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2. Profiling of Natural Killer Interactions With Cancer Cells Using Mass Cytometry

Author

Hallisey, Margaret, Dennis, Jenna, Gabriel, Elizabeth P., Masciarelli, Alyssa, Chen, Jiajia, Abrecht, Charlotte, Brainard, Martha, Marcotte, William M., Dong, Han, Hathaway, Emma, Tarannum, Mubin, Vergara, Juliana A., Schork, Abigail N., Tyan, Kevin, Tarantino, Giuseppe, Liu, David, Romee, Rizwan, Rahma, Osama E., Severgnini, Mariano, Hodi, F. Stephen, and Baginska, Joanna

Published
2023
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8. CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer.

Author

Tarannum, Mubin, Dinh, Khanhlinh, Vergara, Juliana, Birch, Grace, Abdulhamid, Yasmin Z., Kaplan, Isabel E., Ay, Oyku, Maia, Andreia, Beaver, Owen, Sheffer, Michal, Shapiro, Roman, Ali, Alaa Kassim, Han Dong, Dongjoo Ham, James, Bobilev, Eden, James, Sydney, Cameron, Amy B., Quang-De Nguyen, Ganapathy, Suthakar, and Chayawatto, Chayapatou

Subjects
*KILLER cells, *OVARIAN cancer, *OVARIAN epithelial cancer, *CHIMERIC antigen receptors, *CELL cycle, *CELL cycle regulation
Abstract

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological cancers. Cytokine-induced memory-like (CIML) natural killer (NK) cells have shown promising results in preclinical and early-phase clinical trials. In the current study, CIML NK cells demonstrated superior antitumor responses against a panel of EOC cell lines, increased expression of activation receptors, and up-regulation of genes involved in cell cycle/proliferation and down-regulation of inhibitory/suppressive genes. CIML NK cells transduced with a chimeric antigen receptor (CAR) targeting the membrane-proximal domain of mesothelin (MSLN) further improved the antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR arming of the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse

Author

Shapiro, Roman M., Birch, Grace C., Hu, Guangan, Cadavid, Juliana Vergara, Nikiforow, Sarah, Baginska, Joanna, Ali, Alaa K., Tarannum, Mubin, Sheffer, Michal, Abdulhamid, Yasmin Z., Rambaldi, Benedetta, Arihara, Yohei, Reynolds, Carol, Halpern, Max S., Rodig, Scott J., Cullen, Nicole, Wolff, Jacquelyn O., Pfaff, Kathleen L., Lane, Andrew A., Lindsley, R. Coleman, Cutler, Corey S., Antin, Joseph H., Ho, Vincent T., Koreth, John, Gooptu, Mahasweta, Kim, Haesook T., Malmberg, Karl-Johan, Wu, Catherine J., Chen, Jianzhu, Soiffer, Robert J., Ritz, Jerome, and Romee, Rizwan

Subjects
Diseases -- Relapse, Killer cells -- Physiological aspects -- Usage -- Health aspects, Hematopoietic stem cells -- Transplantation, Health care industry
Abstract

BACKGROUND. Responses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell-based therapy is a promising modality to treat post-HCT relapse. METHODS. We initiated this ongoing phase I trial of adoptively transferred cytokine-induced memory-like (CIML) NK cells in patients with myeloid malignancies who relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5 to 10 million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. Highresolution profiling with mass cytometry and single-cell RNA sequencing characterized the expanding and persistent NK cell subpopulations in a longitudinal manner after infusion. RESULTS. In the first 6 enrolled patients on the trial, infusion of CIML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events. Expansion of NK cells was distinct from IL-2 effects on endogenous post-HCT NK cells, and not dependent on CMV viremia. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires. CONCLUSION. Given their rapid expansion and long-term persistence in an immune-compatible environment, CIML NK cells serve as a promising platform for the treatment of posttransplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T cells and tumor targets will lead to improvements in cell-based immunotherapies. TRIAL REGISTRATION. ClinicalTrials.gov NCT04024761. FUNDING. Dunkin' Donuts, NIH/National Cancer Institute, and the Leukemia and Lymphoma Society., Introduction Relapse of acute myeloid leukemia (AML) occurs in up to 50% of patients after allogeneic hematopoietic stem cell transplant (HCT) and heralds an extremely poor prognosis (1). In several [...]

