We identified B cell maturation antigen (BCMA) as a potential therapeutic target in 778 newly diagnosed and relapsed myeloma patients. We constructed an IgG-based BCMA-T cell bispecific antibody (EM801) and showed that it increased CD3 T cell/myeloma cell crosslinking, followed by CD4/CD8 T cell activation, and secretion of interferon-γ, granzyme B, and perforin. This effect is CD4 and CD8 T cell mediated. EM801 induced, at nanomolar concentrations, myeloma cell death by autologous T cells in 34 of 43 bone marrow aspirates, including those from high-risk patients and patients after multiple lines of treatment, tumor regression in six of nine mice in a myeloma xenograft model, and depletion of BCMA cells in cynomolgus monkeys. Pharmacokinetics and pharmacodynamics indicate weekly intravenous/subcutaneous administration.

The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n = 20) that the CD19 − CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19 − CD81+ and CD19 − CD81 − BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19 − CD81 −) clones, 38% intermediate- Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts differentiated (CD19 − CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P = 0.005) and overall survival (HR: 2.1; P = 0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n = 40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.

Recipients of liver transplantation (LT) may develop immunological tolerance. Factors predictive of tolerance are not clearly understood. Transplant recipients with normal liver function tests and without active viral hepatitis or autoimmune disease who presented with side effects of immunosuppression or a high risk of de novo malignancies were selected to participate in this prospective study. Twenty-four patients fulfilled the inclusion criteria and, therefore, underwent a gradual reduction of immunosuppression. Tolerance was defined as normal liver function tests after immunosuppression withdrawal. Basal clinical and immunological characteristics, including lymphocyte counts and subpopulations (T, B, natural killer, CD4 1 , CD8 1 , and regulatory T cells) and the phytohemagglutinin stimulation index (SI), were compared for tolerant and nontolerant patients. Fifteen of the 24 patients (62.5%) were tolerant at a median of 14 months (interquartile range 5 8.5-22.5 months) after complete immunosuppression withdrawal. Tolerant patients had a longer median interval between transplantation and inclusion in the study (156 for tolerant patients versus 71 months for nontolerant patients, P 5 0.003) and a lower median SI (7.49 for tolerant patients versus 41.73 for nontolerant patients, P 5 0.01). We identified 3 groups of patients with different probabilities of tolerance: in the first group (n 5 7 for an interval > 10 years and an SI < 20), 100% reached tolerance; in the second group (n 5 10 for an interval > 10 years and an SI > 20 or an interval < 10 years and an SI < 20), 60% reached tolerance; and in the third group (n 5 7 for an interval < 10 years and an SI > 20), 29% reached tolerance. In conclusion, a high proportion of select LT recipients can reach tolerance over the long term. Two simple basal variables-the time from transplantation and the SI-may help to identify these patients. Liver Transpl 19:937-944, 2013. V C 2013 AASLD. Received February 25, 2013 accepted May 19, 2013. Although the survival of liver transplantation (LT) patients has improved since the early 1980s with refinements in immunosuppression therapy and surgical techniques, the morbidity and mortality rates of these patients are still greater than those of the general population. 1,2 The quality of life and survival are still diminished in comparison with those of ageand sex-matched controls. 3,4 As long-term survival after transplantation has improved, side effects See Editorial on Page 933

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In this paper we describe JCLEC, a Java software system for the development of evolutionary computation applications. This system has been designed as a framework, applying design patterns to maximize its reusability and adaptability to new paradigms with a minimum of programming effort. JCLEC architecture comprises three main modules: the core contains all abstract type definitions and their implementation; experiments runner is a scripting environment to run algorithms in batch mode; finally, GenLab is a graphical user interface that allows users to configure an algorithm, to execute it interactively and to visualize the results obtained. The use of JCLEC system is illustrated though the analysis of one case study: the resolution of the 0/1 knapsack problem by means of evolutionary algorithms.