Therapeutics to harness the immune microenvironment in multiple myeloma

Multiple myeloma (MM) remains an incurable, genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow (BM) microenvironment. Current therapies leverage the unique biology of MM cells and target the immune microenvironment that drives tumor growth and facilitates immune evasion. Proteasome inhibitors and immunomodulatory drugs were initially introduced to complement and have now supplanted cytotoxic chemotherapy as frontline anti-myeloma agents. Recently, monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor T cells were developed to revamp the immune system to overcome immune suppression and improve patient responses. While current MM therapies have markedly extended patient survival, acquired drug resistance inevitably emerges and drives disease progression. The logical progression for the next generation of MM therapies would be to design and validate agents that prevent and/or overcome acquired resistance to immunotherapies. The complex BM microenvironment promotes resistance to both current anti-myeloma agents and emerging immunotherapies. Myeloma cells are intertwined with a complex BM immune microenvironment that contributes to the development of adaptive drug resistance. Here, we describe recently FDA-approved and investigational anti-myeloma agents that directly or indirectly target the BM microenvironment to prevent or overcome drug resistance. Synergistic effects of anti-myeloma agents may foster the development of rationally-designed drug cocktails that prevent BM-mediated resistance to immunotherapies

Interleukin-12 Is the Optimum Cytokine To Expand Human Th17 Cells In Vitro▿

Recently, a new lineage of CD4+ T cells in humans and in mice has been reported. This T helper cell secretes interleukin-17 (IL-17) and has been defined as T helper 17 (Th17). Th17 cells express the IL-23 receptor (IL-23R) and play an important pathogenic role in different inflammatory conditions. In this study, our aim was to characterize the optimum conditions for isolation and propagation of human peripheral blood Th17 cells in vitro and the optimum conditions for isolation of Th17 clones. To isolate Th17 cells, two steps were taken. Initially, we negatively isolated CD4+ T cells from peripheral blood mononuclear cells of a normal human blood donor. Then, we isolated the IL-23R+ cells from the CD4+ T cells. Functional studies revealed that CD4+ IL-23R+ cells could be stimulated ex vivo with anti-CD3/CD28 to secrete both IL-17 and gamma interferon (IFN-γ). Furthermore, we expanded the CD4+ IL-23R+ cells for 1 week in the presence of anti-CD3/CD28, irradiated autologous feeder cells, and different cytokines. Our data indicate that cytokine treatment increased the number of propagated cells 14- to 99-fold. Functional evaluation of the expanded number of CD4+ IL-23R+ cells in the presence of different cytokines with anti-CD3/CD28 revealed that all cytokines used (IL-2, IL-7, IL-12, IL-15, and IL-23) increased the amount of IFN-γ secreted by IL-23R+ CD4+ cells at different levels. Our results indicate that IL-7 plus IL-12 was the optimum combination of cytokines for the expansion of IL-23R+ CD4+ cells and the secretion of IFN-γ, while IL-12 preferentially stimulated these cells to secrete predominately IL-17

Targeting Proteasomes and the MHC Class I Antigen Presentation Machinery to Treat Cancer, Infections and Age-Related Diseases

The majority of T-cell responses involve proteasome-dependent protein degradation and the downstream presentation of oligopeptide products complexed with major histocompatibility complex (MHC) class I (MHC-I) molecules to peptide-restricted CD8+ T-cells. However, evasion of host immunity is a cancer hallmark that is achieved by disruption of host antigen processing and presentation machinery (APM). Consequently, mechanisms of immune evasion promote cancer growth and survival as well as de novo and acquired resistance to immunotherapy. A multitude of cell signaling pathways modulate the APM and MHC-I-dependent antigen presentation. Pharmacologics that specifically target and modulate proteasome structure and activity represent a novel emerging strategy to improve the treatment of cancers and other diseases characterized by aberrant protein accumulation. FDA-approved pharmacologics that selectively activate proteasomes and/or immunoproteasomes can be repositioned to overcome the current bottlenecks that hinder drug development to enhance antigen presentation, modulate the immunopeptidome, and enhance the cytotoxic activity of endogenous or engineered T-cells. Strategies to enhance antigen presentation may also improve the antitumor activity of T-cell immunotherapies, checkpoint inhibitors, and cancer vaccines. Proteasomes represent actionable therapeutic targets to treat difficult-to-treat infectious processes and neurodegenerative diseases that are characterized by the unwanted accrual of insoluble, deleterious, and potentially toxic proteins. Taken together, we highlight the breadth and magnitude of the proteasome and the immense potential to amplify and unmask the immunopeptidomic landscape to improve the treatment of a spectrum of human diseases

Chemical additives migration in rubber

Migration of compounding ingredients is an important factor in the overall properties and performance of rubber articles containing a number of layers for example, a tire, a hose or a conveyor belt. In certain cases, migration of compounding ingredients before, during and after vulcanization in rubber compounds can be of benefit. For example, waxes and p-phenylenediamines antiozonants rely heavily on the migration mechanism to provide optimum protection of rubber products during service against degradation by ozone. In addition, the dispersion of compounding ingredients such as oil, curatives, and antidegradants can be enhanced by diffusion within rubber. In other cases, however, diffusion across a rubber-to-rubber interface can be detrimental to performance. Diffusion will change the distribution of materials which in turn may result in changes in mechanical properties, loss in adhesion or antidegradant protection, and staining of light-colored products. Thus, a better understanding of the migration of chemical additives in rubber could provide the desired distribution of ingredients for obtaining the optimum compound performance

Studies on ethylene-propylene-diene rubber modification by N-chlorothio-N-butyl-benzenesulfonamide

N-Chlorothiosulfonamides have been used to modify ethylene-propylene-diene rubber (EPDM) to enhance the compatibility of EPDM in, e.g., natural rubber (NR)/butadiene rubber (BR)/EPDM blends for ozone resistance. N-Chlorothio-N-butyl-benzenesulfonamide (CTBBS) was selected as a representative for N-chlorothiosulfonamides. In this study, we found that CTBBS behaves differently with various types of EPDM. Three types of EPDM were selected: ethylidene norbornene (ENB)-EPDM, hexadiene (HD)-EPDM, and dicyclopentadiene (DCPD)-EPDM. HD-EPDM showed the greatest effectiveness toward CTBBS-modification. However, this EPDM is not commercially available anymore. On the opposite side, DCPD-EPDM showed the lowest reactivity so that almost no modification could be realized. The result with ENB-EPDM was, that upon application of CTBBS to ENB-EPDM, gelation occurred and, therefore, a low amount of modification was achieved. With the limited modification efficiency for ENB-EPDM, there is no significant improvement when applying the modified ENB-EPDM into NR/BR/EPDM blends