Published
2022
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13. Differentiation of BCMA-specific induced pluripotent stem cells into CD8ab+ T cells targeting myeloma

Author

Bae, Jooeun, primary, Kitayama, Shuichi, additional, Herbert, Zach, additional, Daheron, Laurence, additional, Kurata, Keiji, additional, Keskin, Derin, additional, Livak, Kenneth, additional, Li, Shuqiang, additional, Tarannum, Mubin, additional, Romee, Rizwan, additional, Samur, Mehmet K., additional, Munshi, Nikhil C., additional, Kaneko, Shin, additional, Ritz, Jerome, additional, and Anderson, Kenneth C., additional

Published
2023
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14. Data from Activation of Tumor-Cell STING Primes NK-Cell Therapy

Author

Knelson, Erik H., primary, Ivanova, Elena V., primary, Tarannum, Mubin, primary, Campisi, Marco, primary, Lizotte, Patrick H., primary, Booker, Matthew A., primary, Ozgenc, Ismail, primary, Noureddine, Moataz, primary, Meisenheimer, Brittany, primary, Chen, Minyue, primary, Piel, Brandon, primary, Spicer, Nathaniel, primary, Obua, Bonje, primary, Messier, Cameron M., primary, Shannon, Erin, primary, Mahadevan, Navin R., primary, Tani, Tetsuo, primary, Schol, Pieter J., primary, Lee-Hassett, Anna M., primary, Zlota, Ari, primary, Vo, Ha V., primary, Ha, Minh, primary, Bertram, Arrien A., primary, Han, Saemi, primary, Thai, Tran C., primary, Gustafson, Corinne E., primary, Venugopal, Kartika, primary, Haggerty, Timothy J., primary, Albertson, Thomas P., primary, Hartley, Antja-Voy, primary, Eser, Pinar O., primary, Li, Ze-Hua, primary, Cañadas, Israel, primary, Vivero, Marina, primary, De Rienzo, Assunta, primary, Richards, William G., primary, Abu-Yousif, Adnan O., primary, Appleman, Vicky A., primary, Gregory, Richard C., primary, Parent, Alexander, primary, Lineberry, Neil, primary, Smith, Eric L., primary, Jänne, Pasi A., primary, Miret, Juan J., primary, Tolstorukov, Michael Y., primary, Romee, Rizwan, primary, Paweletz, Cloud P., primary, Bueno, Raphael, primary, and Barbie, David A., primary

Published
2023
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16. Supplementary Data from Activation of Tumor-Cell STING Primes NK-Cell Therapy

Author

Knelson, Erik H., primary, Ivanova, Elena V., primary, Tarannum, Mubin, primary, Campisi, Marco, primary, Lizotte, Patrick H., primary, Booker, Matthew A., primary, Ozgenc, Ismail, primary, Noureddine, Moataz, primary, Meisenheimer, Brittany, primary, Chen, Minyue, primary, Piel, Brandon, primary, Spicer, Nathaniel, primary, Obua, Bonje, primary, Messier, Cameron M., primary, Shannon, Erin, primary, Mahadevan, Navin R., primary, Tani, Tetsuo, primary, Schol, Pieter J., primary, Lee-Hassett, Anna M., primary, Zlota, Ari, primary, Vo, Ha V., primary, Ha, Minh, primary, Bertram, Arrien A., primary, Han, Saemi, primary, Thai, Tran C., primary, Gustafson, Corinne E., primary, Venugopal, Kartika, primary, Haggerty, Timothy J., primary, Albertson, Thomas P., primary, Hartley, Antja-Voy, primary, Eser, Pinar O., primary, Li, Ze-Hua, primary, Cañadas, Israel, primary, Vivero, Marina, primary, De Rienzo, Assunta, primary, Richards, William G., primary, Abu-Yousif, Adnan O., primary, Appleman, Vicky A., primary, Gregory, Richard C., primary, Parent, Alexander, primary, Lineberry, Neil, primary, Smith, Eric L., primary, Jänne, Pasi A., primary, Miret, Juan J., primary, Tolstorukov, Michael Y., primary, Romee, Rizwan, primary, Paweletz, Cloud P., primary, Bueno, Raphael, primary, and Barbie, David A., primary

