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3. In situ Vaccine Plus Checkpoint Blockade Induces Memory Humoral Response.

Author

Baniel, Claire C., Heinze, Clinton M., Hoefges, Anna, Sumiec, Elizabeth G., Hank, Jaquelyn A., Carlson, Peter M., Jin, Won Jong, Patel, Ravi B., Sriramaneni, Raghava N., Gillies, Stephen D., Erbe, Amy K., Schwarz, Ciara N., Pieper, Alexander A., Rakhmilevich, Alexander L., Sondel, Paul M., and Morris, Zachary S.

Subjects
TREATMENT effectiveness, ANTIBODY formation, INTRAVENOUS injections, T cells, B cells
Abstract

In a syngeneic murine melanoma (MEL) model, we recently reported an in situ vaccination response to combined radiation (RT) and intra-tumoral (IT) injection of anti-GD2 hu14. 18-IL2 immunocytokine (IC). This combined treatment resulted in 71% complete and durable regression of 5-week tumors, a tumor-specific memory T cell response, and augmented response to systemic anti-CTLA-4 antibody checkpoint blockade. While the ability of radiation to diversify anti-tumor T cell response has been reported, we hypothesize that mice rendered disease-free (DF) by a RT-based ISV might also exhibit a heightened B cell response. C57BL/6 mice were engrafted with 2 × 106 GD2+ B78 MEL and treated at a target tumor size of ~200 mm3 with 12 Gy RT, IT-IC on day (D)6-D10, and anti-CTLA-4 on D3, 6, and 9. Serum was collected via facial vein before tumor injection, before treatment, during treatment, after becoming DF, and following rejection of subcutaneous 2 × 106 B78 MEL re-challenge on D90. Flow cytometry demonstrated the presence of tumor-specific IgG in sera from mice rendered DF and rejecting re-challenge with B78 MEL at D90 after starting treatment. Consistent with an adaptive endogenous anti-tumor humoral memory response, these anti-tumor antibodies bound to B78 cells and parental B16 cells (GD2-), but not to the unrelated syngeneic Panc02 or Panc02 GD2+ cell lines. We evaluated the kinetics of this response and observed that tumor-specific IgG was consistently detected by D22 after initiation of treatment, corresponding to a time of rapid tumor regression. The amount of tumor-specific antibody binding to tumor cells (as measured by flow MFI) did not correlate with host animal prognosis. Incubation of B16 MEL cells in DF serum, vs. naïve serum, prior to IV injection, did not delay engraftment of B16 metastases and showed similar overall survival rates. B cell depletion using anti-CD20 or anti-CD19 and anti-B220 did not impact the efficacy of ISV treatment. Thus, treatment with RT + IC + anti-CTLA-4 results in adaptive anti-tumor humoral memory response. This endogenous tumor-specific antibody response does not appear to have therapeutic efficacy but may serve as a biomarker for an anti-tumor T cell response. [ABSTRACT FROM AUTHOR]

Published
2020
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4. Interchanging Agents and Humans in Military Simulation

Author

Heinze, Clinton, Goss, Simon, Josefsson, Torgny, Bennett, Kerry, Waugh, Sam, Lloyd, Ian, Murray, Graeme, and Oldfield, John

Abstract

The innovative reapplication of a multiagent system for human-in-the-loop (HIL) simulation was a consequence of appropriate agent-oriented design. The use of intelligent agents for simulating human decision making offers the potential for analysis and design methodologies that do not distinguish between agent and human until implementation. With this as a driver in the design process, the construction of systems in which humans and agents can be interchanged is simplified. Two systems have been constructed and deployed to provide defense analysts with the tools required to advise and assist the Australian Defense Force in the conduct of maritime surveillance and patrol. The experiences gained from this process indicate that it is simpler, both in design and implementation, to add humans to a system designed for intelligent agents than it is to add intelligent agents to a system designed for humans.

