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2. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

Author

Lu, Sydney X., De Neef, Emma, Thomas, James D., Sabio, Erich, Rousseau, Benoit, Gigoux, Mathieu, Knorr, David A., Greenbaum, Benjamin, Elhanati, Yuval, Hogg, Simon J., Chow, Andrew, Ghosh, Arnab, Xie, Abigail, Zamarin, Dmitriy, Cui, Daniel, Erickson, Caroline, Singer, Michael, Cho, Hana, Wang, Eric, Lu, Bin, Durham, Benjamin H., Shah, Harshal, Chowell, Diego, Gabel, Austin M., Shen, Yudao, Liu, Jing, Jin, Jian, Rhodes, Matthew C., Taylor, Richard E., Molina, Henrik, Wolchok, Jedd D., Merghoub, Taha, Diaz, Luis A., Jr., Abdel-Wahab, Omar, and Bradley, Robert K.

Published
2021
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4. Expression of chimeric receptor CD4ζ by natural killer cells derived from human pluripotent stem cells improves in vitro activity but does not enhance suppression of HIV infection in vivo.

Author

Ni, Zhenya, Knorr, David A, Bendzick, Laura, Allred, Jeremy, and Kaufman, Dan S

Subjects
Killer Cells, Natural, Cell Line, Animals, Humans, Mice, HIV-1, HIV Infections, Antigens, CD4, Recombinant Fusion Proteins, Stem Cell Transplantation, Gene Expression Regulation, Embryonic Stem Cells, Induced Pluripotent Stem Cells, HIV-1 infection inhibition, Human embryonic stem cells, In vitro, In vivo, Induced pluripotent stem cells, Natural killer cells, CD4 Antigens, Killer Cells, Natural, Antigens, CD4, Biological Sciences, Technology, Medical and Health Sciences, Immunology
Abstract

Cell-based immunotherapy has been gaining interest as an improved means to treat human immunodeficiency virus (HIV)/AIDS. Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) could become a potential resource. Our previous studies have shown hESC and iPSC-derived natural killer (NK) cells can inhibit HIV-infected targets in vitro. Here, we advance those studies by expressing a HIV chimeric receptor combining the extracellular portion of CD4 to the CD3ζ intracellular signaling chain. We hypothesized that expression of this CD4ζ receptor would more efficiently direct hESC- and iPSC-derived NK cells to target HIV-infected cells. In vitro studies showed the CD4ζ expressing hESC- and iPSC-NK cells inhibited HIV replication in CD4+ T-cells more efficiently than their unmodified counterparts. We then evaluated CD4ζ expressing hESC (CD4ζ-hESC)- and iPSC-NK cells in vivo anti-HIV activity using a humanized mouse model. We demonstrated significant suppression of HIV replication in mice treated with both CD4ζ-modified and -unmodified hESC-/iPSC-NK cells compared with control mice. However, we did not observe significantly increased efficacy of CD4ζ expression in suppression of HIV infection. These studies indicate that hESC/iPSC-based immunotherapy can be used as a unique resource to target HIV/AIDS.

Published
2014

6. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model

Author

Geller, Melissa A, Knorr, David A, Hermanson, David A, Pribyl, Lee, Bendzick, Laura, Mccullar, Valarie, Miller, Jeffrey S, and Kaufman, Dan S

Subjects
Cancer, Rare Diseases, Ovarian Cancer, Orphan Drug, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Adenocarcinoma, Animals, Antigens, Differentiation, Cancer Vaccines, Cell Proliferation, Cell Survival, Cytotoxicity, Immunologic, Female, Humans, Immunotherapy, Adoptive, Injections, Intraperitoneal, Interleukin-2, K562 Cells, Killer Cells, Natural, Lymphocyte Activation, Mice, Mice, Inbred NOD, Ovarian Neoplasms, Peritoneal Cavity, Recurrence, Tumor Burden, Xenograft Model Antitumor Assays, bioluminescent imaging, immunotherapy, natural killer (NK) cells, ovarian cancer, Clinical Sciences, Immunology
Abstract