Published
2023
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19. Abstract 4168: Tumor cell stimulator of interferon genes (STING) activation primes NK cell therapy in mesothelioma

Author

Knelson, Erik H., primary, Ivanova, Elena, additional, Tarannum, Mubin, additional, Campisi, Marco, additional, Lizotte, Patrick H., additional, Booker, Matthew A., additional, Meisenheimer, Brittany, additional, Chen, Minyue, additional, Spicer, Nathaniel, additional, Obua, Bonje, additional, Vo, Ha V., additional, Albertson, Thomas P., additional, Vivero, Marina, additional, Tolstorukov, Michael Y., additional, Romee, Rizwan, additional, Paweletz, Cloud P., additional, Bueno, Raphael, additional, and Barbie, David A., additional

Published
2022
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21. Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia

Author

Dong, Han, primary, Ham, James Dongjoo, additional, Hu, Guangan, additional, Xie, Guozhu, additional, Vergara, Juliana, additional, Liang, Yong, additional, Ali, Alaa, additional, Tarannum, Mubin, additional, Donner, Hannah, additional, Baginska, Joanna, additional, Abdulhamid, Yasmin, additional, Dinh, Khanhlinh, additional, Soiffer, Robert J., additional, Ritz, Jerome, additional, Glimcher, Laurie H., additional, Chen, Jianzhu, additional, and Romee, Rizwan, additional

Published
2022
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22. Activation of Tumor-Cell STING Primes NK-Cell Therapy

Author

Knelson, Erik H., primary, Ivanova, Elena V., additional, Tarannum, Mubin, additional, Campisi, Marco, additional, Lizotte, Patrick H., additional, Booker, Matthew A., additional, Ozgenc, Ismail, additional, Noureddine, Moataz, additional, Meisenheimer, Brittany, additional, Chen, Minyue, additional, Piel, Brandon, additional, Spicer, Nathaniel, additional, Obua, Bonje, additional, Messier, Cameron M., additional, Shannon, Erin, additional, Mahadevan, Navin R., additional, Tani, Tetsuo, additional, Schol, Pieter J., additional, Lee-Hassett, Anna M., additional, Zlota, Ari, additional, Vo, Ha V., additional, Ha, Minh, additional, Bertram, Arrien A., additional, Han, Saemi, additional, Thai, Tran C., additional, Gustafson, Corinne E., additional, Venugopal, Kartika, additional, Haggerty, Timothy J., additional, Albertson, Thomas P., additional, Hartley, Antja-Voy, additional, Eser, Pinar O., additional, Li, Ze-Hua, additional, Cañadas, Israel, additional, Vivero, Marina, additional, De Rienzo, Assunta, additional, Richards, William G., additional, Abu-Yousif, Adnan O., additional, Appleman, Vicky A., additional, Gregory, Richard C., additional, Parent, Alexander, additional, Lineberry, Neil, additional, Smith, Eric L., additional, Jänne, Pasi A., additional, Miret, Juan J., additional, Tolstorukov, Michael Y., additional, Romee, Rizwan, additional, Paweletz, Cloud P., additional, Bueno, Raphael, additional, and Barbie, David A., additional

Published
2022
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23. Innovative Strategies to Improve the Clinical Application of NK Cell-Based Immunotherapy

Author

Tarannum, Mubin, Romee, Rizwan, and Shapiro, Roman M.

Subjects
Killer Cells, Natural, Neoplasms, Immunology, Humans, Immunologic Factors, Immunology and Allergy, Immunotherapy
Abstract

Natural killer cells constitute a part of the innate immune system that mediates an effective immune response towards virus-infected and malignant cells. In recent years, research has focused on exploring and advancing NK cells as an active immunotherapy platform. Despite major advances, there are several key challenges that need to be addressed for the effective translation of NK cell research to clinical applications. This review highlights some of these challenges and the innovative strategies being developed to overcome them, including in vitro expansion, in vivo persistence, infiltration to the tumor site, and prevention of exhaustion.