Published
2002

5. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two: National Harbor, MD, USA. 9-13 November 2016

Author

Ager, Casey, Reilley, Matthew, Nicholas, Courtney, Bartkowiak, Todd, Jaiswal, Ashvin, Curran, Michael, Albershardt, Tina C., Bajaj, Anshika, Archer, Jacob F., Reeves, Rebecca S., Ngo, Lisa Y., Berglund, Peter, ter Meulen, Jan, Denis, Caroline, Ghadially, Hormas, Arnoux, Thomas, Chanuc, Fabien, Fuseri, Nicolas, Wilkinson, Robert W., Wagtmann, Nicolai, Morel, Yannis, Andre, Pascale, Atkins, Michael B., Carlino, Matteo S., Ribas, Antoni, Thompson, John A., Choueiri, Toni K., Hodi, F. Stephen, Hwu, Wen-Jen, McDermott, David F., Atkinson, Victoria, Cebon, Jonathan S., Fitzharris, Bernie, Jameson, Michael B., McNeil, Catriona, Hill, Andrew G., Mangin, Eric, Ahamadi, Malidi, van Vugt, Marianne, van Zutphen, Mariëlle, Ibrahim, Nageatte, Long, Georgina V., Gartrell, Robyn, Blake, Zoe, Simoes, Ines, Fu, Yichun, Saito, Takuro, Qian, Yingzhi, Lu, Yan, Saenger, Yvonne M., Budhu, Sadna, De Henau, Olivier, Zappasodi, Roberta, Schlunegger, Kyle, Freimark, Bruce, Hutchins, Jeff, Barker, Christopher A., Wolchok, Jedd D., Merghoub, Taha, Burova, Elena, Allbritton, Omaira, Hong, Peter, Dai, Jie, Pei, Jerry, Liu, Matt, Kantrowitz, Joel, Lai, Venus, Poueymirou, William, MacDonald, Douglas, Ioffe, Ella, Mohrs, Markus, Olson, William, Thurston, Gavin, Capasso, Cristian, Frascaro, Federica, Carpi, Sara, Tähtinen, Siri, Feola, Sara, Fusciello, Manlio, Peltonen, Karita, Martins, Beatriz, Sjöberg, Madeleine, Pesonen, Sari, Ranki, Tuuli, Kyruk, Lukasz, Ylösmäki, Erkko, Cerullo, Vincenzo, Cerignoli, Fabio, Xi, Biao, Guenther, Garret, Yu, Naichen, Muir, Lincoln, Zhao, Leyna, Abassi, Yama, Cervera-Carrascón, Víctor, Siurala, Mikko, Santos, João, Havunen, Riikka, Parviainen, Suvi, Hemminki, Akseli, Dalgleish, Angus, Mudan, Satvinder, DeBenedette, Mark, Plachco, Ana, Gamble, Alicia, Grogan, Elizabeth W., Krisko, John, Tcherepanova, Irina, Nicolette, Charles, Dhupkar, Pooja, Yu, Ling, Kleinerman, Eugenie S., Gordon, Nancy, Grenga, Italia, Lepone, Lauren, Gameiro, Sofia, Knudson, Karin M., Fantini, Massimo, Tsang, Kwong, Hodge, James, Donahue, Renee, Schlom, Jeffrey, Evans, Elizabeth, Bussler, Holm, Mallow, Crystal, Reilly, Christine, Torno, Sebold, Scrivens, Maria, Foster, Cathie, Howell, Alan, Balch, Leslie, Knapp, Alyssa, Leonard, John E., Paris, Mark, Fisher, Terry, Hu-Lieskovan, Siwen, Smith, Ernest, Zauderer, Maurice, Fogler, William, Franklin, Marilyn, Thayer, Matt, Saims, Dan, Magnani, John L., Gong, Jian, Gray, Michael, Fromm, George, de Silva, Suresh, Giffin, Louise, Xu, Xin, Rose, Jason, Schreiber, Taylor H., Gameiro, Sofia R., Clavijo, Paul E., Allen, Clint T., Hodge, James W., Tsang, Kwong Y., Grogan, Jane, Manieri, Nicholas, Chiang, Eugene, Caplazi, Patrick, Yadav, Mahesh, Hagner, Patrick, Chiu, Hsiling, Waldman, Michelle, Klippel, Anke, Thakurta, Anjan, Pourdehnad, Michael, Gandhi, Anita, Henrich, Ian, Quick, Laura, Young, Rob, Chou, Margaret, Hotson, Andrew, Willingham, Stephen, Ho, Po, Choy, Carmen, Laport, Ginna, McCaffery, Ian, Miller, Richard, Tipton, Kimberly