Search

Your search keyword '"Emens, Leisha A."' showing total 564 results
Start Over Author "Emens, Leisha A."
564 results on '"Emens, Leisha A."'

201. Feasibility Trial of Partial Breast Irradiation With Concurrent Dose-Dense Doxorubicin and Cyclophosphamide in Early-Stage Breast Cancer

Author

Zellars, Richard C., primary, Stearns, Vered, additional, Frassica, Deborah, additional, Asrari, Fariba, additional, Tsangaris, Theodore, additional, Myers, Lee, additional, DiPasquale, Shirley, additional, Lange, Julie R., additional, Jacobs, Lisa K., additional, Emens, Leisha A., additional, Armstrong, Deborah K., additional, Fetting, John H., additional, Garrett-Mayer, Elizabeth, additional, Davidson, Nancy E., additional, and Wolff, Antonio C., additional

Published
2009
Full Text
View/download PDF

208. OX40 Costimulation Synergizes with GM-CSF Whole-Cell Vaccination to Overcome Established CD8+ T Cell Tolerance to an Endogenous Tumor Antigen

Author

Murata, Satoshi, primary, Ladle, Brian H., additional, Kim, Peter S., additional, Lutz, Eric R., additional, Wolpoe, Matthew E., additional, Ivie, Susan E., additional, Smith, Holly M., additional, Armstrong, Todd D., additional, Emens, Leisha A., additional, Jaffee, Elizabeth M., additional, and Reilly, R. Todd, additional

Published
2006
Full Text
View/download PDF

214. HER-2/neu-Specific Monoclonal Antibodies Collaborate with HER-2/neu-Targeted Granulocyte Macrophage Colony-Stimulating Factor Secreting Whole Cell Vaccination to Augment CD8+ T Cell Effector Function and Tumor-Free Survival in Her-2/neu-Transgenic Mice

Author

Wolpoe, Matthew E., primary, Lutz, Eric R., additional, Ercolini, Anne M., additional, Murata, Satoshi, additional, Ivie, Susan E., additional, Garrett, Elizabeth S., additional, Emens, Leisha A., additional, Jaffee, Elizabeth M., additional, and Reilly, R. Todd, additional

Published
2003
Full Text
View/download PDF

218. CD8+T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy

Author

Huseni, Mahrukh A., Wang, Lifen, Klementowicz, Joanna E., Yuen, Kobe, Breart, Beatrice, Orr, Christine, Liu, Li-fen, Li, Yijin, Gupta, Vinita, Li, Congfen, Rishipathak, Deepali, Peng, Jing, Şenbabaoǧlu, Yasin, Modrusan, Zora, Keerthivasan, Shilpa, Madireddi, Shravan, Chen, Ying-Jiun, Fraser, Eleanor J., Leng, Ning, Hamidi, Habib, Koeppen, Hartmut, Ziai, James, Hashimoto, Kenji, Fassò, Marcella, Williams, Patrick, McDermott, David F., Rosenberg, Jonathan E., Powles, Thomas, Emens, Leisha A., Hegde, Priti S., Mellman, Ira, Turley, Shannon J., Wilson, Mark S., Mariathasan, Sanjeev, Molinero, Luciana, Merchant, Mark, and West, Nathaniel R.

Abstract

Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8+cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients.

Published
2023
Full Text
View/download PDF

221. Manipulating Immunological Checkpoints to Maximize Antitumor Immunity.

Author

Teicher, Beverly A., Disis, Mary L., Emens, Leisha A., Reilly, R. Todd, and Jaffee, Elizabeth M.

Abstract

Initial clinical trials have demonstrated the safety and bioactivity of cancer vaccines, but vaccine-induced immune responses have seldom translated into clinically meaningful tumor regressions, particularly in advanced disease. It is increasingly clear that tumor-specific immune tolerance represents a layered system of controls that keep the immune system turned off. Immunoregulatory checkpoints map locoregionally to the tumor microenvironment and draining lymph nodes, and arise from the dynamic interactions between the tumor and the immune system. It is now apparent that cancer vaccines will have to be combined with other therapeutics that abrogate immune tolerance, further amplify vaccine-induced T-cell responses, or modify the tumor microenvironment to make it more conducive to the concerted action of innate and antigen-specific immune effector mechanisms. Here, we review the host-tumor dynamic from the perspective of immune tolerance and review current data supporting the integration of cancer vaccines with standard and novel therapeutic agents that can maximize their activity. [ABSTRACT FROM AUTHOR]

Published
2006
Full Text
View/download PDF

222. Cancer Vaccines in Combination with Multimodality Therapy.

Author

Rosen, Steven T., Khleif, Samir N., Emens, Leisha A., Reilly, R. Todd, and Jaffee, Elizabeth M.

Abstract

Improvements in our understanding of tumor immunology have facilitated significant progress in the development of cancer vaccines. Early clinical trials have generated evidence for the safety of tumor vaccines, and have provided a suggestion of clinically significant bioactivity. They have also highlighted the challenges of cancer vaccine development. These include developing strategies for overcoming immune tolerance, and approaches for identifying the most active tumor rejection antigens for cancer vaccine formulation. Furthermore, these early studies highlight the importance of identifying important pharmacodynamic interactions between standard cancer treatment modalities and tumor vaccines. Surgical debulking is one approach for minimizing the impact of tumor burden, and patients with minimal residual disease are likely to be the most ideal candidates for vaccine therapy. The impact of chemotherapy on vaccine activity is a developing area of clinical research, with regard to both its positive and negative impact on the development of antigenspecific immunity. The impact of ionizing radiation on the immune response to cancer vaccines is an underdeveloped area that also warrants further investigation. Finally, the advent of biologically targeted therapies such as the monoclonal antibodies Trastuzumab and Rituximab offer new opportunities for combining cancer vaccines with novel drugs in combinatorial treatment strategies with the potential for significant synergism. It is clear that the careful preclinical and clinical investigation of these issues will guide the most effective clinical testing of cancer vaccines, and facilitate their ultimate incorporation into standard clinical practice. [ABSTRACT FROM AUTHOR]

Published
2005
Full Text
View/download PDF

223. Cytokine Gene-Modified Cell-Based Cancer Vaccines.

Author

Walker, John M., Morgan, Jeffrey R., Todd Reilly, R., Machiels, Jean-Pascal H., Emens, Leisha A., and Jaffee, Elizabeth M.

Abstract

Antitumor immunity was first suggested in animals that reject tumor challenge after immunization with autologous inactivated tumor cells. Later, the discovery of tumor antigens recognized by T-cells strongly reinforced the concept that the tumor can be targeted by the immune system. In 1991, Boon and colleagues described the first human tumor antigen, MAGE-1, that is expressed in 50-60% of melanomas (1). The identification of T-cell-dependent tumor antigens (MAGE family, BAGE, GAGE, HER2/neu, p53, MART-1, tyrosinase, HPV, and others) has opened the route of antigen-specific immunotherapy strategies (2,3). Despite these important advances in tumor immunology, most tumor antigens are still unknown. Until more common tumor-specific antigens have been identified and their prevalence and relevance have been evaluated, the tumor cell itself remains one of the most convenient sources of antigens. Preclinical studies have shown that immunization with modified inactivated tumor cells can generate systemic antitumor immunity in vivo (4). Currently, many clinical studies are investigating the safety and efficacy of autologous and allogeneic whole cell-based cancer vaccines (5). [ABSTRACT FROM AUTHOR]

Published
2002
Full Text
View/download PDF

225. The immune microenvironment of breast ductal carcinoma in situ

Author

Thompson, Elizabeth, Taube, Janis M, Elwood, Hillary, Sharma, Rajni, Meeker, Alan, Warzecha, Hind Nassar, Argani, Pedram, Cimino-Mathews, Ashley, and Emens, Leisha A

Abstract

The host immune response has a key role in breast cancer progression and response to therapy. However, relative to primary invasive breast cancers, the immune milieu of breast ductal carcinoma in situ(DCIS) is less understood. Here, we profile tumor infiltrating lymphocytes and expression of the immune checkpoint ligand programmed death ligand 1 (PD-L1) in 27 cases of DCIS with known estrogen receptor (ER), progesterone receptor, and human epidermal growth factor 2 (HER-2) expression using tissue microarrays. Twenty-four cases were pure DCIS and three had associated invasive ductal carcinoma. Tumors were stained by immunohistochemistry for PD-L1, as well as the lymphocyte markers CD3, CD4, CD8, FoxP3, and CD20. The expression of PD-L1 by DCIS carcinoma cells and tumor infiltrating lymphocytes was determined, and the average tumor infiltrating lymphocytes per high power field were manually scored. None of the DCIS cells expressed PD-L1, but 81% of DCIS lesions contained PD-L1+ tumor infiltrating lymphocytes. DCIS with moderate-diffuse tumor infiltrating lymphocytes was more likely to have PD-L1+ tumor infiltrating lymphocytes (P=0.004). Tumor infiltrating lymphocytes with high levels of PD-L1 expression (>50% cells) were seen only in triple-negative DCIS (P=0.0008), and PD-L1−tumor infiltrating lymphocytes were seen only in ER+/HER-2−DCIS (P=0.12). The presence of PD-L1+ tumor infiltrating lymphocytes was associated with a younger mean patient age (P=0.01). Further characterization of the DCIS immune microenvironment may identify useful targets for immune-based therapy and breast cancer prevention.