Published
2022

24. Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia

Author

Massachusetts Institute of Technology. Department of Biology, Dong, Han, Ham, James Dongjoo, Hu, Guangan, Xie, Guozhu, Vergara, Juliana, Liang, Yong, Ali, Alaa, Tarannum, Mubin, Donner, Hannah, Baginska, Joanna, Abdulhamid, Yasmin, Dinh, Khanhlinh, Soiffer, Robert J, Ritz, Jerome, Glimcher, Laurie H, Chen, Jianzhu, Romee, Rizwan, Massachusetts Institute of Technology. Department of Biology, Dong, Han, Ham, James Dongjoo, Hu, Guangan, Xie, Guozhu, Vergara, Juliana, Liang, Yong, Ali, Alaa, Tarannum, Mubin, Donner, Hannah, Baginska, Joanna, Abdulhamid, Yasmin, Dinh, Khanhlinh, Soiffer, Robert J, Ritz, Jerome, Glimcher, Laurie H, Chen, Jianzhu, and Romee, Rizwan

Abstract

Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immune-based therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical trials in patients with relapsed/refractory AML. Here, we show that arming CIML NK cells with a neoepitope-specific chimeric antigen receptor (CAR) significantly enhances their antitumor responses to nucleophosphmin-1 (NPM1)-mutated AML while avoiding off-target toxicity. CIML NK cells differentiated from peripheral blood NK cells were efficiently transduced to express a TCR-like CAR that specifically recognizes a neoepitope derived from the cytosolic oncogenic NPM1-mutated protein presented by HLA-A2. These CAR CIML NK cells displayed enhanced activity against NPM1-mutated AML cell lines and patient-derived leukemic blast cells. CAR CIML NK cells persisted in vivo and significantly improved AML outcomes in xenograft models. Single-cell RNA sequencing and mass cytometry analyses identified up-regulation of cell proliferation, protein folding, immune responses, and major metabolic pathways in CAR-transduced CIML NK cells, resulting in tumor-specific, CAR-dependent activation and function in response to AML target cells. Thus, efficient arming of CIML NK cells with an NPM1-mutation-specific TCR-like CAR substantially improves their innate antitumor responses against an otherwise intracellular mutant protein. These preclinical findings justify evaluating this approach in clinical trials in HLA-A2 + AML patients with NPM1c mutations.

Published
2022

26. Expansion, persistence and efficacy of donor memory-like NK cells for the treatment of post-transplant relapse

Author

Shapiro, Roman M., primary, Birch, Grace, additional, Vergara, Juliana, additional, Hu, Guangan, additional, Nikiforow, Sarah, additional, Baginska, Joanna, additional, Ali, Alaa, additional, Tarannum, Mubin, additional, Rambaldi, Benedetta, additional, Arihara, Yohei, additional, Reynolds, Carol, additional, Halpern, Max, additional, Rodig, Scott, additional, Cullen, Nicole, additional, Lane, Andrew A., additional, Lindsley, R. Coleman, additional, Cutler, Corey S., additional, Antin, Joseph H., additional, Ho, Vincent T., additional, Koreth, John, additional, Gooptu, Mahasweta, additional, Kim, Haesook T., additional, Malmberg, Karl-Johan, additional, Wu, Catherine J., additional, Chen, Jianzhu, additional, Soiffer, Robert J., additional, Ritz, Jerome, additional, and Romee, Rizwan, additional

Published
2021
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27. Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia.