Background aimsThere is an urgent need for novel therapeutic strategies for relapsed ovarian cancer. Dramatic clinical anti-tumor effects have been observed with interleukin (IL)-2 activated natural killer (NK) cells; however, intravenous delivery of NK cells in patients with ovarian cancer has not been successful in ameliorating disease. We investigated in vivo engraftment of intraperitoneally (IP) delivered NK cells in an ovarian cancer xenograft model to determine if delivery mode can affect tumor cell killing and circumvent lack of NK cell expansion.MethodsAn ovarian cancer xenograft mouse model was established to evaluate efficacy of IP-delivered NK cells. Tumor burden was monitored by bioluminescent imaging of luciferase-expressing ovarian cancer cells. NK cell persistence, tumor burden and NK cell trafficking were evaluated. Transplanted NK cells were evaluated by flow cytometry and cytotoxicity assays.ResultsIP delivery of human NK cells plus cytokines led to high levels of circulating NK and was effective in clearing intraperitoneal ovarian cancer burden in xenografted mice. NK cells remained within the peritoneal cavity 54 days after injection and had markers of maturation. Additionally, surviving NK cells were able to kill ovarian cancer cells at a rate similar to pre-infusion levels, supporting that in vivo functionality of human NK cells can be maintained after IP infusion.ConclusionsIP delivery of NK cells leads to stable engraftment and antitumor response in an ovarian cancer xenograft model. These data support further pre-clinical and clinical evaluation of IP delivery of allogeneic NK cells in ovarian cancer.

Published
2013

7. Development, expansion, and in vivo monitoring of human NK cells from human embryonic stem cells (hESCs) and and induced pluripotent stem cells (iPSCs).

Author

Bock, Allison M, Knorr, David, and Kaufman, Dan S

Subjects
Killer Cells, Natural, Pluripotent Stem Cells, Humans, Cytological Techniques, Cell Differentiation, Embryonic Stem Cells, Stem Cell Biology, Issue 74, Bioengineering, Biomedical Engineering, Medicine, Physiology, Anatomy, Cellular Biology, Molecular Biology, Biochemistry, Hematology, ESCs, ES Cells, Hematopoietic Stem Cells, HSC, Induced Pluripotent Stem Cells, iPSCs, Luciferases, Firefly, Immunotherapy, Adoptive, stem cells, differentiation, NK cells, in vivo imaging, fluorescent imaging, turboFP650, FACS, cell culture, Killer Cells, Natural, Biochemistry and Cell Biology, Psychology, Cognitive Sciences
Abstract

We present a method for deriving natural killer (NK) cells from undifferentiated hESCs and iPSCs using a feeder-free approach. This method gives rise to high levels of NK cells after 4 weeks culture and can undergo further 2-log expansion with artificial antigen presenting cells. hESC- and iPSC-derived NK cells developed in this system have a mature phenotype and function. The production of large numbers of genetically modifiable NK cells is applicable for both basic mechanistic as well as anti-tumor studies. Expression of firefly luciferase in hESC-derived NK cells allows a non-invasive approach to follow NK cell engraftment, distribution, and function. We also describe a dual-imaging scheme that allows separate monitoring of two different cell populations to more distinctly characterize their interactions in vivo. This method of derivation, expansion, and dual in vivo imaging provides a reliable approach for producing NK cells and their evaluation which is necessary to improve current NK cell adoptive therapies.

