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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2014)

Targeted therapies like vemurafenib and dabrafenib that block oncogenic BRAF result in high response rates and improved overall survival in patients with melanoma. However, the response has limited durability and most tumors relapse. On the contrary, immunotherapy for melanoma results in low response rates that tend to be extremely durable. We hypothesized that combining immunotherapy with BRAF inhibitors and other targeted therapies being developed for melanoma may improve the anti-tumor effects by combining the benefits of both modes of therapy. To test this hypothesis, we developed a BRAFV600E-driven murine model of melanoma, SM1, that is syngeneic to immunocompetent mice. Combined treatment of vemurafenib plus adoptive cell transfer (ACT) immunotherapy demonstrated superior anti-tumor effect compared with single treatments alone in SM1. However, SM1 is an aggressive model in which the tumor bearing mice have to be sacrificed within two to three weeks, and this combination therapy did not lead to sustained tumor responses. We noticed that SM1 secreted colony stimulating factor-1 (CSF-1) that recruits immune suppressive tumor infiltrating myeloid cells (TIMs) including macrophages and myeloid derived suppressor cells (MDSC). We hypothesized that blocking CSF-1 receptor (CSF-1R) with a small molecule tyrosine kinase inhibitors such as PLX3397, as it would inhibit immune suppressive TIMs and synergize with immunotherapy. Combination of PLX3397 and ACT induced superior anti-tumor effect and PLX3397 increased number of tumor infiltrating lymphocytes (TILs) and IFN-gamma; production in T-cells by depleting TIMs. Based on the results of these two studies, we then combined PLX3397 and vemurafenib in the SM1 model and the combination mediated superior anti-tumor response. The macrophage inhibitory effects of PLX3397 treatment and paradoxical activation of immune cells with wild type BRAF mediated by vemurafenib resulted in more TILs with increased IFN-γ production. Taken together, we provide support for the testing of immunotherapy, BRAF, and CSF-1R inhibitors combinations in patients with BRAFV600 mutant metastatic melanoma.

    Cover page: Combination Treatment for Melanoma
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2001)
    Natural killer T (NKT) cells are a highly conserved subset of T cells that have been shown to play a critical role in suppressing T helper cell type 1-mediated autoimmune diseases and graft versus host disease in an interleukin (IL)-4-dependent manner. Thus, it is important to understand how the development of IL-4- versus interferon (IFN)-gamma-producing NKT cells is regulated. Here, we show that NKT cells from adult blood and those from cord blood undergo massive expansion in cell numbers (500-70,000-fold) during a 4-wk culture with IL-2, IL-7, phytohemagglutinin, anti-CD3, and anti-CD28 mAbs. Unlike adult NKT cells that preferentially produce both IL-4 and IFN-gamma, neonatal NKT cells preferentially produce IL-4 after polyclonal activation. Addition of type 2 dendritic cells (DC2) enhances the development of neonatal NKT cells into IL-4(+)IFN-gamma(-) NKT2 cells, whereas addition of type 1 dendritic cells (DC1) induces polarization towards IL-4(-)IFN-gamma(+) NKT1 cells. Adult NKT cells display limited plasticity for polarization induced by DC1 or DC2. Thus, newly generated NKT cells may possess the potent ability to develop into IL-4(+)IFN-gamma(-) NKT2 cells in response to appropriate stimuli and may thereafter acquire the tendency to produce both IL-4 and IFN-gamma.
      Cover page: Distinct Cytokine Profiles of Neonatal Natural Killer T Cells after Expansion with Subsets of Dendritic Cells
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2020)
      Bryostatin 1 is a marine natural product under investigation for HIV/AIDS eradication, the treatment of neurological disorders, and enhanced CAR T/NK cell immunotherapy. Despite its promising activity, bryostatin 1 is neither evolved nor optimized for the treatment of human disease. Here we report the design, synthesis, and biological evaluation of several close-in analogs of bryostatin 1. Using a function-oriented synthesis approach, we synthesize a series of bryostatin analogs designed to maintain affinity for bryostatin's target protein kinase C (PKC) while enabling exploration of their divergent biological functions. Our late-stage diversification strategy provides efficient access to a library of bryostatin analogs, which per our design retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently increase cell surface expression of CD22, a promising CAR T cell target for the treatment of leukemias, highlighting the clinical potential of bryostatin analogs for enhancing targeted immunotherapies.
        Cover page: Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2018)
        HIV latency in resting CD4+ T cell represents a key barrier preventing cure of the infection with antiretroviral drugs alone. Latency reversing agents (LRAs) can activate HIV expression in latently infected cells, potentially leading to their elimination through virus-mediated cytopathic effects, host immune responses, and/or therapeutic strategies targeting cells actively expressing virus. We have recently described several structurally simplified analogs of the PKC modulator LRA bryostatin (termed bryologs) designed to improve synthetic accessibility, tolerability in vivo, and efficacy in inducing HIV latency reversal. Here we report the comparative performance of lead bryologs, including their effects in reducing cell surface expression of HIV entry receptors, inducing proinflammatory cytokines, inhibiting short-term HIV replication, and synergizing with histone deacetylase inhibitors to reverse HIV latency. These data provide unique insights into structure-function relationships between A- and B-ring bryolog modifications and activities in primary cells, and suggest that bryologs represent promising leads for preclinical advancement.
          Cover page: Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents
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