Author

Han Dong, Ham, James Dongjoo, Guangan Hu, Guozhu Xie, Vergara, Juliana, Yong Liang, Ali, Alaa, Tarannum, Mubin, Donner, Hannah, Baginska, Joanna, Abdulhamid, Yasmin, Dinh, Khanhlinh, Soiffer, Robert J., Ritz, Jerome, Glimcher, Laurie H., Jianzhu Chen, and Romee, Rizwan

Subjects
KILLER cells, ACUTE myeloid leukemia, CHIMERIC antigen receptors, ONCOGENIC proteins, BLOOD cells
Abstract

Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immunebased therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical trials in patients with relapsed/refractory AML. Here, we show that arming CIML NK cells with a neoepitope-specific chimeric antigen receptor (CAR) significantly enhances their antitumor responses to nucleophosphmin-1 (NPM1)-mutated AML while avoiding off-target toxicity. CIML NK cells differentiated from peripheral blood NK cells were efficiently transduced to express a TCR-like CAR that specifically recognizes a neoepitope derived from the cytosolic oncogenic NPM1-mutated protein presented by HLA-A2. These CAR CIML NK cells displayed enhanced activity against NPM1-mutated AML cell lines and patient-derived leukemic blast cells. CAR CIML NK cells persisted in vivo and significantly improved AML outcomes in xenograft models. Single-cell RNA sequencing and mass cytometry analyses identified up-regulation of cell proliferation, protein folding, immune responses, and major metabolic pathways in CAR-transduced CIML NK cells, resulting in tumor-specific, CAR-dependent activation and function in response to AML target cells. Thus, efficient arming of CIML NK cells with an NPM1-mutation-specific TCR-like CAR substantially improves their innate antitumor responses against an otherwise intracellular mutant protein. These preclinical findings justify evaluating this approach in clinical trials in HLA-A2+ AML patients with NPM1c mutations. [ABSTRACT FROM AUTHOR]

Published
2022
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29. Mass Cytometry – Based Cytotoxicity Assay for Profiling Natural Killer Cells

Author

Gabriel, Elizabeth P., primary, Masciarelli, Alyssa, additional, Chen, Jiajia, additional, Abrecht, Charlotte, additional, Hallisey, Margaret, additional, Brainard, Martha, additional, Dong, Han, additional, Dennis, Jenna, additional, Hathaway, Emma, additional, Tarannum, Mubin, additional, Vergara, Juliana A., additional, Schork, Abigail N., additional, Tyan, Kevin, additional, Tarantino, Giuseppe, additional, Liu, David, additional, Romee, Rizwan, additional, Rahma, Osama E., additional, Hodi, F. Stephen, additional, Severgnini, Mariano, additional, and Baginska, Joanna K., additional

Published
2021
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33. RNA Fibers as Optimized Nanoscaffolds for siRNA Coordination and Reduced Immunological Recognition

Author

Rackley, Lauren, primary, Stewart, Jaimie Marie, additional, Salotti, Jacqueline, additional, Krokhotin, Andrey, additional, Shah, Ankit, additional, Halman, Justin R., additional, Juneja, Ridhima, additional, Smollett, Jaclyn, additional, Lee, Lauren, additional, Roark, Kyle, additional, Viard, Mathias, additional, Tarannum, Mubin, additional, Vivero‐Escoto, Juan, additional, Johnson, Peter F., additional, Dobrovolskaia, Marina A., additional, Dokholyan, Nikolay V., additional, Franco, Elisa, additional, and Afonin, Kirill A., additional

Published
2018
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37. Physical, chemical, and in vitro toxicological characterization of nanoparticles in chemical mechanical planarization suspensions used in the semiconductor industry: towards environmental health and safety assessments

Author

Speed, David, primary, Westerhoff, Paul, additional, Sierra-Alvarez, Reyes, additional, Draper, Rockford, additional, Pantano, Paul, additional, Aravamudhan, Shyam, additional, Chen, Kai Loon, additional, Hristovski, Kiril, additional, Herckes, Pierre, additional, Bi, Xiangyu, additional, Yang, Yu, additional, Zeng, Chao, additional, Otero-Gonzalez, Lila, additional, Mikoryak, Carole, additional, Wilson, Blake A., additional, Kosaraju, Karshak, additional, Tarannum, Mubin, additional, Crawford, Steven, additional, Yi, Peng, additional, Liu, Xitong, additional, Babu, S. V., additional, Moinpour, Mansour, additional, Ranville, James, additional, Montano, Manuel, additional, Corredor, Charlie, additional, Posner, Jonathan, additional, and Shadman, Farhang, additional

Published
2015
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38. Differentiation of BCMA-specific induced pluripotent stem cells into rejuvenated CD8αβ+T cells targeting multiple myeloma

Author

Bae, Jooeun, Kitayama, Shuichi, Herbert, Zach, Daheron, Laurence, Kurata, Keiji, Keskin, Derin B., Livak, Kenneth, Li, Shuqiang, Tarannum, Mubin, Romee, Rizwan, Samur, Mehmet, Munshi, Nikhil C., Kaneko, Shin, Ritz, Jerome, and Anderson, Kenneth C.