Published
2016
Full Text
View/download PDF

226. List of Contributors

Author

Allavena, Paola, Ascierto, Maria Libera, Bedognetti, Davide, Beury, Daniel W., Bronte, Vincenzo, van der Burg, Sjoerd H., Cai, Zheng, Callahan, Margaret K., Car, Bruce D., Chen, Gang, Chioda, Mariacristina, Chornoguz, Olesya, Demaria, Sandra, Deng, Jiehui, Djeu, Julie Y., Donatelli, Sarah S., Drake, Charles G., Dranoff, Glenn, Durham, Nicholas M., Eisenlohr, Laurence C., Emens, Leisha A., Farsaci, Benedetto, Feehley, Taylor, Filipazzi, Paola, Galdiero, Maria Rosaria, di Genova, Gianfranco, Gilman, Paul B., Greene, Mark I., Greiner, John W., Gulley, James L., Hearnden, Claire, Hodge, James W., Huber, Veronica, Jaffee, Elizabeth M., Jinushi, Masahisa, Jove, Richard, Kershaw, Michael H., Kiss, Robert, Kryczek, Ilona, Lake, Richard A., Lash, Bradley W., Lavelle, Ed C., Lesterhuis, W. Joost, Link, Charles J., Liu, Jing, Luckashenak, Nancy, Madan, Ravi A., Mandik-Nayak, Laura, Mandruzzato, Susanna, Mantovani, Alberto, Marigo, Ilaria, Marincola, Francesco M., Mathieu, Veronique, May, Kenneth F., Jr., Mellor, Andrew L., Merlo, Lauren M.F., Metz, Richard, Mocellin, Simone, Morgan, Richard A., Muller, Alexander J., Munn, David H., Nagai, Yasuhiro, Nagler, Cathryn, Norvell, Amanda, Nowak, Anna K., Ohtani, Takuya, Ostrand-Rosenberg, Suzanne, Ottensmeier, Christian H., Palena, Claudia, Parker, Katherine H., Postow, Michael A., Prendergast, George C., Priceman, Saul J., Punt, Jenni, Rabinovich, Gabriel A., Ramsey, W. Jay, Rivoltini, Licia, Rossi, Gabriela R., Sahakian, Eva, Samanta, Arabinda, Sato-Matsushita, Marimo, Savelyeva, Natalia, Schlom, Jeffrey, Sica, Antonio, Sinha, Pratima, Smith, Courtney, Smyth, Mark J., Sotomayor, Eduardo M., Stevenson, Freda K., Sundblad, Victoria, Teng, Michele W.L., Tsang, Kwong-Yok, Tsuchiya, Hiromichi, Vahanian, Nicholas N., Villagra, Alejandro, Wang, Ena, Wang, Lin, Wei, Shuang, Welters, Marij J.P., Westhouse, Richard A., Woan, Karrune, Wolchok, Jedd D., Yu, Hua, Zhang, Hongtao, Zhao, Ende, Zhu, Zhiqiang, and Zou, Weiping

Published
2013
Full Text
View/download PDF

228. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one: National Harbor, MD, USA. 9-13 November 2016

