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Therapeutic vaccines for malignant brain tumors
Michael P Gustafson,Keith L Knutson,Allan B Dietz
Biologics: Targets and Therapy , 2008,
Abstract: Michael P Gustafson1, Keith L Knutson2, Allan B Dietz11Division of Transfusion Medicine; 2Department of Immunology, Mayo Clinic, Rochester, MN, USAAbstract: Malignant gliomas are the most common and aggressive form of brain tumors. Current therapy consists of surgical resection, followed by radiation therapy and concomitant chemotherapy. Despite these treatments, the prognosis for patients is poor. As such, investigative therapies including tumor vaccines have targeted this devastating condition. Recent clinical trials involving immunotherapy, specifically dendritic cell (DC) based vaccines, have shown promising results. Overall, these vaccines are well tolerated with few documented side effects. In many patients receiving vaccines, tumor progression was delayed and the median overall survival of these patients was prolonged. Despite these encouraging results, several factors have limited the efficacy of DC vaccines. Here we discuss the potential of DC vaccines as adjuvant therapy and current obstacles of generating highly pure and potent DC vaccines in the context of malignant glioma. Taken together, the results from earlier clinical studies justify additional clinical trials aimed at improving the efficacy of DC vaccines.Keywords: malignant glioma, glioblastoma multiforme, vaccine, immunotherapy, dendritic cells
Vasoprotective effects of human CD34+ cells: towards clinical applications
Thomas J Kiernan, Barry A Boilson, Tyra A Witt, Allan B Dietz, Amir Lerman, Robert D Simari
Journal of Translational Medicine , 2009, DOI: 10.1186/1479-5876-7-66
Abstract: Human CD34+ cells were separated from peripheral buffy coats using automatic magnetic cell separation. Carotid arterial injury was performed in male Sprague-Dawley nude rats using a 2F Fogarty balloon catheter. Freshly harvested CD34+ cells or saline alone was administered locally for 20 minutes by endoluminal instillation. Structural and functional analysis of the arteries was performed 28 days later.Morphometric analysis demonstrated that human CD34+ cell delivery was associated with a significant reduction in intimal formation 4 weeks following balloon injury as compared with saline (I/M ratio 0.79 ± 0.18, and 1.71 ± 0.18 for CD34, and saline-treated vessels, respectively P < 0.05). Vasoreactivity studies showed that maximal relaxation of vessel rings from human CD34+ treated animals was significantly enhanced compared with saline-treated counterparts (74.1 ± 10.2, and 36.8 ± 12.1% relaxation for CD34+ cells and saline, respectively, P < 0.05)Delivery of human CD34+ cells limits neointima formation and improves arterial reactivity after vascular injury. These studies advance the concept of cell delivery to effect vascular remodeling toward a potential human cellular product.Cellular therapies hold great promise for the treatment of human disease. The development of cell-based therapeutics for humans requires preclinical testing in animal models. There are inherent limitations to the use of autologous animal products for preclinical testing. First, the use of autologous animal products fails to address the specific efficacy of the intended human product. Second, immunophenotyping of animal products may be limited by a lack of reagents which are available for use in humans and thus fail to predicate human results. To overcome these limitations and in order to develop novel human cellular products, immunodeficient animals may be used to test the delivery of these products.We and others have demonstrated the vasculoprotective effects of local delivery of circulation
Comprehensive assessment of circulating immune cell populations in response to stereotactic body radiation therapy in patients with liver cancer
Allan B. Dietz,Christopher L. Hallemeier,Dennis A. Gastineau,Lewis R. Roberts,Sean S. Park,Svetlana Bornschlegl
- , 2017, DOI: 10.1016/j.adro.2017.08.003