Published
2013

9. Abstract 5742: Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

Author

Thomas, James D., primary, Lu, Sydney X., additional, De Neef, Emma, additional, Sabio, Erich, additional, Rousseau, Benoit, additional, Gigoux, Mathieu, additional, Knorr, David A., additional, Greenbaum, Benjamin, additional, Elhanati, Yuval, additional, Hogg, Simon J., additional, Chow, Andrew, additional, Ghosh, Arnab, additional, Xie, Abigail, additional, Zamarin, Dmitriy, additional, Cui, Daniel, additional, Erickson, Caroline, additional, Singer, Michael, additional, Cho, Hana, additional, Wang, Eric, additional, Lu, Bin, additional, Durham, Benjamin H., additional, Shah, Harshal, additional, Chowell, Diego, additional, Gabel, Austin M., additional, Shen, Yudao, additional, Liu, Jing, additional, Jin, Jian, additional, Rhodes, Matthew C., additional, Taylor, Richard E., additional, Molina, Henrik, additional, Wolchok, Jedd D., additional, Merghoub, Taha, additional, Jr, Luis A. Diaz, additional, Abdel-Wahab, Omar, additional, and Bradley, Robert K., additional

Published
2023
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11. Systematic Evaluation of AML-Associated Antigens Identifies Novel Anti-U5 snRNP200 Therapeutic Antibodies for the Treatment of AML

Author

Knorr, Katherine, primary, Erickson, Caroline, additional, Wang, Eric, additional, Rahman, Jahan, additional, Mi, Xiaoli, additional, Lu, Sydney, additional, Fox, Nina, additional, Penson, Alex, additional, Hogg, Simon, additional, Stanley, Robert, additional, Inoue, Daichi, additional, Knorr, David, additional, Ravetch, Jeffrey, additional, and Abdel-Wahab, Omar, additional

Published
2022
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12. CTIM-23. DOSE ESCALATION TRIAL OF FC-ENGINEERED ANTI-CD40 MONOCLONAL ANTIBODY (2141-V11) ADMINISTERED INTRATUMORALLY WITH D2C7-IT VIA CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMAS (RMGS)

Author

Desjardins, Annick, primary, Chandramohan, Vidya, additional, Landi, Daniel, additional, Peters, Katherine B, additional, Johnson, Margaret, additional, Khasraw, Mustafa, additional, Low, Justin, additional, Threatt, Stevie, additional, Bullock, Chevelle, additional, II, James E Herndon, additional, Lipp, Eric S, additional, Sampson, John, additional, Friedman, Allan, additional, Friedman, Henry S, additional, Ashley, David, additional, Knorr, David, additional, Ravetch, Jeffrey, additional, and Bigner, Darell, additional

Published
2022
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15. Timing and Immune Status after Cellular Therapies Predict Response to COVID-19 Vaccines

Author

Tamari, Roni, primary, Politikos, Ioannis, additional, Knorr, David, additional, Vardhana, Santosha, additional, Young, Jennifer, additional, Marcello, Leeann, additional, Doddi, Sital, additional, Devlin, Sean M, additional, Ramanathan, Lakshmi, additional, Pessin, Melissa S., additional, Dunn, Erica, additional, Palazzo, Meighan A., additional, Bravo, Christina, additional, Papanicolaou, Genovefa A., additional, Kamboj, Mini, additional, Perales, Miguel-Angel, additional, Chung, David J., additional, and Shah, Gunjan L, additional

Published
2021
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21. Predictors of Humoral Response to SARS-CoV-2 Vaccination after Hematopoietic Cell Transplantation and CAR T-cell Therapy

Author

Tamari, Roni, primary, Politikos, Ioannis, additional, Knorr, David A., additional, Vardhana, Santosha A., additional, Young, Jennifer C., additional, Marcello, LeeAnn T., additional, Doddi, Sital, additional, Devlin, Sean M., additional, Ramanathan, Lakshmi V., additional, Pessin, Melissa S., additional, Dunn, Erica, additional, Palazzo, Meighan, additional, Bravo, Christina D., additional, Papanicolaou, Genovefa A., additional, Kamboj, Mini, additional, Perales, Miguel Angel, additional, Chung, David J., additional, and Shah, Gunjan L., additional

Published
2021
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22. Disease- and Therapy-Specific Impact on Humoral Immune Responses to COVID-19 Vaccination in Hematologic Malignancies