Author

Lundqvist, Andreas, van Hoef, Vincent, Zhang, Xiaonan, Wennerberg, Erik, Lorent, Julie, Witt, Kristina, Sanz, Laia Masvidal, Liang, Shuo, Murray, Shannon, Larsson, Ola, Kiessling, Rolf, Mao, Yumeng, Sidhom, John-William, Bessell, Catherine A., Havel, Jonathan, Schneck, Jonathan, Chan, Timothy A., Sachsenmeier, Eliot, Woods, David, Berglund, Anders, Ramakrishnan, Rupal, Sodre, Andressa, Weber, Jeffrey, Zappasodi, Roberta, Li, Yanyun, Qi, Jingjing, Wong, Philip, Sirard, Cynthia, Postow, Michael, Newman, Walter, Koon, Henry, Velcheti, Vamsidhar, Callahan, Margaret K., Wolchok, Jedd D., Merghoub, Taha, Lum, Lawrence G., Choi, Minsig, Thakur, Archana, Deol, Abhinav, Dyson, Gregory, Shields, Anthony, Haymaker, Cara, Uemura, Marc, Murthy, Ravi, James, Marihella, Wang, Daqing, Brevard, Julie, Monaghan, Catherine, Swann, Suzanne, Geib, James, Cornfeld, Mark, Chunduru, Srinivas, Agrawal, Sudhir, Yee, Cassian, Wargo, Jennifer, Patel, Sapna P., Amaria, Rodabe, Tawbi, Hussein, Glitza, Isabella, Woodman, Scott, Hwu, Wen-Jen, Davies, Michael A., Hwu, Patrick, Overwijk, Willem W., Bernatchez, Chantale, Diab, Adi, Massarelli, Erminia, Segal, Neil H., Ribrag, Vincent, Melero, Ignacio, Gangadhar, Tara C., Urba, Walter, Schadendorf, Dirk, Ferris, Robert L., Houot, Roch, Morschhauser, Franck, Logan, Theodore, Luke, Jason J., Sharfman, William, Barlesi, Fabrice, Ott, Patrick A., Mansi, Laura, Kummar, Shivaani, Salles, Gilles, Carpio, Cecilia, Meier, Roland, Krishnan, Suba, McDonald, Dan, Maurer, Matthew, Gu, Xuemin, Neely, Jaclyn, Suryawanshi, Satyendra, Levy, Ronald, Khushalani, Nikhil, Wu, Jennifer, Zhang, Jinyu, Basher, Fahmin, Rubinstein, Mark, Bucsek, Mark, Qiao, Guanxi, MacDonald, Cameron, Hylander, Bonnie, Repasky, Elizabeth, Chatterjee, Shilpak, Daenthanasanmak, Anusara, Chakraborty, Paramita, Toth, Kyle, Meek, Megan, Garrett-Mayer, Elizabeth, Nishimura, Michael, Paulos, Chrystal, Beeson, Craig, Yu, Xuezhong, Mehrotra, Shikhar, Zhao, Fei, Evans, Kathy, Xiao, Christine, Holtzhausen, Alisha, Hanks, Brent A., Scharping, Nicole, Menk, Ashley V., Moreci, Rebecca, Whetstone, Ryan, Dadey, Rebekah, Watkins, Simon, Ferris, Robert, Delgoffe, Greg M., Peled, Jonathan, Devlin, Sean, Staffas, Anna, Lumish, Melissa, Rodriguez, Kori Porosnicu, Ahr, Katya, Perales, Miguel, Giralt, Sergio, Taur, Ying, Pamer, Eric, van den Brink, Marcel R. M., Jenq, Robert, Annels, Nicola, Pandha, Hardev, Simpson, Guy, Mostafid, Hugh, Harrington, Kevin, Melcher, Alan, Grose, Mark, Davies, Bronwyn, Au, Gough, Karpathy, Roberta, Shafren, Darren, Ricca, Jacob, Zamarin, Dmitriy, Batista, Luciana, Marliot, Florence, Vasaturo, Angela, Carpentier, Sabrina, Poggionovo, Cécile, Frayssinet, Véronique, Fieschi, Jacques, Van den Eynde, Marc, Pagès, Franck, Galon, Jérôme, Hermitte, Fabienne, Smith, Sean G., Nguyen, Khue, Ravindranathan, Sruthi, Koppolu, Bhanu, Zaharoff, David, Schvartsman, Gustavo, Bassett, Roland, McQuade, Jennifer L., Haydu, Lauren E., Kline, Douglas, Chen, Xiufen, Fosco, Dominick, Kline, Justin, Overacre, Abigail, Chikina, Maria, Brunazzi, Erin, Shayan, Gulidanna, Horne, William, Kolls, Jay, Bruno, Tullia C., Workman, Creg, Vignali, Dario, Adusumilli, Prasad S., Ansa-Addo, Ephraim A, Li, Zihai, Gerry, Andrew, Sanderson, Joseph P., Howe, Karen, Docta, Roslin, Gao, Qian, Bagg, Eleanor A. L., Tribble, Nicholas, Maroto, Miguel, Betts, Gareth, Bath, Natalie, Melchiori, Luca, Lowther, Daniel E., Ramachandran, Indu, Kari, Gabor, Basu, Samik, Binder-Scholl, Gwendolyn, Chagin, Karen, Pandite, Lini, Holdich, Tom, Amado, Rafael, Zhang, Hua, Glod, John, Bernstein, Donna, Jakobsen, Bent, Mackall, Crystal, Wong, Ryan, Silk, Jonathan D., Adams, Katherine, Hamilton, Garth, Bennett, Alan D., Brett, Sara, Jing, Junping, Quattrini, Adriano, Saini, Manoj, Wiedermann, Guy, Brewer, Joanna, Duong, MyLinh, Lu, An, Chang, Peter, Mahendravada, Aruna, Shinners, Nicholas, Slawin, Kevin, Spencer, David M., Foster, Aaron E., Bayle, J. Henri, Bergamaschi, Cristina, Ng, Sinnie Sin Man, Nagy, Bethany, Jensen, Shawn, Hu, Xintao, Alicea, Candido, Fox, Bernard, Felber, Barbara, Pavlakis, George, Chacon, Jessica, Yamamoto, Tori, Garrabrant, Thomas, Cortina, Luis, Powell, Daniel J., Donia, Marco, Kjeldsen, Julie Westerlin, Andersen, Rikke, Westergaard, Marie Christine Wulff, Bianchi, Valentina, Legut, Mateusz, Attaf, Meriem, Dolton, Garry, Szomolay, Barbara, Ott, Sascha, Lyngaa, Rikke, Hadrup, Sine Reker, Sewell, Andrew Kelvin, Svane, Inge Marie, Fan, Aaron, Kumai, Takumi, Celis, Esteban, Frank, Ian, Stramer, Amanda, Blaskovich, Michelle A., Wardell, Seth, Fardis, Maria, Bender, James, Lotze, Michael T., Goff, Stephanie L., Zacharakis, Nikolaos, Assadipour, Yasmine, Prickett, Todd D., Gartner, Jared J., Somerville, Robert, Black, Mary, Xu, Hui, Chinnasamy, Harshini, Kriley, Isaac, Lu, Lily, Wunderlich, John, Robbins, Paul F., Rosenberg, Steven, Feldman, Steven A., Trebska-McGowan, Kasia, Malekzadeh, Parisa, Payabyab, Eden, Sherry, Richard, Gokuldass, Aishwarya, Kopits, Charlene, Rabinovich, Brian, Green, Daniel S., Kamenyeva, Olena, Zoon, Kathryn C., Annunziata, Christina M., Hammill, Joanne, Helsen, Christopher, Aarts, Craig, Bramson, Jonathan, Harada, Yui, Yonemitsu, Yoshikazu, Mwawasi, Kenneth, Denisova, Galina, Giri, Rajanish, Jin, Benjamin, Campbell, Tracy, Draper, Lindsey M., Stevanovic, Sanja, Yu, Zhiya, Weissbrich, Bianca, Restifo, Nicholas P., Trimble, Cornelia L., Hinrichs, Christian S., Tsang, Kwong, Fantini, Massimo, Hodge, James W., Fujii, Rika, Fernando, Ingrid, Jochems, Caroline, Heery, Christopher, Gulley, James, Soon-Shiong, Patrick, Schlom, Jeffrey, Jing, Weiqing, Gershan, Jill, Blitzer, Grace, Weber, James, McOlash, Laura, Johnson, Bryon D., Kiany, Simin, Gangxiong, Huang, Kleinerman, Eugenie S., Klichinsky, Michael, Ruella, Marco, Shestova, Olga, Kenderian, Saad, Kim, Miriam, Scholler, John, June, Carl H., Gill, Saar, Moogk, Duane, Zhong, Shi, Liadi, Ivan, Rittase, William, Fang, Victoria, Dougherty, Janna, Perez-Garcia, Arianne, Osman, Iman, Zhu, Cheng, Varadarajan, Navin, Frey, Alan, Krogsgaard, Michelle, Landi, Daniel, Fousek, Kristen, Mukherjee, Malini, Shree, Ankita, Joseph, Sujith, Bielamowicz, Kevin, Byrd, Tiara, Ahmed, Nabil, Hegde, Meenakshi, Lee, Sylvia, Byrd, David, Thompson, John, Bhatia, Shailender, Tykodi, Scott, Delismon, Judy, Chu, Liz, Abdul-Alim, Siddiq, Ohanian, Arpy, DeVito, Anna Marie, Riddell, Stanley, Margolin, Kim, Magalhaes, Isabelle, Mattsson, Jonas, Uhlin, Michael, Nemoto, Satoshi, Villarroel, Patricio Pérez, Nakagawa, Ryosuke, Mule, James J., Mailloux, Adam W., Mata, Melinda, Nguyen, Phuong, Gerken, Claudia, DeRenzo, Christopher, Gottschalk, Stephen, Mathieu, Mélissa, Pelletier, Sandy, Stagg, John, Turcotte, Simon, Minutolo, Nicholas, Sharma, Prannda, Tsourkas, Andrew, Mockel-Tenbrinck, Nadine, Mauer, Daniela, Drechsel, Katharina, Barth, Carola, Freese, Katharina, Kolrep, Ulrike, Schult, Silke, Assenmacher, Mario, Kaiser, Andrew, Mullinax, John, Hall, MacLean, Le, Julie, Kodumudi, Krithika, Royster, Erica, Richards, Allison, Gonzalez, Ricardo, Sarnaik, Amod, Pilon-Thomas, Shari, Nielsen, Morten, Krarup-Hansen, Anders, Hovgaard, Dorrit, Petersen, Michael Mørk, Loya, Anand Chainsukh, Junker, Niels, Rivas, Charlotte, Parihar, Robin, Rooney, Cliona M., Qin, Haiying, Nguyen, Sang, Su, Paul, Burk, Chad, Duncan, Brynn, Kim, Bong-Hyun, Kohler, M. Eric, Fry, Terry, Rao, Arjun A., Teyssier, Noam, Pfeil, Jacob, Sgourakis, Nikolaos, Salama, Sofie, Haussler, David, Richman, Sarah A., Nunez-Cruz, Selene, Gershenson, Zack, Mourelatos, Zissimos, Barrett, David, Grupp, Stephan, Milone, Michael, Rodriguez-Garcia, Alba, Robinson, Matthew K., Adams, Gregory P., Santos, João, Havunen, Riikka, Siurala, Mikko, Cervera-Carrascón, Víctor, Parviainen, Suvi, Antilla, Marjukka, Hemminki, Akseli, Sethuraman, Jyothi, Santiago, Laurelis, Chen, Jie Qing, Dai, Zhimin, Sha, Huizi, Su, Shu, Ding, Naiqing, Liu, Baorui, Pasetto, Anna, Helman, Sarah R., Rosenberg, Steven A., Burgess, Melissa, Zhang, Hui, Lee, Tien, Klingemann, Hans, Nghiem, Paul, Kirkwood, John M., Rossi, John M., Sherman, Marika, Xue, Allen, Shen, Yueh-wei, Navale, Lynn, Kochenderfer, James N., Bot, Adrian, Veerapathran, Anandaraman, Wiener, Doris, Waller, Edmund K., Li, Jian-Ming, Petersen, Christopher, Blazar, Bruce R., Li, Jingxia, Giver, Cynthia R., Wang, Ziming, Grossenbacher, Steven K., Sturgill, Ian, Canter, Robert J., Murphy, William J., Zhang, Congcong, Burger, Michael C., Jennewein, Lukas, Waldmann, Anja, Mittelbronn, Michel, Tonn, Torsten, Steinbach, Joachim P., Wels, Winfried S., Williams, Jason