Abstract

•A pre-clinical framework to epigenetically reprogram BCMA-specific CD8ab+memory T cells using iPSC technology to target multiple myeloma.•BCMA-specific iPSC-derived hematopoietic progenitor cells having specific regulatory elements that control CD8+T cell lineage commitment.

Published
2023
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39. Physical, chemical, and in vitrotoxicological characterization of nanoparticles in chemical mechanical planarization suspensions used in the semiconductor industry: towards environmental health and safety assessmentsElectronic supplementary information (ESI) available: Supplementary information includes some analytical methods and in-depth discussion of ENP fate during on-site industrial wastewater treatment. See DOI: 10.1039/c5en00046g

Author

Speed, David, Westerhoff, Paul, Sierra-Alvarez, Reyes, Draper, Rockford, Pantano, Paul, Aravamudhan, Shyam, Chen, Kai Loon, Hristovski, Kiril, Herckes, Pierre, Bi, Xiangyu, Yang, Yu, Zeng, Chao, Otero-Gonzalez, Lila, Mikoryak, Carole, Wilson, Blake A., Kosaraju, Karshak, Tarannum, Mubin, Crawford, Steven, YiCurrent address: Department of Civil, Peng, Environmental, Engineering, Geomatics, Un, Florida Atlantic, Liu, Xitong, Babu, S. V., Moinpour, Mansour, Ranville, James, Montano, Manuel, Corredor, Charlie, Posner, Jonathan, and Shadman, Farhang

Abstract

This tutorial review focuses on aqueous slurries of dispersed engineered nanoparticles (ENPs) used in chemical mechanical planarization (CMP) for polishing wafers during manufacturing of semiconductors. A research consortium was assembled to procure and conduct physical, chemical, and in vitrotoxicity characterization of four ENPs used in CMP. Based on input from experts in semiconductor manufacturing, slurries containing fumed silica (f-SiO2), colloidal silica (c-SiO2), ceria (CeO2), and alumina (Al2O3) were selected and subsequently obtained from a commercial CMP vendor to represent realistic ENPs in simplified CMP fluids absent of proprietary stabilizers, oxidants, or other chemical additives that are known to be toxic. ENPs were stable in suspension for months, had highly positive or negative zeta potentials at their slurry working pH, and had mean diameters measured by dynamic light scattering (DLS) of 46 ± 1 nm for c-SiO2, 148 ± 5 nm for f-SiO2,132 ± 1 nm for CeO2, and 129 ± 2 nm for Al2O3, all of which were larger than the sub 100 nm diameter primary particle sizes measured by electron microscopy. The concentration of ENPs in all four slurries that caused 50% inhibition (IC-50) was greater than 1 mg mL−1based on in vitroassays using bioluminescence of the bacterium Aliivibrio fischeriand the proliferation, viability, and integrity of human cells (adenocarcinomic human alveolar basal epithelial cell line A549). The general practice in the CMP industry is to dilute the slurry waste stream so actual abrasive concentrations are typically orders of magnitude smaller than 1 mg mL−1, which is lower than IC-50 levels. In contrast to recent reports, we observed similar toxicological characteristics between c-SiO2and f-SiO2, and the materials exhibited similar X-ray diffraction (XRD) spectra but different morphology observed using electron microscopy. The ENPs and CMP slurries used in this study have been made available to a number of other research groups, and it is the intention of the consortium for this paper to provide a basis for characterizing and understanding human and environmental exposures for this important class of industrial ENPs.

