Browsing by Author "Zhang, Shuhong"

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    CELLULAR THERAPY AND HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CANCER
    (Office of the Vice Chancellor for Research, 2010-04-09) Farag, Sherif S.; Srivastava, Shivani; Schwartz, Jennifer; Nelson, Robert; Homsi, Yasser; Zhang, Shuhong; Dinauer, Mary; Cornetta, Kenneth; March, Kieth; Pelus, Louis; Broxmeyer, Hal
    The Center for Cellular Therapy and Hematopoietic Stem Cell Transplantation for Cancer was established in July 2007 to promote translational and clinical research in cellular therapy for cancer. The primary goal of the Center is translate discoveries from bench-to-clinic through phase I and early phase II cellular therapy clinical trials. To achieve this objective, the Center has brought together the unique expertise in hematopoiesis, immunology, gene therapy, graft engineering, and clinical hematopoietic stem cell transplantation (HCT) available at IUPUI. Since its establishment, we have completed two phase I clinical trials developing novel preparative regimens for allogeneic and autologous stem cell transplantation for patients with refractory leukemia and lymphoma, respectively. In addition, we have also initiated 5 additional early phase clinical trials that directly translate IUPUI laboratory discoveries to patients with hematological cancers. The Center has successfully competed for external funding through peerreviewed grants and pharmaceutical contracts. In this presentation, we highlight some important examples of the Center’s ongoing and completed research. An important clinical research focus of our Center is the ability to extend the curative potential of allogeneic HCT to patients without suitably HLA-matched donors. We are currently exploring ways to improve the outcomes of umbilical cord blood (UCB) and haplotype-mismatched stem cell transplantation for patients with hematological cancers. The discovery in Dr. Broxmeyer’s Laboratory, Indiana University, Indianapolis, that inhibition of the enzyme CD26 promotes homing and engraftment of limiting numbers of UCB stem cells has been translated to the first clinical trial in vivo CD26 inhibition using sitagliptin in adult leukemia patients undergoing UCB transplantation. Our preliminary data indicates that high-dose sitagliptin is well tolerated and appears to shorten the time of engraftment. As our data is further confirmed in this pilot study, we plan to investigate this potentially paradigm changing approach in a larger national study. As an extension of this research, Dr. Pelus’ Laboratory, Indiana University, Indianapolis, has shown that short-term ex vivo treatment of hematopoietic progenitors using PGE2 will also promote engraftment. We are currently investigating the potential synergy of PGE2 treatment with CD26 inhibition to further enhance engraftment, which if results appear promising will also be translated to a phase I clinical trial. In haplotypemismatched allogeneic HCT, mismatching of donor KIR receptors on natural killer (NK) cells with recipient KIR ligands expressed on the patient’s tumor cells exerts a NK cell-mediated antileukemia effect that contributes to reduced relapse after transplantation. We (Dr. Farag’s Laboratory, Indiana University, Indianapolis) have shown that in vivo donor derived NK cells developing from donor stem cells have an “inhibitory” receptor phenotype that may suboptimally function against leukemia. This has resulted in a phase I trial of purified NK cell infusion following mismatched HCT to investigate the feasibility and safety of this approach, as a prelude to a larger study to investigate its efficacy. Although the highest dose level of NK cells has not yet been investigated, the preliminary data indicates that such a novel approach is feasible. In additional studies based on our laboratory findings, we are exploring the harnessing of NK cells in the therapy of cancer through the monoclonal antibodies that block KIR receptors in combination with immuno-modulatory agents (e.g., lenalidomide) and antibodies that promote antibody-dependent cellular cytotoxicity (e.g., rituximab, anti-CS1). We have initiated patents for these discoveries, and are currently planning to transplant these into phase I clinical trials. Other ongoing research includes enhancing immune function against cancer through STAT3 inhibition to overcome tumor-mediated impairment of dendritic cell maturation, ex vivo specific expansion of cytotoxic of NK cell subsets for clinical use, and enhancing immune cell function following transplantation. The continued success of our Center will depend on a continuing pipeline of novel laboratory discoveries and their translation to early phase clinical trials to assess feasibility and safety as a prelude to larger trials assessing efficacy. Initial funding of the Center by IUPUI has allowed the Center’s conception, and the bringing together of basic and clinical researchers to the “research table” to make this translational/clinical research endeavor a reality, and has allowed us to be competitive for external funding. An important developing outcome of this initiative is the preparation for a Program Project grant in Mobilization and Engraftment of Stem Cells.