B., Zha, Yuanyuan, Gajewski, Thomas F., Williams, LaTerrica C., Krenciute, Giedre, Kalra, Mamta, Louis, Chrystal, Xin, Gang, Schauder, David, Jiang, Aimin, Joshi, Nikhil, Cui, Weiguo, Zeng, Xue, Zhao, Zeguo, Hamieh, Mohamad, Eyquem, Justin, Gunset, Gertrude, Bander, Neil, Sadelain, Michel, Askmyr, David, Abolhalaj, Milad, Lundberg, Kristina, Greiff, Lennart, Lindstedt, Malin, Angell, Helen K., Kim, Kyoung-Mee, Kim, Seung-Tae, Kim, Sung, Sharpe, Alan D., Ogden, Julia, Davenport, Anna, Hodgson, Darren R., Barrett, Carl, Lee, Jeeyun, Kilgour, Elaine, Hanson, Jodi, Caspell, Richard, Karulin, Alexey, Lehmann, Paul, Ansari, Tameem, Schiller, Annemarie, Sundararaman, Srividya, Roen, Diana, Ayers, Mark, Levitan, Diane, Arreaza, Gladys, Liu, Fang, Mogg, Robin, Bang, Yung-Jue, O’Neil, Bert, Cristescu, Razvan, Friedlander, Philip, Wassman, Karl, Kyi, Chrisann, Oh, William, Bhardwaj, Nina, Bornschlegl, Svetlana, Gustafson, Michael P., Gastineau, Dennis A., Parney, Ian F., Dietz, Allan B., Carvajal-Hausdorf, Daniel, Mani, Nikita, Schalper, Kurt, Rimm, David, Chang, Serena, Kurland, John, Ahlers, Christoph Matthias, Jure-Kunkel, Maria, Cohen, Lewis, Maecker, Holden, Kohrt, Holbrook, Chen, Shuming, Crabill, George, Pritchard, Theresa, McMiller, Tracee, Pardoll, Drew, Pan, Fan, Topalian, Suzanne, Danaher, Patrick, Warren, Sarah, Dennis, Lucas, White, Andrew M., D’Amico, Leonard, Geller, Melissa, Disis, Mary L., Beechem, Joseph, Odunsi, Kunle, Fling, Steven, Derakhshandeh, Roshanak, Webb, Tonya J., Dubois, Sigrid, Conlon, Kevin, Bryant, Bonita, Hsu, Jennifer, Beltran, Nancy, Müller, Jürgen, Waldmann, Thomas, Duhen, Rebekka, Duhen, Thomas, Thompson, Lucas, Montler, Ryan, Weinberg, Andrew, Kates, Max, Early, Brandon, Yusko, Erik, Schreiber, Taylor H., Bivalacqua, Trinity J., Lunceford, Jared, Nebozhyn, Michael, Murphy, Erin, Loboda, Andrey, Kaufman, David R., Albright, Andrew, Cheng, Jonathan, Kang, S. Peter, Shankaran, Veena, Piha-Paul, Sarina A., Yearley, Jennifer, Seiwert, Tanguy, Ribas, Antoni, McClanahan, Terrill K., Sher, Xinwei, Liu, Xiao Qiao, Joe, Andrew, Plimack, Elizabeth, Forrest-Hay, Alex, Guyre, Cheryl A., Narumiya, Kohei, Delcommenne, Marc, Hirsch, Heather A., Deshpande, Amit, Reeves, Jason, Shu, Jenny, Zi, Tong, Michaelson, Jennifer, Law, Debbie, Trehu, Elizabeth, Sathyanaryanan, Sriram, Hodkinson, Brendan P., Hutnick, Natalie A., Schaffer, Michael E., Gormley, Michael, Hulett, Tyler, Ballesteros-Merino, Carmen, Dubay, Christopher, Afentoulis, Michael, Reddy, Ashok, David, Larry, Jayant, Kumar, Agrawal, Swati, Agrawal, Rajendra, Jeyakumar, Ghayathri, Kim, Seongho, Kim, Heejin, Silski, Cynthia, Suisham, Stacey, Heath, Elisabeth, Vaishampayan, Ulka, Vandeven, Natalie, Viller, Natasja Nielsen, O’Connor, Alison, Chen, Hui, Bossen, Bolette, Sievers, Eric, Uger, Robert, Johnson, Lisa, Kao, Hsiang-Fong, Hsiao, Chin-Fu, Lai, Shu-Chuan, Wang, Chun-Wei, Ko, Jenq-Yuh, Lou, Pei-Jen, Lee, Tsai-Jan, Liu, Tsang-Wu, Hong, Ruey-Long, Kearney, Staci J., Black, Joshua C., Landis, Benjamin J., Koegler, Sally, Hirsch, Brooke, Gianani, Roberto, Kim, Jeffrey, He, Ming-Xiao, Zhang, Bingqing, Su, Nan, Luo, Yuling, Ma, Xiao-Jun, Park, Emily, Kim, Dae Won, Copploa, Domenico, Kothari, Nishi, doo Chang, Young, Kim, Richard, Kim, Namyong, Lye, Melvin, Wan, Ee, Knaus, Hanna A., Berglund, Sofia, Hackl, Hubert, Karp, Judith E., Gojo, Ivana, Luznik, Leo, Hong, Henoch S., Koch, Sven D., Scheel, Birgit, Gnad-Vogt, Ulrike, Kallen, Karl-Josef, Wiegand, Volker, Backert, Linus, Kohlbacher, Oliver, Hoerr, Ingmar, Fotin-Mleczek, Mariola, Billingsley, James M., Koguchi, Yoshinobu, Conrad, Valerie, Miller, William, Gonzalez, Iliana, Poplonski, Tomasz, Meeuwsen, Tanisha, Howells-Ferreira, Ana, Rattray, Rogan, Campbell, Mary, Bifulco, Carlo, Bahjat, Keith, Curti, Brendan, Vetsika, E-K, Kallergi, G., Aggouraki, Despoina, Lyristi, Z., Katsarlinos, P., Koinis, Filippos, Georgoulias, V., Kotsakis, Athanasios, Martin, Nathan T., Aeffner, Famke, Cerkovnik, Logan, Pratte, Luke, Kim, Rebecca, Krueger, Joseph, Martínez-Usatorre, Amaia, Jandus, Camilla, Donda, Alena, Carretero-Iglesia, Laura, Speiser, Daniel E., Zehn, Dietmar, Rufer, Nathalie, Romero, Pedro, Panda, Anshuman, Mehnert, Janice, Hirshfield, Kim M., Riedlinger, Greg, Damare, Sherri, Saunders, Tracie, Sokol, Levi, Stein, Mark, Poplin, Elizabeth, Rodriguez-Rodriguez, Lorna, Silk, Ann, Chan, Nancy, Frankel, Melissa, Kane, Michael, Malhotra, Jyoti, Aisner, Joseph, Kaufman, Howard L., Ali, Siraj, Ross, Jeffrey, White, Eileen, Bhanot, Gyan, Ganesan, Shridar, Monette, Anne, Bergeron, Derek, Amor, Amira Ben, Meunier, Liliane, Caron, Christine, Morou, Antigoni, Kaufmann, Daniel, Liberman, Moishe, Jurisica, Igor, Mes-Masson, Anne-Marie, Hamzaoui, Kamel, Lapointe, Rejean, Mongan, Ann, Ku, Yuan-Chieh, Tom, Warren, Sun, Yongming, Pankov, Alex, Looney, Tim, Au-Young, Janice, Hyland, Fiona, Conroy, Jeff, Morrison, Carl, Glenn, Sean, Burgher, Blake, Ji, He, Gardner, Mark, Omilian, Angela R., Bshara, Wiam, Angela, Omilian, Obeid, Joseph M., Erdag, Gulsun, Smolkin, Mark E., Deacon, Donna H., Patterson, James W., Chen, Lieping, Bullock, Timothy N., Slingluff, Craig L., Loffredo, John T., Vuyyuru, Raja, Beyer, Sophie, Spires, Vanessa M., Fox, Maxine, Ehrmann, Jon M., Taylor, Katrina A., Korman, Alan J., Graziano, Robert F., Page, David, Sanchez, Katherine, Martel, Maritza, De Macedo, Mariana Petaccia, Qin, Yong, Reuben, Alex, Spencer, Christine, Guindani, Michele, Racolta, Adriana, Kelly, Brian, Jones, Tobin, Polaske, Nathan, Theiss, Noah, Robida, Mark, Meridew, Jeffrey, Habensus, Iva, Zhang, Liping, Pestic-Dragovich, Lidija, Tang, Lei, Sullivan, Ryan J., Olencki, Thomas, Hutson, Thomas, Roder, Joanna, Blackmon, Shauna, Roder, Heinrich, Stewart, John, Amin, Asim, Ernstoff, Marc S., Clark, Joseph I., Atkins, Michael B., Sosman, Jeffrey, McDermott, David F., Kluger, Harriet, Halaban, Ruth, Snzol, Mario, Asmellash, Senait, Steingrimsson, Arni, Wang, Chichung, Roman, Kristin, Clement, Amanda, Downing, Sean, Hoyt, Clifford, Harder, Nathalie, Schmidt, Guenter, Schoenmeyer, Ralf, Brieu, Nicolas, Yigitsoy, Mehmet, Madonna, Gabriele, Botti, Gerardo, Grimaldi, Antonio, Ascierto, Paolo A., Huss, Ralf, Athelogou, Maria, Hessel, Harald, Buchner, Alexander, Stief, Christian, Binnig, Gerd, Kirchner, Thomas, Sellappan, Shankar, Thyparambil, Sheeno, Schwartz, Sarit, Cecchi, Fabiola, Nguyen, Andrew, Vaske, Charles, Hembrough, Todd, Spacek, Jan, Vocka, Michal, Zavadova, Eva, Skalova, Helena, Dundr, Pavel, Petruzelka, Lubos, Francis, Nicole, Tilman, Rau T., Hartmann, Arndt, Netikova, Irena, Stump, Julia, Tufman, Amanda, Berger, Frank, Neuberger, Michael, Hatz, Rudolf, Lindner, Michael, Sanborn, Rachel E., Handy, John, Huber, Rudolf M., Winter, Hauke, Reu, Simone, Sun, Cheng, Xiao, Weihua, Tian, Zhigang, Arora, Kshitij, Desai, Niyati, Kulkarni, Anupriya, Rajurkar, Mihir, Rivera, Miguel, Deshpande, Vikram, Ting, David, Tsai, Katy, Nosrati, Adi, Goldinger, Simone, Hamid, Omid, Algazi, Alain, Tumeh, Paul, Hwang, Jimmy, Liu, Jacqueline, Chen, Lawrence, Dummer, Reinhard, Rosenblum, Michael, Daud, Adil, Tsao, Tsu-Shuen, Ashworth-Sharpe, Julia, Johnson, Donald, Bhaumik, Srabani, Bieniarz, Christopher, Couto, Joseph, Farrell, Michael, Ghaffari, Mahsa, Hubbard, Antony, Kosmeder, Jerome, Lee, Cleo, Marner, Erin, Uribe, Diana, Zhang, Hongjun, Zhang, Jian, Zhang, Wenjun, Zhu, Yifei, Morrison, Larry, Tsujikawa, Takahiro, Borkar, Rohan N., Azimi, Vahid, Kumar, Sushil, Thibault, Guillaume, Mori, Motomi, El Rassi, Edward, Clayburgh, Daniel R., Kulesz-Martin, Molly F., Flint, Paul W., Coussens, Lisa M., Villabona, Lisa, Masucci, Giuseppe V., Geiss, Gary, Birditt, Brian, Mei, Qian, Huang, Alan, Eagan, Maribeth A., Ignacio, Eduardo, Elliott, Nathan, Dunaway, Dwayne, Jung, Jaemyeong, Merritt, Chris, Sprague, Isaac, Webster, Philippa, Liang, Yan, Wenthe, Jessica, Enblad, Gunilla, Karlsson, Hannah, Essand, Magnus, Savoldo, Barbara, Dotti, Gianpietro, Höglund, Martin, Brenner, Malcolm K., Hagberg, Hans, Loskog, Angelica, Bernett, Matthew J., Moore, Gregory L., Hedvat, Michael, Bonzon, Christine, Chu, Seung, Rashid, Rumana, Avery, Kendra N., Muchhal, Umesh, Desjarlais, John, Kraman, Matthew, Kmiecik, Katarzyna, Allen, Natalie, Faroudi, Mustapha, Zimarino, Carlo, Wydro, Mateusz, Doody, Jacqueline, Srinivasa, Sreesha P., Govindappa, Nagaraja, Reddy, Praveen, Dubey, Aparajita, Periyasamy, Sankar, Adekandi, Madhukara, Dey, Chaitali, Joy, Mary, van Loo, Pieter