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Open Access Publications from the University of California

Scholarly Works (72 results)

  • Article
  • Peer Reviewed
UCLA Previously Published Works (2016)
The immune checkpoint therapy is a relatively recent strategy that aims to tweak the immune system to effectively attack cancer cells. The understanding of the immune responses and their regulation at the intracellular level and the development of fully humanized monoclonal antibodies are the pillars of an approach that could elicit durable clinical responses and even remission in some patients with cancer. Most of the immune checkpoints that regulate the T-cell responses (activation and inhibition) operate through proteins present on the cytoplasmic membrane of the immune cells. Therefore, specific antibodies capable of blocking the inhibitory signals should lead to unrestrained immune responses that supersede the inhibitory mechanisms, which are naturally present in the tumor microenviroment. The best-known and most successful targets for immune checkpoint therapy are the cytotoxic T-lymphocyte antigen-4 and programmed cell death-1 coreceptors. Tremelimumab (CP-675,206) is a fully humanized monoclonal antibody specific for cytotoxic T-lymphocyte antigen-4, which has been successfully used to treat patients with metastatic melanoma and some other cancers. Although still a work in progress, the use of tremelimumab as an immune checkpoint therapeutic agent is a promising approach alone or in combination with other anticancer drugs. Here, we review the use of this antibody in a number of clinical trials against solid tumors.
    Cover page: Tremelimumab: research and clinical development.
    • Article
    LBL Publications (2007)
    An x-ray streak camera with high resolution in both temporal and spatial dimensions has been developed. It is achieved by using extraction-mesh acceleration and a large opening aperture magnetic solenoid lens design. High resolutions in the temporal and spatial dimensions can be retained in a wide 53 ps time window. A temporal resolution of 233 fs and a spatial resolution of 10 m have been demonstrated using an Au photocathode.
      Cover page: An x-ray streak camera with high spatio-temporal resolution
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2014)

      Background

      The clinical use of BRAF inhibitors for treatment of metastatic melanoma is limited by the development of drug resistance. In this study we investigated whether co-targeting the MAPK and the PI3K-AKT pathway can prevent emergence of resistance or provide additional growth inhibitory effects in vitro.

      Methods

      Anti-tumor effects of the combination of the BRAF inhibitor (BRAFi) dabrafenib and GSK2141795B (AKTi) in a panel of 23 BRAF mutated melanoma cell lines were evaluated on growth inhibition by an ATP-based luminescent assay, on cell cycle and apoptosis by flow cytometry and on cell signaling by western blot. Moreover, we investigated the possibilities of delaying or reversing resistance or achieving further growth inhibition by combining AKTi with dabrafenib and/or the MEK inhibitor (MEKi) trametinib by using long term cultures.

      Results

      More than 40% of the cell lines, including PTEN-/- and AKT mutants showed sensitivity to AKTi (IC50 < 1.5 μM). The combination of dabrafenib and AKTi synergistically potentiated growth inhibition in the majority of cell lines with IC50 > 5 nM dabrafenib. Combinatorial treatment induced apoptosis only in cell lines sensitive to AKTi. In long term cultures of a PTEN-/- cell line, combinatorial treatment with the MAPK inhibitors, dabrafenib and trametinib, and AKTi markedly delayed the emergence of drug resistance. Moreover, combining AKTi with the MAPK inhibitors from the beginning provided superior growth inhibitory effects compared to addition of AKTi upon development of resistance to MAPK inhibitors in this particular cell line.

      Conclusions

      AKTi combined with BRAFi-based therapy may benefit patients with tumors harboring BRAF mutations and particularly PTEN deletions or AKT mutations.
        Cover page: Effects of AKT inhibitor therapy in response and resistance to BRAF inhibition in melanoma
        • Article
        Lawrence Berkeley National Laboratory (2005)

        The spin dynamics of ferromagnetic thin films following an excitation by ultrashort 100-fs near-infrared laser pulses has recently received much attention. Here, a new approach is described using x-ray magnetic circular dichroism to investigated emagnetization and magnetization switching processes. In contrast to magneto-optical measurements, x-ray dichroism has the advantage of determining separately the spin and orbital components of the magnetic moment. The relatively low time resolution of the synchrotron x-ray probe pulses (80 ps FWHM) is overcome by employing an ultrafast x-ray streak camera with a time resolution of <1 ps. A description of the experimental setup including the x-ray/IR laser pulse synchronization and the streak camera is given.

          Cover page: Ultrafast magnetization dynamics studies using an x-ray streak camera
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2016)
          The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAF (V600E) mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma. With our mouse model of syngeneic BRAF (V600E) driven melanoma (SM1), we tested whether the addition of an immunostimulatory Ab targeting CD137 (4-1BB) and/or CD134 (OX40) would enhance the antitumor effect of dabrafenib, trametinib and anti-PD-1 or anti-PD-L1 therapy. In vitro studies showed that the combination group of dabrafenib, trametinib and anti-PD-1 increases CD8(+) tumor infiltrating lymphocytes (TILs), as well as CD4(+) T cells and tumor-associated macrophages (TAMs). An upregulation of PD-L1 was observed in the combination of dabrafenib, trametinib and anti-PD-1 therapy. Combination of dabrafenib, trametinib and anti-PD-1, with either anti-CD137 or anti-CD134, showed a superior antitumor effect, but the five-agent combination was not superior to the four-agent combinations. In conclusion, the combination of dabrafenib, trametinib, anti-PD1 or anti-PD-L1 therapy results in robust antitumor activity, which is further improved by adding the immune-stimulating Ab anti-CD137 or anti-CD134. Our findings support the testing of these combinations in patients with BRAF (V600E) mutant metastatic melanoma.
            Cover page: Combined treatment with dabrafenib and trametinib with immune-stimulating antibodies for BRAF mutant melanoma
            • Article
            Lawrence Berkeley National Laboratory (2008)

