Browsing by Author "Schwartz, Jennifer"

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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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    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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    Multimodality, Online Oncology Learning Curriculum: An Adaptable, Asynchronous Learning Resource
    (2024-04-26) Pham, Phillip; Dandu, Vidya; King, Jennifer; Schwartz, Jennifer
    Background/Objective: Dedicated educational sessions can improve residents’ interest in a career in oncology. Challenges remain with creating effective learning resources tailored to multiple learning styles on busy oncology rotations. Here, we aimed to build an effective and adaptable oncology curriculum for learners using online, multimodality, and interactive learning tools and resources. Methods: Using the Canvas® online learning management system, modules covering specific cancer types were created, each with a pre-survey to assess learners’ evaluation of their own knowledge and comfort of the specific cancer type, a brief video or audio file covering high-yield material about the cancer type, interactive case-based questions to review and reinforce content, and a post-survey to assess the change in knowledge and comfort in clinical application of the material. As initial modules were built, learner preference for module style was evaluated and subsequent modules were adapted based on that feedback. Pre- and post-surveys were rated on a 5-point Likert scale. Median values and interquartile ranges are reported. A one-sided t-test was used to compare responses. Results: Two initial modules were created. The lung cancer module included a high-yield voice-over PowerPoint presentation followed by interactive, case-based questions. The breast cancer module used a high-yield podcast with accompanying note handout followed by interactive case-based questions. After the completion of these two modules, six learners completed a ranking for preference of module learning style. Four learners preferred voice-over PowerPoint with case-based questions afterward, while the other two preferred upfront cases to work through followed by a voice-over PowerPoint for reinforcement. Of the listed module styles, a podcast was preferred the least. With this feedback, two additional modules were created, one with cases before a PowerPoint and another voice-over PowerPoint followed by cases. Overall, 21 learners have completed both pre- and post-survey responses for comparison. Median rating of the learners’ knowledge of a specific cancer type increased from 2-Fair (2) on the pre-survey to 4-Agree (1) after completing the learning module (p<0.001). All learners felt more comfortable with their clinical application of the cancer topic after completing the module, median 2(2) on pre-survey vs. 4(1) on post-survey (p<0.001). Median rating for feeling that knowledge of the specific cancer type increased after the module was 4-Agree (3). Discussion/Conclusions: Using learning science principles and an adaptive framework, this online, asynchronous oncology curriculum has resulted in improvements in learners’ perceived knowledge and clinical application of oncology topics. Further modules are being created and adapted in response to learners’ feedback.