Fokko, Veninga, Henrike, Shamsili, Setareh, Throsby, Mark, Dolstra, Harry, Bakker, Lex, Alva, Ajjai, Gschwendt, Juergen, Loriot, Yohann, Bellmunt, Joaquim, Feng, Dai, Poehlein, Christian, Powles, Thomas, Antonarakis, Emmanuel S., Drake, Charles G., Wu, Haiyan, De Bono, Johann, Bannerji, Rajat, Byrd, John, Gregory, Gareth, Opat, Stephen, Shortt, Jake, Yee, Andrew J., Raje, Noopur, Thompson, Seth, Balakumaran, Arun, Kumar, Shaji, Rini, Brian I., Choueiri, Toni K., Mariani, Mariangela, Albiges, Laurence, Haanen, John B., Larkin, James, Schmidinger, Manuela, Magazzù, Domenico, di Pietro, Alessandra, Motzer, Robert J., Borch, Troels Holz, Kongsted, Per, Pedersen, Magnus, Met, Özcan, Boudadi, Karim, Wang, Hao, Vasselli, James, Baughman, Jan E., Wigginton, Jon, Abdallah, Rehab, Ross, Ashley, Park, Jiwon, Grossenbacher, Steven, Luna, Jesus I., Withers, Sita, Culp, William, Chen, Mingyi, Monjazeb, Arta, Kent, Michael S., Chandran, Smita, Danforth, David, Yang, James, Klebanoff, Christopher, Goff, Stephanie, Paria, Biman, Sabesan, Arvind, Srivastava, Abhishek, Kammula, Udai, Richards, Jon, Faries, Mark, Andtbacka, Robert H. I., Diaz, Luis A., Le, Dung T., Yoshino, Takayuki, André, Thierry, Bendell, Johanna, Koshiji, Minori, Zhang, Yayan, Kang, S Peter, Lam, Bao, Jäger, Dirk, Bauer, Todd M., Wang, Judy S., Lee, Jean K., Manji, Gulam A., Kudchadkar, Ragini, Kauh, John S., Tang, Shande, Laing, Naomi, Falchook, Gerald, Garon, Edward B., Halmos, Balazs, Rina, Hui, Leighl, Natasha, Lee, Sung Sook, Walsh, William, Dragnev, Konstanin, Piperdi, Bilal, Rodriguez, Luis Paz-Ares, Shinwari, Nabeegha, Wei, Ziewn, Maas, Mary L, Deeds, Michael, Armstrong, Adam, Peterson, Tim, Steinmetz, Sue, Herzog, Thomas, Backes, Floor J., Copeland, Larry, Del Pilar Estevez Diz, Maria, Hare, Thomas W., Huh, Warner, Kim, Byoung-Gie, Moore, Kathleen M., Oaknin, Ana, Small, William, Tewari, Krishnansu S., Monk, Bradley J., Kamat, Ashish M., Nam, Kijoeng, De Santis, Maria, Dreicer, Robert, Hahn, Noah M., Perini, Rodolfo, Siefker-Radtke, Arlene, Sonpavde, Guru, de Wit, Ronald, Witjes, J. Alfred, Keefe, Stephen, Bajorin, Dean, Armand, Philippe, Kuruvilla, John, Moskowitz, Craig, Hamadani, Mehdi, Zinzani, Pier Luigi, Chlosta, Sabine, Bartlett, Nancy, Sabado, Rachel, Saenger, Yvonne, William, Loging, Donovan, Michael Joseph, Sacris, Erlinda, Mandeli, John, Salazar, Andres M., Powderly, John, Brody, Joshua, Nemunaitis, John, Emens, Leisha, Patnaik, Amita, McCaffery, Ian, Miller, Richard, Laport, Ginna, Coveler, Andrew L., Smith, David C., Grilley-Olson, Juneko E., Goel, Sanjay, Gardai, Shyra J., Law, Che-Leung, Means, Gary, Manley, Thomas, Marrone, Kristen A., Rosner, Gary, Anagnostou, Valsamo, Riemer, Joanne, Wakefield, Jessica, Zanhow, Cynthia, Baylin, Stephen, Gitlitz, Barbara, Brahmer, Julie, Signoretti, Sabina, Li, Wenting, Schloss, Charles, Michot, Jean-Marie, Ding, Wei, Christian, Beth, Marinello, Patricia, Shipp, Margaret, Najjar, Yana G., Lin, Butterfield, Lisa H., Tarhini, Ahmad A., Davar, Diwakar, Zarour, Hassane, Rush, Elizabeth, Sander, Cindy, Fu, Siqing, Bauer, Todd, Molineaux, Chris, Bennett, Mark K., Orford, Keith W., Papadopoulos, Kyriakos P., Padda, Sukhmani K., Shah, Sumit A., Colevas, A Dimitrios, Narayanan, Sujata, Fisher, George A., Supan, Dana, Wakelee, Heather A., Aoki, Rhonda, Pegram, Mark D., Villalobos, Victor M., Liu, Jie, Takimoto, Chris H., Chao, Mark, Volkmer, Jens-Peter, Majeti, Ravindra, Weissman, Irving L., Sikic, Branimir I., Yu, Wendy, Conlin, Alison, Ruzich, Janet, Lewis, Stacy, Acheson, Anupama, Kemmer, Kathleen, Perlewitz, Kelly, Moxon, Nicole M., Mellinger, Staci, McArthur, Heather, Juhler-Nøttrup, Trine, Desai, Jayesh, Markman, Ben, Sandhu, Shahneen, Gan, Hui, Friedlander, Michael L., Tran, Ben, Meniawy, Tarek, Lundy, Joanne, Colyer, Duncan, Ameratunga, Malaka, Norris, Christie, Yang, Jason, Li, Kang, Wang, Lai, Luo, Lusong, Qin, Zhen, Mu, Song, Tan, Xuemei, Song, James, Millward, Michael, Katz, Matthew H. G., Bauer, Todd W., Varadhachary, Gauri R., Acquavella, Nicolas, Merchant, Nipun, Petroni, Gina, Rahma, Osama E., Chen, Mei, Song, Yang, Puhlmann, Markus, Khattri, Arun, Brisson, Ryan, Harvey, Christopher, Shah, Jatin, Mateos, Maria Victoria, Matsumoto, Morio, Blacklock, Hilary, Rocafiguera, Albert Oriol, Goldschmidt, Hartmut, Iida, Shinsuke, Yehuda, Dina Ben, Ocio, Enrique, Rodríguez-Otero, Paula, Jagannath, Sundar, Lonial, Sagar, Kher, Uma, San-Miguel, Jesus, de Oliveira, Moacyr Ribeiro, Yimer, Habte, Rifkin, Robert, Schjesvold, Fredrik, Ghori, Razi, Spreafico, Anna, Lee, Victor, Ngan, Roger K. C., To, Ka Fai, Ahn, Myung Ju, Ng, Quan Sing, Lin, Jin-Ching, Swaby, Ramona F., Gause, Christine, Saraf, Sanatan, Chan, Anthony T. C., Lam, Elaine, Tannir, Nizar M., Meric-Bernstam, Funda, Gross, Matt, MacKinnon, Andy, Whiting, Sam, Voss, Martin, Yu, Evan Y., Albertini, Mark R., Ranheim, Erik A., Hank, Jacquelyn A., Zuleger, Cindy, McFarland, Thomas, Collins, Jennifer, Clements, Erin, Weber, Sharon, Weigel, Tracey, Neuman, Heather, Hartig, Greg, Mahvi, David, Henry, MaryBeth, Gan, Jacek, Yang, Richard, Carmichael, Lakeesha, Kim, KyungMann, Gillies, Stephen D., Sondel, Paul M., Subbiah, Vivek, Noffsinger, Lori, Hendricks, Kyle, Bosch, Marnix, Lee, Jay M., Lee, Mi-Heon, Goldman, Jonathan W., Baratelli, Felicita E., Schaue, Dorthe, Wang, Gerald, Rosen, Frances, Yanagawa, Jane, Walser, Tonya C., Lin, Ying Q., Adams, Sharon, Marincola, Franco M., Tumeh, Paul C., Abtin, Fereidoun, Suh, Robert, Reckamp, Karen, Wallace, William D., Zeng, Gang, Elashoff, David A., Sharma, Sherven, Dubinett, Steven M., Pavlick, Anna C., Gastman, Brian, Hanks, Brent, Keler, Tibor, Davis, Tom, Vitale, Laura A., Sharon, Elad, Morishima, Chihiro, Cheever, Martin, Heery, Christopher R., Kim, Joseph W., Lamping, Elizabeth, Marte, Jennifer, McMahon, Sheri, Cordes, Lisa, Fakhrejahani, Farhad, Madan, Ravi, Salazar, Rachel, Zhang, Maggie, Helwig, Christoph, Gulley, James L, Li, Roger, Amrhein, John, Cohen, Zvi, Champagne, Monique, Kamat, Ashish, Aznar, M. Angela, Labiano, Sara, Diaz-Lagares, Angel, Esteller, Manel, Sandoval, Juan, Barbee, Susannah D., Bellovin, David I., Timmer, John C., Wondyfraw, Nebiyu, Johnson, Susan, Park, Johanna, Chen, Amanda, Mkrtichyan, Mikayel, Razai, Amir S., Jones, Kyle S., Hata, Chelsie Y., Gonzalez, Denise, Deveraux, Quinn, Eckelman, Brendan P., Borges, Luis, Bhardwaj, Rukmini, Puri, Raj K., Suzuki, Akiko, Leland, Pamela, Joshi, Bharat H., Bartkowiak, Todd, Jaiswal, Ashvin, Ager, Casey, Ai, Midan, Budhani, Pratha, Chin, Renee, Hong, David, Curran, Michael, Hastings, William D., Pinzon-Ortiz, Maria, Murakami, Masato, Dobson, Jason R., Quinn, David, Wagner, Joel P., Rong, Xianhui, Shaw, Pamela, Dammassa, Ernesta, Guan, Wei, Dranoff, Glenn, Cao, Alexander, Fulton, Ross B., Leonardo, Steven, Fraser, Kathryn, Kangas, Takashi O., Ottoson, Nadine, Bose, Nandita, Huhn, Richard D., Graff, Jeremy, Lowe, Jamie, Gorden, Keith, Uhlik, Mark, O’Neill, Thomas, Widger, Jenifer, Crocker, Andrea, He, Li-Zhen, Weidlick, Jeffrey, Sundarapandiyan, Karuna, Ramakrishna, Venky, Storey, James, Thomas, Lawrence J., Goldstein, Joel, Marsh, Henry C., Grailer, Jamison, Gilden, Julia, Stecha, Pete, Garvin, Denise, Hartnett, Jim, Fan, Frank, Cong, Mei, Cheng, Zhi-jie Jey, Hinner, Marlon J., Aiba, Rachida-Siham Bel, Schlosser, Corinna, Jaquin, Thomas, Allersdorfer, Andrea, Berger, Sven, Wiedenmann, Alexander, Matschiner, Gabriele, Schüler, Julia, Moebius, Ulrich, Rothe, Christine, Shane, Olwill A., Horton, Brendan, Spranger, Stefani, Moreira, Dayson, Adamus, Tomasz, Zhao, Xingli, Swiderski, Piotr, Pal, Sumanta, Kortylewski, Marcin, Kosmides, Alyssa, Necochea, Kevin, Mahoney, Kathleen M., Shukla, Sachet A., Patsoukis, Nikolaos, Chaudhri, Apoorvi, Pham, Hung, Hua, Ping, Bu, Xia, Zhu, Baogong, Hacohen, Nir, Wu, Catherine J., Fritsch, Edward, Boussiotis, Vassiliki A., Freeman, Gordon J., Moran, Amy E., Polesso, Fanny, Lukaesko, Lisa, Rådestad, Emelie, Egevad, Lars, Sundberg, Berit, Henningsohn, Lars, Levitsky, Victor, Rafelson, William, Reagan, John L., Fast, Loren, Sasikumar, Pottayil, Sudarshan, Naremaddepalli, Ramachandra, Raghuveer, Gowda, Nagesh, Samiulla, Dodheri, Chandrasekhar, Talapaneni, Adurthi, Sreenivas, Mani, Jiju, Nair, Rashmi, Dhudashia, Amit, Gowda, Nagaraj, Ramachandra, Murali, Sankin, Alexander, Gartrell, Benjamin, Cumberbatch, Kerwin, Huang, Hongying, Stern, Joshua, Schoenberg, Mark, Zang, Xingxing, Swanson, Ryan, Kornacker, Michael, Evans, Lawrence, Rickel, Erika, Wolfson, Martin, Valsesia-Wittmann, Sandrine, Shekarian, Tala, Simard, François, Nailo, Rodrigo, Dutour, Aurélie, Jallas, Anne-Catherine, Caux, Christophe, and Marabelle, Aurélien