Abstract: Stereotactic body radiation therapy (SBRT) can positively influence an antitumor immune response by inducing necrotic cell death. SBRT also been shown to eliminate tumors outside the radiation therapy field through an immune-mediated process known as the abscopal effect. Recent advances in immunotherapy may provide new therapeutic approaches for patients with liver cancer. Therefore, understanding the immune status of patients with cancer will likely guide how immunotherapy might be used in combination with SBRT. We hypothesized that we would observe changes in circulating blood immune cell populations of patients who received SBRT for liver tumors. Therefore, we assessed 110 immunophenotypes in the peripheral blood of 10 patients with liver cancer or metastases to the liver pretreatment and 2 posttreatment time points. Patients with liver cancer and metastatic patients both exhibited several immunophenotypic abnormalities at baseline compared with a group of healthy volunteer controls. In longitudinal studies, SBRT caused a specific reduction in CD3+ T cell counts and immature CD56brCD16？ NK cell counts. The immune profiling and potential identification of circulating biomarkers shown here could lead to the design of combinatorial approaches with SBRT and immunotherapy to optimize the timing of treatment and direct the most effective immunotherapy with SBRT
Induced pluripotent stem cells from GMP-grade hematopoietic progenitor cells and mononuclear myeloid cells
Seiga Ohmine, Allan B Dietz, Michael C Deeds, Katherine A Hartjes, David R Miller, Tayaramma Thatava, Toshie Sakuma, Yogish C Kudva, Yasuhiro Ikeda
Stem Cell Research & Therapy , 2011, DOI: 10.1186/scrt87
Abstract: We examined the feasibility of reprogramming mobilized GMP-grade hematopoietic progenitor cells (HPCs) and peripheral blood mononuclear cells (PBMCs) and tested the pluripotency of derived iPS clones.Ectopic expression of OCT4, SOX2, KLF4, and c-MYC in HPCs and PBMCs resulted in rapid iPSC derivation. Long-term time-lapse imaging revealed efficient iPSC growth under serum- and feeder-free conditions with frequent mitotic events. HPC- and PBMC-derived iPS cells expressed pluripotency-associated markers, including SSEA-4, TRA-1-60, and NANOG. The global gene-expression profiles demonstrated the induction of endogenous pluripotent genes, such as LIN28, TERT, DPPA4, and PODXL, in derived iPSCs. iPSC clones from blood and other cell sources showed similar ultrastructural morphologies and genome-wide gene-expression profiles. On spontaneous and guided differentiation, HPC- and PBMC-derived iPSCs were differentiated into cells of three germ layers, including insulin-producing cells through endodermal lineage, verifying the pluripotency of the blood-derived iPSC clones.Because the use of blood cells allows minimally invasive tissue procurement under GMP conditions and rapid cellular reprogramming, mobilized HPCs and unmobilized PBMCs would be ideal somatic cell sources for clinical-grade iPSC derivation, especially from diabetes patients complicated by slow-healing wounds.Because embryonic stem (ES) cells can self-renew indefinitely and differentiate into any cell present in the adult organism, ES cells provide a unique platform for regenerative medicine approaches. In early 2009, the US Food and Drug Administration (FDA) approved the first clinical trial using ES cells in patients with spinal cord injuries. Although the FDA temporarily placed the trial on hold because of concerns over the risk of ES-derived cyst formation, the clinical hold was lifted, and the first patient for ES cell treatment was enrolled by Geron in late 2010 [1]. The use of ES-derived, terminally diff
Immunosuppressive CD14+HLA-DRlo/neg monocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes
Allan B. Dietz,Ann L. Oberg,Debabrata Mukhopadhyay,Gloria M. Petersen,Michael P. Gustafson,Naureen Javeed,Shamit K. Dutta,Suresh T. Chari,William R. Bamlet,Yi Lin
- , 2017, DOI: 10.1080/2162402X.2016.1252013
Abstract:
Preparing clinical-grade myeloid dendritic cells by electroporation-mediated transfection of in vitro amplified tumor-derived mRNA and safety testing in stage IV malignant melanoma
Svetomir N Markovic, Allan B Dietz, Carl W Greiner, Mary L Maas, Greg W Butler, Douglas J Padley, Peggy A Bulur, Jacob B Allred, Edward T Creagan, James N Ingle, Dennis A Gastineau, Stanimir Vuk-Pavlovic
Journal of Translational Medicine , 2006, DOI: 10.1186/1479-5876-4-35
Abstract: We prepared immature DCs (IDCs) from CD14+ cells isolated from leukapheresis products and extracted total RNA from freshly resected melanoma tissue. We reversely transcribed the RNA while attaching a T7 promoter to the products that we subsequently amplified by PCR. We transcribed the amplified cDNA in vitro and introduced the expanded RNA into IDCs by electroporation followed by DC maturation and cryopreservation. Isolated and expanded mRNA was analyzed for the presence of melanoma-associated tumor antigens gp100, tyrosinase or MART1. To test product safety, we injected five million DCs subcutaneously at three-week intervals for up to four injections into six patients suffering from stage IV malignant melanoma.Three preparations contained all three transcripts, one isolate contained tyrosinase and gp100 and one contained