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    Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease
    (Massachusetts Medical Society, 2021-01-07) Farag, Sherif S.; Zaid, Mohammad Abu; Schwartz, Jennifer E.; Thakrar, Teresa C.; Blakley, Ann J.; Abonour, Rafat; Robertson, Michael J.; Broxmeyer, Hal E.; Zhang, Shuhong; Medicine, School of Medicine
    Background: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known. Methods: We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation. Results: A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation. Conclusions: In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation.
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    High-dose sitagliptin for systemic inhibition of dipeptidylpeptidase-4 to enhance engraftment of single cord umbilical cord blood transplantation
    (Impact Journals, 2017-11-27) Farag, Sherif S.; Nelson, Robert; Cairo, Mitchell S.; O’Leary, Heather A.; Zhang, Shuhong; Huntley, Carol; Delgado, David; Schwartz, Jennifer; Zaid, Mohammad Abu; Abonour, Rafat; Robertson, Michael; Broxmeyer, Hal; Medicine, School of Medicine
    Delayed engraftment remains a limitation of umbilical cord blood (UCB) transplantation. We previously showed that inhibition of dipeptidylpeptidase (DPP)-4 using sitagliptin 600 mg daily was safe with encouraging results on engraftment, but inhibition was not sustained. We evaluated the efficacy and feasibility of higher doses of sitagliptin to enhance engraftment of UCB in patients with hematological cancers. Fifteen patients, median age 41 (range, 18-59) years, received single UCB grafts matched at 4 (n=11) or 5 (n=4) of 6 HLA loci with median nucleated cell dose of 3.5 (range, 2.57-4.57) x107/kg. Sitagliptin 600 mg every 12 hours was administered days -1 to +2. All patients engrafted by day 30, with 12 (80%) engrafting by day 21. The median time to neutrophil engraftment was 19 (range, 12-30) days. Plasma DPP-4 activity was better inhibited with a mean residual trough DPP-4 activity of 70%±19%. Compared to patients previously treated with 600 mg/day, sitagliptin 600 mg every 12 hours appeared to improve engraftment, supporting the hypothesis that more sustained DPP-4 inhibition is required. In-vivo inhibition of DPP-4 using high-dose sitagliptin compares favorably with other approaches to enhance UCB engraftment with greater simplicity, and may show synergy in combination with other strategies.
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    The novel histone deacetylase inhibitor, AR-42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells
    (Wiley, 2011-07-01) Zhang, Shuhong; Suvannasankha, Attaya; Crean, Colin D.; White, Valerie L.; Chen, Ching-Shih; Farag, Sherif S.; Department of Internal Medicine, IU School of Medicine
    Multiple myeloma (MM) remains incurable with current therapy, indicating the need for continued development of novel therapeutic agents. We evaluated the activity of a novel phenylbutyrate-derived histone deacetylase inhibitor, AR-42, in primary human myeloma cells and cell lines. AR-42 was cytotoxic to MM cells at a mean LC(50) of 0.18 ± 0.06 μmol/l at 48 hr and induced apoptosis with cleavage of caspases 8, 9 and 3, with cell death largely prevented by caspase inhibition. AR-42 downregulated the expression of gp130 and inhibited activation of STAT3, with minimal effects on the PI3K/Akt and MAPK pathways, indicating a predominant effect on the gp130/STAT-3 pathway. AR-42 also inhibited interleukin (IL)-6-induced STAT3 activation, which could not be overcome by exogenous IL-6. AR-42 also downregulated the expression of STAT3-regulated targets, including Bcl-xL and cyclin D1. Overexpression of Bcl-xL by a lentivirus construct partly protected against cell death induced by AR-42. The cyclin dependent kinase inhibitors, p16 and p21, were also significantly induced by AR-42, which together with a decrease in cyclin D1, resulted in G(1) and G(2) cell cycle arrest. In conclusion, AR-42 has potent cytotoxicity against MM cells mainly through gp130/STAT-3 pathway. The results provide rationale for clinical investigation of AR-42 in MM.