Published
2016
Full Text
View/download PDF

229. A subset of malignant phyllodes tumors harbors alterations in the Rb/p16 pathway.

Author

Cimino-Mathews, Ashley, Hicks, Jessica L., Sharma, Rajni, Vang, Russell, Illei, Peter B., De Marzo, Angelo, Emens, Leisha A., and Argani, Pedram

Subjects
BREAST tumors, NOCTUIDAE, P16 gene, BREAST cancer, IMMUNOHISTOCHEMISTRY, SYSTEMATIC reviews, IN situ hybridization
Abstract

Breast phyllodes tumors are fibroepithelial neoplasms with variable risk of aggressive local recurrence and distant metastasis, and the molecular pathogenesis is unclear. Here, we systematically study p16 and Rb expression in 34 phyllodes tumors in relation to proliferation. Tissue microarrays were constructed from 10 benign, 10 borderline, and 14 malignant phyllodes (5 cores/tumor) and from 10 fibroadenomas (2 cores/tumor). Tissue microarrays were labeled by immunohistochemistry for p16, Rb, and Ki-67 and by in situ hybridization for high-risk human papillomavirus. Cytoplasmic and nuclear p16 were scored by percentage labeling (0%-100%, diffuse N95%) and intensity. Nuclear Rb was scored by percentage labeling (0%-100%, diffuse N75%) and intensity. p16 and Rb labeling were repeated on whole sections of cases with Rb loss on the tissue microarray. Twenty-nine percent (4/14) malignant phyllodes showed diffuse strong p16 labeling with Rb loss in malignant cells (diffuse p16+/Rb-), whereas 21% (3/14) malignant phyllodes showed the reverse pattern of p16 loss with diffuse strong Rb (p16-/diffuse Rb+). Results were consistent between tissue microarrays and whole sections. No borderline phyllodes, benign phyllodes, or fibroadenoma showed diffuse p16+/Rb- or p16-/diffuse Rb+ phenotypes. No cases contained high-risk human papillomavirus. Average Ki-67 proliferation indices were 15% in malignant phyllodes, 1.7% in borderline phyllodes, 0.5% in benign phyllodes, and 0% in fibroadenoma. Ki-67 was highest in malignant phyllodes with diffuse p16+/Rb- labeling. In summary, 50% malignant phyllodes display evidence of Rb/p16 pathway alterations, likely reflecting p16 or Rb inactivation. These and other mechanisms may contribute to the increased proliferation in malignant phyllodes relative to other fibroepithelial neoplasms. [ABSTRACT FROM AUTHOR]

Published
2013
Full Text
View/download PDF

230. Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study.

Author

Cimino-Mathews, Ashley, Xiaobu Ye, Meeker, Alan, Argani, Pedram, and Emens, Leisha A.

Subjects
TRIPLE-negative breast cancer, CANCER relapse, LYMPHOCYTES, PILOT projects, IMMUNOLOGY, GENE expression
Abstract

Tumor-infiltrating lymphocytes (TILs) convey clinically relevant information for primary breast cancers (PBCs). However, limited data characterizing the immunobiology of metastatic breast cancers (MBCs) are available. Here, we examine TILs in surgically resected MBCs relative to their matched PBCs. Tissue microarrays of PBCs and MBCs were labeled for CD3 (total T cells), CD4 (helper T cells), CD8 (cytotoxic T cells), FoxP3 (regulatory T cells), and CD20 (B cells) to characterize TILs. Expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor-2 (HER-2) classified the tumors as luminal (ER+/PR+/HER-2-), triple negative (ER-/PR-/HER-2-), or HER-2+ (ER-/PR-/HER-2+). These analyses reveal 5 novel findings. First, MBCs overall contained fewer TILs (mean, 35.1 CD3+ TILs/high-power field [hpf]) than their matched PBCs (mean, 23.6 CD3+ TILS/ hpf), with fewer CD20+ cells than CD3+ cells in PBC and MBC (P = .0247). Second, the number of CD3+, CD8+, CD4+, and FoxP3 TILs was decreased in triple-negative MBCs relative to matched PBCs, whereas only CD8+ TILs were decreased in luminal MBCs relative to matched PBCs. Third, triple-negative MBCs contain fewer TILS (mean, 16 CD3+ TILs/hpf) than luminal MBCs (mean, 21.7 CD3+ TILs/hpf). Fourth, brain metastases contained fewer TILs relative to MBC from other sites. Finally, in this series, a CD8+/ FoxP3+ T-cell ratio of 3 or greater in PBCs was associated with improved overall survival from diagnosis, whereas a CD8+/FoxP3+ T-cell ratio less than 3 in MBCs at first relapse was associated with improved overall survival. These findings suggest that evaluating the immunologic microenvironment of both PBCs and MBCs may yield important clinical information to guide breast cancer prognosis and therapy. [ABSTRACT FROM AUTHOR]

Published
2013
Full Text
View/download PDF

231. Chemoimmunotherapy: reengineering tumor immunity.

Author

Chen, Gang and Emens, Leisha

Subjects
*CANCER chemotherapy, *CANCER immunotherapy, *IMMUNOSUPPRESSIVE agents, *ANTINEOPLASTIC agents, *IMMUNE response, *CELL death, *CANCER cells
Abstract

Cancer chemotherapy drugs have long been considered immune suppressive. However, more recent data indicate that some cytotoxic drugs effectively treat cancer in part by facilitating an immune response to the tumor when given at the standard dose and schedule. These drugs induce a form of tumor cell death that is immunologically active, thereby inducing an adaptive immune response specific for the tumor. In addition, cancer chemotherapy drugs can promote tumor immunity through ancillary and largely unappreciated immunologic effects on both the malignant and normal host cells present within the tumor microenvironment. These more subtle immunomodulatory effects are dependent on the drug itself, its dose, and its schedule in relation to an immune-based intervention. The recent approvals of two new immune-based therapies for prostate cancer and melanoma herald a new era in cancer treatment and have led to heightened interest in immunotherapy as a valid approach to cancer treatment. A detailed understanding of the cellular and molecular basis of interactions between chemotherapy drugs and the immune system is essential for devising the optimal strategy for integrating new immune-based therapies into the standard of care for various cancers, resulting in the greatest long-term clinical benefit for cancer patients. [ABSTRACT FROM AUTHOR]

Published
2013
Full Text
View/download PDF

232. Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade.

Author

Emens LA and Emens, Leisha A

Subjects
BREAST tumor treatment, THERAPEUTIC use of monoclonal antibodies, CANCER vaccines, TUMOR antigens, ANTIGENS, BREAST tumors, IMMUNOTHERAPY, RESEARCH funding, THERAPEUTICS, VACCINES
Abstract

Breast cancer is immunogenic, and infiltrating immune cells in primary breast tumors convey important clinical prognostic and predictive information. Furthermore, the immune system is critically involved in clinical responses to some standard cancer therapies. Early breast cancer vaccine trials have established the safety and bioactivity of breast cancer immunotherapy, with hints of clinical activity. Novel strategies for modulating regulators of immunity, including regulatory T cells, myeloid-derived suppressor cells and immune checkpoint pathways (monoclonal antibodies specific for the cytotoxic T-lymphocyte antigen-4 or programmed death), are now available. In particular, immune checkpoint blockade has enormous therapeutic potential. Integrative breast cancer immunotherapies that strategically combine established breast cancer therapies with breast cancer vaccines, immune checkpoint blockade or both should result in durable clinical responses and increased cures. [ABSTRACT FROM AUTHOR]

Published
2012
Full Text
View/download PDF

233. Re-purposing cancer therapeutics for breast cancer immunotherapy.

Author

Emens, Leisha

Subjects
*CANCER treatment, *BREAST cancer, *IMMUNOTHERAPY, *IMMUNE response, *PROSTATE cancer, *IMMUNOMODULATORS, *DOXORUBICIN, *CYCLOPHOSPHAMIDE
Abstract

After decades of work to develop immune-based therapies for cancer, the first drugs designed specifically to engage the host anti-tumor immune response for therapeutic benefit were recently approved for clinical use. Sipuleucel-T, a vaccine for advanced prostate cancer, and ipilimumab, a monoclonal antibody that mitigates the negative impact of cytotoxic T lymphocyte antigen-4 signaling on tumor immunity, provide a modest clinical benefit in some patients. The arrival of these drugs in the clinic is a significant advance that we can capitalize on for even better clinical outcomes. The strategic and scientifically rational integration of vaccines and other direct immunomodulators with standard cancer therapeutics should lead to therapeutic synergy and high rates of tumor rejection. This review focuses on the use of cyclophosphamide, doxorubicin, and HER-2-specific monoclonal antibodies to dissect mechanisms of immune tolerance relevant to breast cancer patients and illustrates how appropriate preclinical models can powerfully inform clinical translation. The immune-modulating activity of targeted, pathway-specific, small molecule therapeutics is also discussed. Fully understanding how cancer drugs impact the immune system should lead to the ultimate personalized cancer medicine: effective combinatorial immunotherapy strategies that simultaneously target signaling pathways essential for tumor growth and progression, and systematically break multiple, distinct immune tolerance pathways to maximize tumor rejection and effect cure. [ABSTRACT FROM AUTHOR]

Published
2012
Full Text
View/download PDF

234. A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer.

Author

Higgins, Michaela, Prowell, Tatiana, Blackford, Amanda, Byrne, Celia, Khouri, Nagi, Slater, Shannon, Jeter, Stacie, Armstrong, Deborah, Davidson, Nancy, Emens, Leisha, Fetting, John, Powers, Pendleton, Wolff, Antonio, Green, Hannah, Thibert, Jacklyn, Rae, James, Folkerd, Elizabeth, Dowsett, Mitchell, Blumenthal, Roger, and Garber, Judy

Abstract

Observational studies have demonstrated a decreased incidence of cancers among users of HMG CoA reductase inhibitors (statins) and a reduced risk of recurrence among statin users diagnosed with early stage breast cancer. We initiated a prospective study to identify potential biomarkers of simvastatin chemopreventive activity that can be validated in future trials. The contralateral breast of women with a previous history of breast cancer was used as a high-risk model. Eligible women who had completed all planned treatment of a prior stage 0-III breast cancer received simvastatin 40 mg orally daily for 24-28 weeks. At baseline and end-of-study, we measured circulating concentrations of high-sensitivity C-reactive protein (hsCRP), estrogens, and fasting lipids; breast density on contralateral breast mammogram; and quality of life by Rand Short Form 36-Item health survey. Fifty women were enrolled with a median age of 53 years. Total cholesterol, LDL cholesterol, triglyceride, and hsCRP fell significantly during the study ( P values < 0.001, <0.001, 0.003, and 0.05, respectively). Estrone sulfate concentrations decreased with simvastatin treatment ( P = 0.01 overall), particularly among post-menopausal participants ( P = 0.006). We did not observe a significant change in circulating estradiol or estrone concentrations, contralateral mammographic breast density, or reported physical functioning or pain scores. This study demonstrates the feasibility of short-term biomarker modulation studies using the contralateral breast of high-risk women. Simvastatin appears to modulate estrone sulfate concentrations and its potential chemopreventive activity in breast cancer warrants further investigation. [ABSTRACT FROM AUTHOR]