Published
2015
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40. Examining the Cellular Uptake and Toxicity of Engineered Nanomaterials

Author

Kosaraju, Karshak, Tarannum, Mubin, Crawford, Steven, Garde, Komal, and Aravamudhan, Shyam

Abstract

Engineered Nanomaterials (ENs) such as silica, ceria and alumina nanoparticles have been extensively used in health care, energy and electronics. However, their toxicity and cellular uptake, which are strongly dependent on their physiochemical properties and on cell interaction, are largely unknown. The objective of this work is to study and quantify the cellular uptake of silica, ceria and alumina ENs. First, comprehensive characterization using DLS, zeta potential, BET, XRD, FTIR, Raman, SEM and TEM was done. Then, cell exposure studies were carried out on A549 lung epithetical cells to study cell viability and membrane integrity. Lastly, cellular uptake of ENs was studied by using techniques such as Confocal Raman Spectroscopy and ICP-OES and Electrochemical Cell-substrate Impedance Sensing (ECIS). ICP-OES analysis showed uptake of silica, ceria and alumina, while Confocal Raman indicated the uptake of Ceria ENs. Time-course effects of EN on A549 cells were studied using ECIS measurements.

Published
2014

41. Nonpathogenic E. coli engineered to surface display cytokines as a new platform for immunotherapy.

Author

Yang S, Sheffer M, Kaplan IE, Wang Z, Tarannum M, Dinh K, Abdulhamid Y, Shapiro R, Porter R, Soiffer R, Ritz J, Koreth J, Wei Y, Chen P, Zhang K, Márquez-Pellegrin V, Bonanno S, Joshi N, Guan M, Yang M, Li D, Bellini C, Chen J, Wu CJ, Barbie D, Li J, and Romee R

Abstract

Given the safety, tumor tropism, and ease of genetic manipulation in non-pathogenic Escherichia coli ( E. coli ), we designed a novel approach to deliver biologics to overcome poor trafficking and exhaustion of immune cells in the tumor microenvironment, via the surface display of key immune-activating cytokines on the outer membrane of E. coli K-12 DH5α. Bacteria expressing murine decoy-resistant IL18 mutein (DR18) induced robust CD8 + T and NK cell-dependent immune responses leading to dramatic tumor control, extending survival, and curing a significant proportion of immune-competent mice with colorectal carcinoma and melanoma. The engineered bacteria demonstrated tumor tropism, while the abscopal and recall responses suggested epitope spreading and induction of immunologic memory. E. coli K-12 DH5α engineered to display human DR18 potently activated mesothelin-targeting CAR NK cells and safely enhanced their trafficking into the tumors, leading to improved control and survival in xenograft mice bearing mesothelioma tumor cells, otherwise resistant to NK cells. Gene expression analysis of the bacteria-primed CAR NK cells showed enhanced TNFα signaling via NFkB and upregulation of multiple activation markers. Our novel live bacteria-based immunotherapeutic platform safely and effectively induces potent anti-tumor responses in otherwise hard-to-treat solid tumors, motivating further evaluation of this approach in the clinic., Competing Interests: Compete interests R.R., J.L., S.Y., and M.S. are named inventors on a patent application that describes the surface display of engineered bacteria. R.R. has a sponsored research agreement with Crispr Therapeutics, Skyline Therapeutics and serves on the scientific advisory board of Glycostem Therapeutics. R.R and J.C are co-founders of the InnDura Therapeutics. J.R. received research funding from Kite/Gilead, Novartis and Oncternal Therapeutics and serves on advisory boards for Akron Biotech, Clade Therapeutics, Garuda Therapeutics, LifeVault Bio, Novartis and Smart Immune. Additional Declarations: Yes there is potential Competing Interest. R.R., J.L., S.Y., and M.S. are named inventors on a patent application that describes the surface display of engineered bacteria. R.R. has a sponsored research agreement with Crispr Therapeutics, Skyline Therapeutics and serves on the scientific advisory board of Glycostem Therapeutics. R.R and J.C are co-founders of the InnDura Therapeutics. J.R. received research funding from Kite/Gilead, Novartis and Oncternal Therapeutics and serves on advisory boards for Akron Biotech, Clade Therapeutics, Garuda Therapeutics, LifeVault Bio, Novartis and Smart Immune.

Published
2024
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