A., Wong, Kenneth R., Singson, Victoria, Wong, Chihunt, Chan, Chanty, Huang, Yuanhiu, Liu, Shouchun, Richardson, Jennifer H., Kavanaugh, W. Michael, West, James, Irving, Bryan A., Jaini, Ritika, Loya, Matthew, Eng, Charis, Johnson, Melissa L., Adjei, Alex A., Opyrchal, Mateusz, Ramalingam, Suresh, Janne, Pasi A., Dominguez, George, Gabrilovich, Dmitry, de Leon, Laura, Hasapidis, Jeannette, Diede, Scott J., Ordentlich, Peter, Cruickshank, Scott, Meyers, Michael L., Hellmann, Matthew D., Kalinski, Pawel, Zureikat, Amer, Edwards, Robert, Muthuswamy, Ravi, Obermajer, Nataša, Urban, Julie, Butterfield, Lisa H., Gooding, William, Zeh, Herbert, Bartlett, David, Zubkova, Olga, Agapova, Larissa, Kapralova, Marina, Krasovskaia, Liudmila, Ovsepyan, Armen, Lykov, Maxim, Eremeev, Artem, Bokovanov, Vladimir, Grigoryeva, Olga, Karpov, Andrey, Ruchko, Sergey, Shuster, Alexandr, Khalil, Danny N., Campesato, Luis Felipe, Li, Yanyun, Lazorchak, Adam S., Patterson, Troy D., Ding, Yueyun, Sasikumar, Pottayil, Sudarshan, Naremaddepalli, Gowda, Nagaraj, Ramachandra, Raghuveer, Samiulla, Dodheri, Giri, Sanjeev, Eswarappa, Rajesh, Ramachandra, Murali, Tuck, David, Wyant, Timothy, Leshem, Jasmin, Liu, Xiu-fen, Bera, Tapan, Terabe, Masaki, Bossenmaier, Birgit, Niederfellner, Gerhard, Reiter, Yoram, Pastan, Ira, Xia, Leiming, Xia, Yang, Hu, Yangyang, Wang, Yi, Bao, Yangyi, Dai, Fu, Huang, Shiang, Hurt, Elaine, Hollingsworth, Robert E., Lum, Lawrence G., Chang, Alfred E., Wicha, Max S., Li, Qiao, Mace, Thomas, Makhijani, Neil, Talbert, Erin, Young, Gregory, Guttridge, Denis, Conwell, Darwin, Lesinski, Gregory B., Gonzales, Rodney JM Macedo, Huffman, Austin P., Wang, Ximi K., Reshef, Ran, MacKinnon, Andy, Chen, Jason, Gross, Matt, Marguier, Gisele, Shwonek, Peter, Sotirovska, Natalija, Steggerda, Susanne, Parlati, Francesco, Makkouk, Amani, Bennett, Mark K., Emberley, Ethan, Huang, Tony, Li, Weiqun, Neou, Silinda, Pan, Alison, Zhang, Jing, Zhang, Winter, Marshall, Netonia, Marron, Thomas U., Agudo, Judith, Brown, Brian, Brody, Joshua, McQuinn, Christopher, Farren, Matthew, Komar, Hannah, Shakya, Reena, Ludwug, Thomas, Morillon, Y. Maurice, Hammond, Scott A., Greiner, John W., Nath, Pulak R., Schwartz, Anthony L., Maric, Dragan, Roberts, David D., Naing, Aung, Papadopoulos, Kyriakos P., Autio, Karen A., Wong, Deborah J., Patel, Manish, Falchook, Gerald, Pant, Shubham, Ott, Patrick A., Whiteside, Melinda, Patnaik, Amita, Mumm, John, Janku, Filip, Chan, Ivan, Bauer, Todd, Colen, Rivka, VanVlasselaer, Peter, Brown, Gail L., Tannir, Nizar M., Oft, Martin, Infante, Jeffrey, Lipson, Evan, Gopal, Ajay, Neelapu, Sattva S., Armand, Philippe, Spurgeon, Stephen, Leonard, John P., Sanborn, Rachel E., Melero, Ignacio, Gajewski, Thomas F., Maurer, Matthew, Perna, Serena, Gutierrez, Andres A., Clynes, Raphael, Mitra, Priyam, Suryawanshi, Satyendra, Gladstone, Douglas, Callahan, Margaret K., Crooks, James, Brown, Sheila, Gauthier, Audrey, de Boisferon, Marc Hillairet, MacDonald, Andrew, Brunet, Laura Rosa, Rothwell, William T., Bell, Peter, Wilson, James M., Sato-Kaneko, Fumi, Yao, Shiyin, Zhang, Shannon S., Carson, Dennis