Published
2012
Full Text
View/download PDF

235. Docetaxel metabolism is not altered by imatinib: findings from an early phase study in metastatic breast cancer.

Author

Connolly, Roisin, Rudek, Michelle, Garrett-Mayer, Elizabeth, Jeter, Stacie, Donehower, Michele, Wright, Laurie, Zhao, Ming, Fetting, John, Emens, Leisha, Stearns, Vered, Davidson, Nancy, Baker, Sharyn, and Wolff, Antonio

Abstract

Docetaxel is primarily metabolized by CYP3A4 and susceptible to alterations in clearance by CYP3A4 inhibition and induction. Imatinib is a CYP3A4 inhibitor. A phase I study of docetaxel and imatinib in metastatic breast cancer (MBC) was conducted to test the hypothesis that imatinib decreased docetaxel clearance. Docetaxel was administered weekly × 3 with daily imatinib, repeated every 28 days; during cycle 1, imatinib was started on day 8. Docetaxel and imatinib pharmacokinetics, and hepatic CYP3A4 activity (erythromycin breath test) were evaluated during cycles 1 and 2. Toxicity and efficacy were assessed. Twelve patients were enrolled to three docetaxel/imatinib dose levels: 20 mg/m/600 mg (DL1), 25 mg/m/600 mg (DL2), and 25 mg/m/400 mg (DL2a). Median number of prior chemotherapy regimens was 2 (range, 0-8). Toxicities were primarily observed at DL2; dose-limiting toxicities were Grade 3 transaminase elevations and diarrhea, and 5 patients had grade 2 nausea. Two patients had partial responses (7 months); two stable disease (2 and 4 months); five had progressive disease. Despite a 42% decrease in CYP3A4 activity after 3 weeks of imatinib co-administration, docetaxel clearance was unchanged. Mean ± standard deviation steady-state imatinib trough concentration (2.6 ± 1.2 μg/ml) was approximately 2.6-fold higher than previously observed in other cancer populations, and likely contributed to the poor tolerability of the combination in MBC. In conclusion, imatinib inhibited CYP3A4 but did not affect docetaxel clearance. Clinically, further investigation of this combination in MBC is not warranted due to excessive toxicities. However, these unexpected pharmacokinetic findings support further investigation of mechanisms underlying docetaxel elimination pathways. [ABSTRACT FROM AUTHOR]

Published
2011
Full Text
View/download PDF

236. The multikinase inhibitor Sorafenib reverses the suppression of IL-12 and enhancement of IL-10 by PGE2 in murine macrophages

Author

Edwards, Justin P. and Emens, Leisha A.

Subjects
*ENZYME inhibitors, *INTERLEUKIN-12, *INTERLEUKIN-10, *PROSTAGLANDINS E, *MACROPHAGES, *CYTOKINES, *MITOGEN-activated protein kinases, *ENZYME regulation
Abstract

Abstract: Classical activating stimuli like LPS drive macrophages to secrete a battery of inflammatory cytokines, including interleukin (IL)-12/23, through Toll-like receptor (TLR) signaling. TLR activation in the presence of some factors, including prostaglandin E2 (PGE2), promotes an anti-inflammatory cytokine profile, with production of IL-10 and suppression of IL-12/23 secretion. Extracellular signal-regulated kinase (ERK) is a key regulator of macrophage IL-10 production. Since it inhibits ERK, we investigated the impact of Sorafenib on the cytokine profile of macrophages. In the presence of PGE2, Sorafenib restored the secretion of IL-12 and suppressed IL-10 production. Moreover, IL-12 secretion was enhanced by Sorafenib under conditions of TLR ligation alone. Furthermore, the impact of tumor culture supernatants, cholera toxin, and cAMP analogs (which suppress IL-12 secretion), was reversed by Sorafenib. Sorafenib inhibited the activation of the MAP kinase p38 and its downstream target mitogen and stress activated protein kinase (MSK), and partially inhibited protein kinase B (AKT) and its subsequent inactivation of the downstream target glycogen synthase kinase 3-β (GSK3-β). Interference with these pathways, which are pivotal in determining the balance of inflammatory versus anti-inflammatory cytokines, provides a potential mechanism by which Sorafenib can modulate the macrophage cytokine phenotype. These data raise the possibility that the use of Sorafenib as cancer therapy could potentially reverse the immunosuppressive cytokine profile of tumor-associated macrophages, rendering the tumor microenvironment more conducive to an anti-tumor immune response. [ABSTRACT FROM AUTHOR]

Published
2010
Full Text
View/download PDF

238. Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation.

Author

Emens LA, Asquith JM, Leatherman JM, Kobrin BJ, Petrik S, Laiko M, Levi J, Daphtary MM, Biedrzycki B, Wolff AC, Stearns V, Disis ML, Ye X, Piantadosi S, Fetting JH, Davidson NE, Jaffee EM, Emens, Leisha A, Asquith, Justin M, and Leatherman, James M

Published
2009
Full Text
View/download PDF

239. Editorial.

Author

Emens, Leisha A.

Subjects
*CANCER, *VACCINES, *CANCER treatment, *IMMUNE response, *HOMEOSTASIS
Abstract

The article discusses the role of cancer vaccines toward the next revolution in cancer therapy. Active immunization to induce a therapeutic host antitumor immune response has great potential to complement traditional cancer therapies in a non-overlapping way. It is aimed at retooling the existing host-tumor interaction, tipping the balance of immunologic homeostasis in favor of the cancer patient.

Published
2006
Full Text
View/download PDF

240. Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response.

Author

Ercolini, Anne M., Ladle, Brian H., Manning, Elizabeth A., Pfamienstiel, Lukas W., Armstrong, Todd D., Machiels, Jean-Pascal H., Bieler, Joan G., Emens, Leisha A., Reilly, R. Todd, and Jaffee, Elizabeth M.

Subjects
T cells, ANTINEOPLASTIC agents, CYCLOPHOSPHAMIDE, IMMUNE response, CANCER vaccines, TUMOR antigens, TRANSGENIC mice, DRUG therapy
Abstract

A major barrier to successful antitumor vaccination is tolerance of high-avidity T cells specific to tumor antigens. In keeping with this notion, HER-2/neu (neu)-targeted vaccines, which raise strong CD8+ T cell responses to a dominant peptide (RNEU420-429) in WT FVB/N mice and protect them from a neu-expressing tumor challenge, fail to do so in MMTV-neu (neu-N) transgenic mice. However, treatment of neu-N mice with vaccine and cyclophosphamide-containing chemotherapy resulted in tumor protection in a proportion of mice. This effect was specifically abrogated by the transfer of neu-N-derived CD4+ CD25+ T cells. RNEU420-429-specific CD8+ T cells were identified only in neu-N mice given vaccine and cyclophosphamide chemotherapy which rejected tumor challenge. Tetramer-binding studies demonstrated that cyclophosphamide pretreatment allowed the activation of high-avidity RNEU420-429-specific CD8+ T cells comparable to those generated from vaccinated FVB/N mice. Cyctophosphamide seemed to inhibit regulatory T (T reg) cells by selectively depleting the cycling population of CD4+CD25+ T cells in neu-N mice. These findings demonstrate that neu-N mice possess latent pools of high-avidity neu-specific CD8+ T cells that can be recruited to produce an effective antitumor response if T reg cells are blocked or removed by using approaches such as administration of cyclophosphamide before vaccination. [ABSTRACT FROM AUTHOR]

Published
2005
Full Text
View/download PDF

242. Virtual patient analysis identifies strategies to improve the performance of predictive biomarkers for PD-1 blockade.

Author

Arulraj, Theinmozhi, Hanwen Wang, Deshpande, Atul, Varadhan, Ravi, Emens, Leisha A., Jaffee, Elizabeth M., Fertig, Elana J., Santa-Maria, Cesar A., and Popel, Aleksander S.

Subjects
*TRIPLE-negative breast cancer, *TUMOR markers, *PATIENT selection, *FEATURE selection, *SIMULATED patients
Abstract

Patients with metastatic triple-negative breast cancer (TNBC) show variable responses to PD-1 inhibition. Efficient patient selection by predictive biomarkers would be desirable but is hindered by the limited performance of existing biomarkers. Here, we leveraged in silico patient cohorts generated using a quantitative systems pharmacology model of metastatic TNBC, informed by transcriptomic and clinical data, to explore potential ways to improve patient selection. We evaluated and quantified the performance of 90 biomarker candidates, including various cellular and molecular species, at different cutoffs by a cutoff-based biomarker testing algorithm combined with machine learning-based feature selection. Combinations of pretreatment biomarkers improved the specificity compared to single biomarkers at the cost of reduced sensitivity. On the other hand, early on-treatment biomarkers, such as the relative change in tumor diameter from baseline measured at two weeks after treatment initiation, achieved remarkably higher sensitivity and specificity. Further, blood-based biomarkers had a comparable ability to tumor-or lymph node-based biomarkers in identifying a subset of responders, potentially suggesting a less invasive way for patient selection. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

245. A New Landscape of Testing and Therapeutics in Metastatic Breast Cancer

Author

Jagannathan, Geetha, White, Marissa J., Xian, Rena R., Emens, Leisha A., and Cimino-Mathews, Ashley

Abstract

Predictive biomarker testing on metastatic breast cancer is essential for determining patient eligibility for targeted therapeutics. The National Comprehensive Cancer Network currently recommends assessment of specific biomarkers on metastatic tumor subtypes, including hormone receptors, HER2, and BRCA1/2mutations, on all newly metastatic breast cancers subtypes; programmed death-ligand 1 on metastatic triple-negative carcinomas; and PIK3CAmutation status on estrogen receptor-positive carcinomas. In select circumstances mismatch repair protein deficiency and/or microsatellite insufficiency, tumor mutation burden, and NTRKtranslocation status are also testing options. Novel biomarker testing, such as detecting PIK3CAmutations in circulating tumor DNA, is expanding in this rapidly evolving arena.

Published
2021
Full Text
View/download PDF

246. Perspectives in immunotherapy: meeting report from the "Immunotherapy Bridge 2018" (28–29 November, 2018, Naples, Italy).