Author

Chung, David J., primary, Shah, Gunjan L., additional, Devlin, Sean M., additional, Ramanathan, Lakshmi V., additional, Doddi, Sital, additional, Pessin, Melissa S., additional, Hoover, Elizabeth, additional, Marcello, LeeAnn T., additional, Young, Jennifer C., additional, Boutemine, Sawsan R., additional, Serrano, Edith, additional, Sharan, Saumya, additional, Momotaj, Saddia, additional, Margetich, Lauren, additional, Bravo, Christina D., additional, Papanicolaou, Genovefa A., additional, Kamboj, Mini, additional, Mato, Anthony R., additional, Roeker, Lindsey E., additional, Hultcrantz, Malin, additional, Mailankody, Sham, additional, Lesokhin, Alexander M., additional, Vardhana, Santosha A., additional, and Knorr, David A., additional

Published
2021
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29. A unique approach to teaching electronic packaging

Author

Knorr, David B. and Rymaszewski, Eugene J.

Subjects
Electronic packaging -- Study and teaching, Business, Engineering and manufacturing industries, Science and technology
Abstract

Electronic packaging is quickly becoming an important aspect of electronic system perfornmance. The teaching of electronic packaging requires an interdisciplinary approach which takes design functions and technology options into account. The electronic packaging course at Rensselaer Polytechnic Institute is described.

Published
1993

30. Annotation of Somatic Genomic Variants in Hematologic Diseases Using OncoKB, a Precision Oncology Knowledgebase

Author

Suehnholz, Sarah P., primary, Kundra, Ritika, additional, Roshal, Mikhail, additional, Xiao, Wenbin, additional, Petrova-Drus, Kseniya, additional, Yabe, Mariko, additional, Ho, Caleb, additional, Zhang, Hongxin, additional, Knorr, David, additional, Miles, Linde A, additional, Millman, Scott, additional, Nissan, Moriah H., additional, LaFave, Lindsay M., additional, Arcila, Maria E, additional, Berger, Michael F., additional, Zehir, Ahmet, additional, Ptashkin, Ryan, additional, Gao, Jianjiong, additional, Solit, David B., additional, Dogan, Ahmet, additional, Levine, Ross L., additional, Schultz, Nikolaus, additional, and Chakravarty, Debyani, additional

Published
2019
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36. Antibody Purification with AssayMAP, a High Throughput Microchromatography Platform

Author

Beban, Marc, Tang, Ning, van den Heuvel, Zachary, and Knorr, David

Subjects
Scientific Poster Abstracts
Abstract

The Agilent AssayMAP Bravo microchromatography platform was developed to fulfill a growing demand for a system capable of performing robust, high-throughput analytical scale protein sample preparations. The platform, built on the Agilent Bravo liquid handler, uses a specially modified liquid handling head capable of processing up to 96 samples simultaneously and uses interchangeable AssayMAP cartridges filled with a variety of chromatography media. Ultra-low dead-volume syringes are capable of driving fluids into or out of cartridges at rates from below 1 μL/min. to 375 μL/second for true chromatography performance. Cartridges are available with protein A, streptavidin, and reverse-phase resins. Additional workflows are being added continuously. This work describes purification of poly- and monoclonal antibodies from different media backgrounds constructed to mimic those encountered during antibody screening, production, and scale-up in commercial settings. A well-characterized monoclonal antibody (mAb) was added at different concentrations to phosphate buffered saline or supernatant media harvested from Chinese hamster ovary cell culture. Automated purifications were performed with the AssayMAP platform using cartridges containing immobilized protein A. Yields from each antibody dilution were not altered by the background media, or the presence of up to 10% fetal bovine serum in the media. Examination via LC-MS of molecular weight, and glycosylation patterns of the AssayMAP-purified material were identical to those of the input mAb molecule. Additional media cartridges are being developed to widen the possible uses for this platform. By increasing sample throughput, the AssayMAP Bravo platform will shorten timelines for development of new antibodies for research and therapeutics.