            An ultrafast x-ray detector system is under development at Lawrence Berkeley National Laboratory (LBNL) for application primarily to studyies of ultrafast magnetization dynamics. The system consists of a fs laser, an x-ray streak camera and an ellipitically polarization undulator (EPU) beamline. Polarized x-rays from an EPU can be used to measure x-ray magnetic circular dichroism (XMCD) of a sample. XMCD has the unique ability to independently measure orbit and spin magnetization with sub-monolayer sensitivity and element specificity. The streak camera has simultaneously a sub-picosecond temporal resolution and a high spatial resolution. The combination of the streak camera and EPU allows us to study the transfer of angular momentum from spin to orbit to the lattice in the sample on an ultrafast time scale. We describe here the performance of the ultrafast detector, the laser and the x-ray synchronization system. The observation of the demagnetization process of different samples demonstrates the ability of the apparatus.

              Cover page: An ultrafast x-ray detector system at an elliptically polarizing undulator beamline
              • Article
              LBL Publications (2007)
                Cover page: An ultrafast x-ray detecting system at an elliptically polarization undulator beamline
                • Article
                • Peer Reviewed
                Lawrence Berkeley National Laboratory (2008)
                  Cover page: Element-specific spin and orbital momentum dynamics of Fe/Gd multilayers
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2009)

                  Background

                  Th17 cells are CD4+ cells that produce interleukin 17 (IL-17) and are potent inducers of tissue inflammation and autoimmunity. We studied the levels of this T cell subset in peripheral blood of patients treated with the anti-CTLA4 antibody tremelimumab since its major dose limiting toxicities are inflammatory and autoimmune in nature.

                  Methods

                  Peripheral blood mononuclear cells (PBMC) were collected before and after receiving tremelimumab within two clinical trials, one with tremelimumab alone (21 patients) and another together with autologous dendritic cells (DC) pulsed with the melanoma epitope MART-126-35 (6 patients). Cytokines were quantified directly in plasma from patients and after in vitro stimulation of PBMC. We also quantified IL-17 cytokine-producing cells by intracellular cytokine staining (ICS).

                  Results

                  There were no significant changes in 13 assayed cytokines, including IL-17, when analyzing plasma samples obtained from patients before and after administration of tremelimumab. However, when PBMC were activated in vitro, IL-17 cytokine in cell culture supernatant and Th17 cells, detected as IL-17-producing CD4 cells by ICS, significantly increased in post-dosing samples. There were no differences in the levels of Th17 cells between patients with or without an objective tumor response, but samples from patients with inflammatory and autoimmune toxicities during the first cycle of therapy had a significant increase in Th17 cells.

                  Conclusion

                  The anti-CTLA4 blocking antibody tremelimumab increases Th17 cells in peripheral blood of patients with metastatic melanoma. The relation between increases in Th17 cells and severe autoimmune toxicity after CTLA4 blockade may provide insights into the pathogenesis of anti-CTLA4-induced toxicities.
                    Cover page: CTLA4 blockade increases Th17 cells in patients with metastatic melanoma
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2024)
                    People living with HIV (PLWH) are at higher risk of developing lymphoma. In this study, we performed cytometry by time-of-flight (CyTOF) on peripheral blood mononuclear cells of cART-naïve HIV+ individuals and cART-naïve HIV+ individuals prior to AIDS-associated non-Hodgkin lymphoma (pre-NHL) diagnosis. Participants were enrolled in the Los Angeles site of the MACS/WIHS Combined Cohort Study (MWCCS). Uniform Manifold Approximation and Projection (UMAP) and unsupervised clustering analysis were performed to identify differences in the expression of B-cell activation markers and/or oncogenic markers associated with lymphomagenesis. CD10+CD27- B cells, CD20+CD27- B cells, and B-cell populations with aberrant features (CD20+CD27+CXCR4+CD71+ B cells and CD20+CXCR4+cMYC+ B cells) were significantly elevated in HIV+ cART-naïve compared to HIV-negative samples. CD20+CD27+CD24+CXCR4+CXCR5+ B cells, CD20+CD27+CD10+CD24+CXCR4+cMYC+ B cells, and a cluster of CD20+CXCR4hiCD27-CD24+CXCR5+CD40+CD4+AICDA+ B cells were significantly elevated in HIV+ pre-NHL (cART-naïve) compared to HIV+ cART-naïve samples. A potentially clonal cluster of CD20+CXCR4+CXCR5+cMYC+AICDA+ B cells and a cluster of germinal center B-cell-like cells (CD19-CD20+CXCR4+Bcl-6+PD-L1+cMYC+) were also found in the circulation of HIV+ pre-NHL (cART-naïve) samples. Moreover, significantly elevated clusters of CD19+CD24hiCD38hi cMYC+ AICDA+ B regulatory cells were identified in HIV+ pre-NHL (cART-naïve) compared to HIV+ cART-naïve samples. The present study identifies unique B-cell subsets in PLWH with potential pre-malignant features that may contribute to the development of pre-tumor B cells in PLWH and that may play a role in lymphomagenesis.
                      Cover page: Characterization of unique B-cell populations in the circulation of people living with HIV prior to non-Hodgkin lymphoma diagnosis
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