Author

Ascierto, Paolo A., Bifulco, Carlo, Buonaguro, Luigi, Emens, Leisha A., Ferris, Robert L., Fox, Bernard A., Delgoffe, Greg M., Galon, Jérôme, Gridelli, Cesare, Merlano, Marco, Nathan, Paul, Odunsi, Kunle, Okada, Hideho, Paulos, Chrystal M., Pignata, Sandro, Schalper, Kurt A., Spranger, Stefani, Tortora, Giampaolo, Zarour, Hassane, and Butterfield, Lisa H.

Subjects
SKIN cancer, IMMUNOTHERAPY, TUMOR microenvironment, IMMUNE response
Abstract

Immunotherapy is now widely established as a potent and effective treatment option across several types of cancer. However, there is increasing recognition that not all patients respond to immunotherapy, focusing attention on the immune contexture of the tumor microenvironment (TME), drivers of the immune response and mechanisms of tumor resistance to immunity. The development of novel immunotherapeutics and their use in combination with checkpoint inhibitors and other standard of care and novel treatment modalities is an area of particular attention across several tumor types, including melanoma, lung, ovarian, breast, pancreatic, renal, head and neck, brain and non-melanoma skin cancers. The 4th Immunotherapy Bridge meeting (28–29 November, 2018, Naples, Italy) focused on a wide range of evolving topics and trends in the field of cancer immunotherapy and key presentations from this meeting are summarised in this report. [ABSTRACT FROM AUTHOR]

Published
2019
Full Text
View/download PDF

247. Tumor immune microenvironment and genomic evolution in a patient with metastatic triple negative breast cancer and a complete response to atezolizumab.

Author

Molinero, Luciana, Li, Yijin, Chang, Ching-Wei, Maund, Sophia, Berg, Maureen, Harrison, Jeanne, Fassò, Marcella, O'Hear, Carol, Hegde, Priti, and Emens, Leisha A.

Subjects
TRIPLE-negative breast cancer, TUMOR microenvironment, ANDROGEN receptors
Abstract

Background: Metastatic TNBC (mTNBC) has a poor prognosis and few treatment options. The anti-PD-L1 antibody atezolizumab demonstrated clinical activity in mTNBC patients with PD-L1-positive tumor-infiltrating immune cells. The current study describes the tumor immune microenvironment (TiME) and genomic evolution across sequential therapies in a patient with a 31-year history of TNBC and a complete response (CR) to atezolizumab monotherapy. Materials and methods: In 1986, the patient had surgery and radiotherapy (XRT) for newly diagnosed TNBC, followed by surgery and adjuvant chemotherapy for two locoregional recurrences. She developed mTNBC in 2009 and was sequentially treated with capecitabine, gemcitabine-carboplatin-iniparib (GCI), XRT and an experimental vaccine. She experienced disease progression (PD) to all these therapies. In 2013, she had a PD-L1 positive tumor and enrolled in a phase 1 atezolizumab monotherapy study (PCD4989g; NCT01375842). She received atezolizumab for 1 year with initial pseudo-progression followed by a partial response. After 1 year without treatment she experienced PD, reinitiated atezolizumab and subsequently achieved CR. Tumor specimens were collected at numerous times between 2008 and 2015 and assessed by immunohistochemistry, RNA-seq and DNA-seq. Results: TiME biomarkers, including CD8, ICs and PD-L1 on IC, increased after capecitabine and remained high after GCI, XRT and through pseudo-progression on atezolizumab. At PD post-atezolizumab exposure, TiME biomarkers decreased but PD-L1 status remained positive. Immune-related RNA signatures confirmed these findings. TNBC subtyping revealed evolution from luminal androgen receptor (LAR) to basal-like immune activated (BLIA). Genomic profiling showed truncal alterations in RB1 and TP53, while the presence of other genomic alterations varied over time. Tumor mutational burden peaked after XRT and declined after atezolizumab exposure. Conclusions: This case report describes the evolution of TiME and TNBC molecular subtypes/genomics over time with sequential therapies in a TNBC patient with a CR to atezolizumab monotherapy. These data suggest the TiME is pliable and may be manipulated to maximize response to immunotherapy (NCT01375842, https://clinicaltrials.gov/ct2/show/NCT01375842?term=NCT01375842&rank=1). [ABSTRACT FROM AUTHOR]

Published
2019
Full Text
View/download PDF

248. Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors.

Author

Zhu, Li, Narloch, Jessica L., Onkar, Sayali, Joy, Marion, Broadwater, Gloria, Luedke, Catherine, Hall, Allison, Kim, Rim, Pogue-Geile, Katherine, Sammons, Sarah, Nayyar, Naema, Chukwueke, Ugonma, Brastianos, Priscilla K., Anders, Carey K., Soloff, Adam C., Vignali, Dario A. A., Tseng, George C., Emens, Leisha A., Lucas, Peter C., and Blackwell, Kimberly L.

Subjects
METASTATIC breast cancer, SUPPRESSOR cells, BREAST cancer, TUMORS, DENDRITIC cells
Abstract

The interplay between the immune system and tumor progression is well recognized. However, current human breast cancer immunophenotyping studies are mostly focused on primary tumors with metastatic breast cancer lesions remaining largely understudied. To address this gap, we examined exome-capture RNA sequencing data from 50 primary breast tumors (PBTs) and their patient-matched metastatic tumors (METs) in brain, ovary, bone and gastrointestinal tract. We used gene expression signatures as surrogates for tumor infiltrating lymphocytes (TILs) and compared TIL patterns in PBTs and METs. Enrichment analysis and deconvolution methods both revealed that METs had a significantly lower abundance of total immune cells, including CD8+ T cells, regulatory T cells and dendritic cells. An exception was M2-like macrophages, which were significantly higher in METs across the organ sites examined. Multiplex immunohistochemistry results were consistent with data from the in-silico analysis and showed increased macrophages in METs. We confirmed the finding of a significant reduction in immune cells in brain METs (BRMs) by pathologic assessment of TILs in a set of 49 patient-matched pairs of PBT/BRMs. These findings indicate that METs have an overall lower infiltration of immune cells relative to their matched PBTs, possibly due to immune escape. RNAseq analysis suggests that the relative levels of M2-like macrophages are increased in METs, and their potential role in promoting breast cancer metastasis warrants further study. [ABSTRACT FROM AUTHOR]

Published
2019
Full Text
View/download PDF

249. Development of [ 18 F]FPy-WL12 as a PD-L1 Specific PET Imaging Peptide.

Author

Lesniak, Wojciech G., Mease, Ronnie C., Chatterjee, Samit, Kumar, Dhiraj, Lisok, Ala, Wharram, Bryan, Kalagadda, Venkateswara Rao, Emens, Leisha A., Pomper, Martin G., and Nimmagadda, Sridhar

Subjects
PROGRAMMED cell death 1 receptors, POSITRON emission tomography, APOPTOSIS, FLOW cytometry
Abstract

Expression of programmed cell death ligand 1 (PD-L1) within tumors is an important biomarker for guiding immune checkpoint therapies; however, immunohistochemistry-based methods of detection fail to provide a comprehensive picture of PD-L1 levels in an entire patient. To facilitate quantification of PD-L1 in the whole body, we developed a peptide-based, high-affinity PD-L1 imaging agent labeled with [18F]fluoride for positron emission tomography (PET) imaging. The parent peptide, WL12, and the nonradioactive analog of the radiotracer, 19FPy-WL12, inhibit PD-1/PD-L1 interaction at low nanomolar concentrations (half maximal inhibitory concentration [IC50], 26-32 nM). The radiotracer, [18F]FPy-WL12, was prepared by conjugating 2,3,5,6-tetrafluorophenyl 6-[18F]fluoronicotinate ([18F]FPy-TFP) to WL12 and assessed for specificity in vitro in 6 cancer cell lines with varying PD-L1 expression. The uptake of the radiotracer reflected the PD-L1 expression assessed by flow cytometry. Next, we performed the in vivo evaluation of [18F]FPy-WL12 in mice bearing cancer xenografts by PET imaging, ex vivo biodistribution, and blocking studies. In vivo data demonstrated a PD-L1-specific uptake of [18F]FPy-WL12 in tumors that is reduced in mice receiving a blocking dose. The majority of [18F]FPy-WL12 radioactivity was localized in the tumors, liver, and kidneys indicating the need for optimization of the labeling strategy to improve the in vivo pharmacokinetics of the radiotracer. [ABSTRACT FROM AUTHOR]

Published
2019
Full Text
View/download PDF

250. Toward integrative cancer immunotherapy: targeting the tumor microenvironment

Author

Emens, Leisha A., Silverstein, Samuel C., Khleif, Samir, Marincola, Francesco M., and Galon, Jérôme

Subjects
Tumors--Treatment, Cancer--Immunotherapy, Medicine--Research, Oncology, Medicine, Biochemistry, 3. Good health
Abstract

The development of cancer has historically been attributed to genomic alterations of normal host cells. Accordingly, the aim of most traditional cancer therapies has been to destroy the transformed cells themselves. There is now widespread appreciation that the progressive growth and metastatic spread of cancer cells requires the cooperation of normal host cells (endothelial cells, fibroblasts, other mesenchymal cells, and immune cells), both local to, and at sites distant from, the site at which malignant transformation occurs. It is the balance of these cellular interactions that both determines the natural history of the cancer, and influences its response to therapy. This active tumor-host dynamic has stimulated interest in the tumor microenvironment as a key target for both cancer diagnosis and therapy. Recent data has demonstrated both that the presence of CD8+ T cells within a tumor is associated with a good prognosis, and that the eradication of all malignantly transformed cells within a tumor requires that the intra-tumoral concentration of cytolytically active CD8+ effector T cells remain above a critical concentration until every tumor cell has been killed. These findings have stimulated two initiatives in the field of cancer immunotherapy that focus on the tumor microenvironment. The first is the development of the immune score as part of the routine diagnostic and prognostic evaluation of human cancers, and the second is the development of combinatorial immune-based therapies that reduce tumor-associated immune suppression to unleash pre-existing or therapeutically-induced tumor immunity. In support of these efforts, the Society for the Immunotherapy of Cancer (SITC) is sponsoring a workshop entitled "Focus on the Target: The Tumor Microenvironment" to be held October 24-25, 2012 in Bethesda, Maryland. This meeting should support development of the immune score, and result in a position paper highlighting opportunities for the development of integrative cancer immunotherapies that sculpt the tumor microenvironment to promote definitive tumor rejection.

Catalog

Books, media, physical & digital resources
See catalog results