Published
2012

37. TNFα-induced neutral sphingomyelinase-2 modulates synaptic plasticity by controlling the membrane insertion of NMDA receptors

Author

Wheeler, David, Knapp, Edward, Bandaru, Veera V.R., Wang, Yue, Knorr, David, Poirier, Christophe, Mattson, Mark P., Geiger, Jonathan D., and Haughey, Norman J.

Subjects
Spectrometry, Mass, Electrospray Ionization, Patch-Clamp Techniques, In Vitro Techniques, Ceramides, Benzylidene Compounds, Hippocampus, Receptors, N-Methyl-D-Aspartate, Article, Fatty Acids, Monounsaturated, Rats, Sprague-Dawley, Membrane Microdomains, Fluorescence Resonance Energy Transfer, Serine, Animals, Enzyme Inhibitors, Phosphorylation, Cells, Cultured, Neurons, Aniline Compounds, Gangliosidosis, GM1, Neuronal Plasticity, Tumor Necrosis Factor-alpha, musculoskeletal, neural, and ocular physiology, Excitatory Postsynaptic Potentials, Embryo, Mammalian, Rats, Protein Transport, Sphingomyelin Phosphodiesterase, nervous system, Mutation, Calcium
Abstract

The insertion and removal of NMDA receptors from the synapse are critical events that modulate synaptic plasticity. While a great deal of progress has been made on understanding the mechanisms that modulate trafficking of NMDA receptors, we do not currently understand the molecular events required for the fusion of receptor containing vesicles with the plasma membrane. Here, we show that sphingomyelin phosphodiesterase 3 (also known as neutral sphingomyelinase-2) is critical for tumor necrosis factor (TNF) alpha-induced trafficking of NMDA receptors and synaptic plasticity. TNFalpha initiated a rapid increase in ceramide that was associated with increased surface localization of NMDA receptor NR1 subunits and a specific clustering of NR1 phosphorylated on serines 896 and 897 into lipid rafts. Brief applications of TNFalpha increased the rate and amplitude of NMDA-evoked calcium bursts and enhanced excitatory post-synaptic currents. Pharmacological inhibition or genetic mutation of neutral sphingomyelinase-2 prevented TNFalpha-induced generation of ceramide, phosphorylation of NR1 subunits, clustering of NR1, enhancement of NMDA-evoked calcium flux and excitatory post-synaptic currents.

Published
2009

47. Identification and Differentiation of Tilletia indica and T. walkeri Using the Polymerase Chain Reaction

Author

Frederick, Reid D., Snyder, Karen E., Tooley, Paul W., Berthier-Schaad, Yvette, Peterson, Gary L., Bonde, Morris R., Schaad, Norman W., Knorr, David A., Frederick, Reid D., Snyder, Karen E., Tooley, Paul W., Berthier-Schaad, Yvette, Peterson, Gary L., Bonde, Morris R., Schaad, Norman W., and Knorr, David A.

Abstract

Karnal bunt of wheat, caused by Tilletia indica, was found in regions of the southwestern United States in 1996. Yield losses due to Karnal bunt are slight, and the greatest threat of Karnal bunt to the U.S. wheat industry is the loss of its export market. Many countries either prohibit or restrict wheat imports from countries with Karnal bunt. In 1997, teliospores morphologically resembling T. indica were isolated from bunted ryegrass seeds and wheat seed washes. Previously developed PCR assays failed to differentiate T. indica from the recently discovered ryegrass pathogen, T. walkeri. The nucleotide sequence of a 2.3 kb region of mitochondrial DNA, previously amplified by PCR only from T. indica, was determined for three isolates of T. indica and three isolates of T. walkeri. There was greater than 99% identity within either the T. indica group or the T. walkeri group of isolates, whereas there was »3% divergence between isolates of these two Tilletia species. Five sets of PCR primers were made specific to T. indica, and three sets were designed specifically for T. walkeri based upon nucleotide differences within the mitochondrial DNA region. In addition, a 212 bp amplicon was developed as a target sequence in a fluorogenic 5¢ nuclease PCR assay using the TaqMan system for the detection and discrimination of T. indica and T. walkeri.

Published
2000

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