none. Electrotransfection of DCs did not affect viability and phenotype of fresh mature DCs. However, post-thaw viability was lower (69 ± 12 percent) in comparison to non-electroporated cells (82 ± 12 percent; p = 0.001). No patient exhibited grade 3 or 4 toxicity upon DC injections.Standardized preparation of viable clinical-grade DCs transfected with tumor-derived and in vitro amplified mRNA is feasible and their administration is safe.Dendritic cells (DCs) have been used in numerous recent clinical trials as vaccines intended to break tolerance to tumors and induce tumor-specific therapeutic immunity [1]. To break tolerance to the tumor, DCs must effectively present tumor-associated antigen(s). Antigens have been delivered to DC as whole-tumor lysates, natural or synthetic peptides, recombinant viruses, tumor specific RNA, and recombinant DNA [2]. Most of these sources have been used for clinical trials, particularly tumor lysates; however, tumor lysates are a limited and inconsistent source of antigenic material. The optimal method for antigen delivery to DCs is still controversial [2].A current discussion of antigen delivery to DCs concluded t
Quantum and Wave Dynamical Chaos in Superconducting Microwave Billiards
B. Dietz,A. Richter
Physics , 2015, DOI: 10.1063/1.4915527
Abstract: Experiments with superconducting microwave cavities have been performed in our laboratory for more than two decades. The purpose of the present article is to recapitulate some of the highlights achieved. We briefly review (i) results obtained with flat, cylindrical microwave resonators, so-called microwave billiards, concerning the universal fluctuation properties of the eigenvalues of classically chaotic systems with no, a threefold and a broken symmetry; (ii) summarize our findings concerning the wave-dynamical chaos in three-dimensional microwave cavities; (iii) present a new approach for the understanding of the phenomenon of dynamical tunneling which was developed on the basis of experiments that were performed recently with unprecedented precision, and finally, (iv) give an insight into an ongoing project, where we investigate universal properties of (artificial) graphene with superconducting microwave photonic crystals that are enclosed in a microwave resonator, i.e., so-called Dirac billiards.
Molecular Validation of Chondrogenic Differentiation and Hypoxia Responsiveness of Platelet-Lysate Expanded Adipose Tissue–Derived Human Mesenchymal Stromal Cells
A. Noelle Larson,Aaron J. Krych,Allan B. Dietz,Amel Dudakovic,Andre J. van Wijnen,Catalina Galeano-Garces,Dirk R. Larson,Emily T. Camilleri,Hee-Jeong Im,Jay Smith,Marcel Karperien,Scott M. Riester,Wenchun Qu
- , 2017, DOI: 10.1177/1947603516659344
Abstract: To determine the optimal environmental conditions for chondrogenic differentiation of human adipose tissue–derived mesenchymal stromal/stem cells (AMSCs). In this investigation we specifically investigate the role of oxygen tension and 3-dimensional (3D) culture systems
Photonuclear Reactions induced by Intense Short Laser Pulses
B. Dietz,H. A. Weidenmueller
Physics , 2010, DOI: 10.1016/j.physletb.2010.07.061
Abstract: A measurement of the decay in time of nuclei excited by an intense short laser pulse of energy E(0) yields the Fourier transform of the autocorrelation function of the associated scattering matrix. We determine the optimal length (in time) of the pulse and evaluate the time-decay function using random-matrix theory. That function is shown to contain information not otherwise available. We approximate that function in a manner that is useful for the analysis of data. For E(0) below the threshold energy E(n) of the first neutron channel, the time-decay function is exponential in time t while it is the product of an exponential and a power in t for E(0) > E(n). The comparison of the measured decay functions in both energy domains yields an unambiguous and novel test of random-matrix theory in nuclei.
Correlation Widths in Quantum--Chaotic Scattering
B. Dietz,A. Richter,H. A. Weidenmueller
Physics , 2010, DOI: 10.1016/j.physletb.2011.02.009
Abstract: An important parameter to characterize the scattering matrix S for quantum-chaotic scattering is the width Gamma_{corr} of the S-matrix autocorrelation function. We show that the "Weisskopf estimate" d/(2pi) sum_c T_c (where d is the mean resonance spacing, T_c with 0 <= T_c <= 1 the "transmission coefficient" in channel c and where the sum runs over all channels) provides a very good approximation to Gamma_{corr} even when the number of channels is small. That same conclusion applies also to the cross-section correlation function.
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