cells. This is the first evidence that peptide therapy may be effective in treatment of residual tumours and provides a rationale for the development of peptide vaccines as a modality for cancer therapy.

D b−/− x β 2 microglobulin ( β 2m) null mice transgenic for a chimeric HLA-A2.1/D b - β 2m single chain (HHD mice) are an effective biological tool to evaluate the antitumour cytotoxic T-lymphocyte response of known major histocompatibility-restricted peptide tumour-associated antigens, and to screen for putative unknown novel peptides. We utilised HHD lymphocytes to identify immunodominant epitopes of colon carcinoma overexpressed genes. We screened with HHD-derived lymphocytes over 500 HLA-A2.1-restricted peptides derived from colon carcinoma overexpressed genes. This procedure culminated in the identification of seven immunogenic peptides, three of these were derived from the ‘human 1-8D gene from interferon inducible gene’ ( 1-8D ). The 1-8D gene was shown to be overexpressed in fresh tumour samples. The three 1-8D peptides were both antigenic and immunogenic in the HHD mice. The peptides induce cytotoxic T lymphocytes that were able to kill a colon carcinoma cell line HCT/HHD, in vitro and retard its growth in vivo . One of the peptides shared by all the 1-8 gene family primed efficiently normal human cytotoxic T lymphocyte precursors. These results highlight the 1-8D gene and its homologues as putative immunodominant tumour-associated antigens of colon carcinoma.

Development of cytokine gene-modified autologous tumor vaccines must take into account the strictly paracrine physiology of cytokines whose expression at the tumor microenvironment is important for the successful induction of tumor-specific immunity. In this study, we investigated the efficacy of a tumor vaccine composed of inactivated autologous cells transfected with two plasmid vectors encoding a mutant membranebound murine granulocyte-macrophage colony-stimulating factor (MuGM-CSF) and murine interferon-gamma (MuIFN-gamma). Expression of both cytokines as cell surface ligands on the highly metastatic D122 clone of Lewis lung carcinoma led to abrogation of their tumorigenicity and metastatic phenotype. More importantly, vaccination with irradiated tumor cells expressing the membrane-bound GM-CSF and IFN-gamma induced a cytotoxic T lymphocyte (CTL) response that protected syngeneic mice against a subsequent challenge with D122 cells as a primary tumor in preimmunized mice as well as against lung metastasis developing after surgical removal of the primary tumor in naive mice. Autologous cells expressing the membrane-bound GM-CSF and IFN-gamma exhibited comparable efficacy as an antimetastatic vaccine to a vaccine composed of transfectants expressing wild-type secreted cytokine molecules. These results indicate that membrane-bound cytokines can cause enhanced immunogenicity when transfected into tumor cells for the induction of antitumor immunity.

Functional PDGFα receptors are selectively expressed on highly lung-metastasizing clones of the 3LL Lewis lung carcinoma, but not on low-mestastatic clones. The highly metastatic clones are also growth induced in vitro by PDGF and lung conditioned medium. To investigate whether modification of PDGFα receptor expression or function can affect metastatic capability, we transfected cells of a low-metastatic 3LL clone with a full length PDGFα receptor gene and cells of a highly-metastatic clone with a truncated kinase domain PDGFα receptor gene. Introduction of the full length PDGFα receptor conferred upon low-metastatic cells the ability to grow in vitro in the presence of PDGF-AA and to colonize the lung in experimental and spontaneous metastases assays. Conversely, introduction of a truncated version of the PDGFα receptor into highly metastatic cells reduced their metastatic load to control levels. Accordingly, their responses to PDGF-AA, including growth stimulation and receptor autophosphorylation, were reduced. These results demonstrate that PDGFα receptor expression and function can control the capacity of tumor cells to generate metastases in the lung. The response of this receptor to lung-derived PDGF-like factors may define a paracrine mode of metastatic cell growth in the target organ.

Interleukin 12 (IL-12) is a disulfide-linked heterodimer molecule produced predominantly by professional antigen presenting cells. It promotes the induction of sundry biological effects with significant relevance to antitumor immunity, such as enhancing a T(H)1 helper response, an in vivo antiangiogenic effect, induction of adhesion molecules that assist in lymphocyte homing to sites of tumor growth, and a direct stimulatory effect on both T-cells and NK cells. We tested the efficacy of an antimetastatic vaccine composed of autologous murine D122 cells transfected with both subunits of IL-12 cDNA to express biologically-active IL-12 molecule. Expression of IL-12 by D122 cells significantly reduced their tumorigenicity and metastatic potential in immunocompetent syngeneic hosts. Furthermore, vaccination of mice with 2 x 10(6) irradiated IL-12-transfected D122 cells engendered a protective CTL response which rejected a subsequent challenge with parental D122 cells and eradicated lung micrometastasis in animals whose primary tumors have been surgically removed. The antitumor effects of IL-12 were mediated primarily by its ability to induce gammaIFN expression in vivo. CD8+ T-cells as well as NK cells were crucial in the execution of the antitumor effects of IL-12. These results suggest that autologous tumor cells expressing IL-12 by gene transfer are a potent antitumor vaccine able to induce a systemic immune response against poorly immunogenic and spontaneously metastatic tumors.

Functional PDGFalpha receptors are selectively expressed on highly lung-metastasizing clones of the 3LL Lewis lung carcinoma, but not on low-mestastatic clones. The highly metastatic clones are also growth induced in vitro by PDGF and lung conditioned medium. To investigate whether modification of PDGFalpha receptor expression or function can affect metastatic capability, we transfected cells of a low-metastatic 3LL clone with a full length PDGFalpha receptor gene and cells of a highly-metastatic clone with a truncated kinase domain PDGFalpha receptor gene. Introduction of the full length PDGFalpha receptor conferred upon low-metastatic cells the ability to grow in vitro in the presence of PDGF-AA and to colonize the lung in experimental and spontaneous metastases assays. Conversely, introduction of a truncated version of the PDGFalpha receptor into highly metastatic cells reduced their metastatic load to control levels. Accordingly, their responses to PDGF-AA, including growth stimulation and receptor autophosphorylation, were reduced. These results demonstrate that PDGFalpha receptor expression and function can control the capacity of tumor cells to generate metastases in the lung. The response of this receptor to lung-derived PDGF-like factors may define a paracrine mode of metastatic cell growth in the target organ.