A., Guiducci, Cristina, Coffman, Robert L., Kitaura, Kazutaka, Matsutani, Takaji, Suzuki, Ryuji, Hayashi, Tomoko, Cohen, Ezra E. W., Schaer, David, Li, Yanxia, Dobkin, Julie, Amatulli, Michael, Hall, Gerald, Doman, Thompson, Manro, Jason, Dorsey, Frank Charles, Sams, Lillian, Holmgaard, Rikke, Persaud, Krishnadatt, Ludwig, Dale, Surguladze, David, Kauh, John S., Novosiadly, Ruslan, Kalos, Michael, Driscoll, Kyla, Pandha, Hardev, Ralph, Christy, Harrington, Kevin, Curti, Brendan, Akerley, Wallace, Gupta, Sumati, Melcher, Alan, Mansfield, David, Kaufman, David R., Schmidt, Emmett, Grose, Mark, Davies, Bronwyn, Karpathy, Roberta, Shafren, Darren, Shamalov, Katerina, Cohen, Cyrille, Sharma, Naveen, Allison, James, Shekarian, Tala, Valsesia-Wittmann, Sandrine, Caux, Christophe, Marabelle, Aurelien, Slomovitz, Brian M., Moore, Kathleen M., Youssoufian, Hagop, Posner, Marshall, Tewary, Poonam, Brooks, Alan D., Xu, Ya-Ming, Wijeratne, Kithsiri, Gunatilaka, Leslie A. A., Sayers, Thomas J., Vasilakos, John P., Alston, Tesha, Dovedi, Simon, Elvecrog, James, Grigsby, Iwen, Herbst, Ronald, Johnson, Karen, Moeckly, Craig, Mullins, Stefanie, Siebenaler, Kristen, SternJohn, Julius, Tilahun, Ashenafi, Tomai, Mark A., Vogel, Katharina, Vietsch, Eveline E., Wellstein, Anton, Wythes, Martin, Crosignani, Stefano, Tumang, Joseph, Alekar, Shilpa, Bingham, Patrick, Cauwenberghs, Sandra, Chaplin, Jenny, Dalvie, Deepak, Denies, Sofie, De Maeseneire, Coraline, Feng, JunLi, Frederix, Kim, Greasley, Samantha, Guo, Jie, Hardwick, James, Kaiser, Stephen, Jessen, Katti, Kindt, Erick, Letellier, Marie-Claire, Li, Wenlin, Maegley, Karen, Marillier, Reece, Miller, Nichol, Murray, Brion, Pirson, Romain, Preillon, Julie, Rabolli, Virginie, Ray, Chad, Ryan, Kevin, Scales, Stephanie, Srirangam, Jay, Solowiej, Jim, Stewart, Al, Streiner, Nicole, Torti, Vince, Tsaparikos, Konstantinos, Zheng, Xianxian, Driessens, Gregory, Gomes, Bruno, Kraus, Manfred, Xu, Chunxiao, Zhang, Yanping, Kradjian, Giorgio, Qin, Guozhong, Qi, Jin, Xu, Xiaomei, Marelli, Bo, Yu, Huakui, Guzman, Wilson, Tighe, Rober, Salazar, Rachel, Lo, Kin-Ming, English, Jessie, Radvanyi, Laszlo, Lan, Yan, Postow, Michael, Senbabaoglu, Yasin, Gasmi, Billel, Zhong, Hong, Liu, Cailian, Hirschhorhn-Cymerman, Daniel, Zha, Yuanyuan, Malnassy, Gregory, Fulton, Noreen, Park, Jae-Hyun, Stock, Wendy, Nakamura, Yusuke, Liu, Hongtao, Ju, Xiaoming, Kosoff, Rachelle, Ramos, Kimberly, Coder, Brandon, Petit, Robert, Princiotta, Michael, Perry, Kyle, Zou, Jun, Arina, Ainhoa, Fernandez, Christian, Zheng, Wenxin, Beckett, Michael A., Mauceri, Helena J., Fu, Yang-Xin, Weichselbaum, Ralph R., Lewis, Whitney, Han, Yanyan, Wu, Yeting, Yang, Chou, Huang, Jing, Wu, Dongyun, Li, Jin, Liang, Xiaoling, Zhou, Xiangjun, Hou, Jinlin, Hassan, Raffit, Jahan, Thierry, Antonia, Scott J., Kindler, Hedy L., Alley, Evan W., Honarmand, Somayeh, Liu, Weiqun, Leong, Meredith L., Whiting, Chan C., Nair, Nitya, Enstrom, Amanda, Lemmens, Edward E., Tsujikawa, Takahiro, Kumar, Sushil, Coussens, Lisa M., Murphy, Aimee L., Brockstedt, Dirk G., Koch, Sven D., Sebastian, Martin, Weiss, Christian, Früh, Martin, Pless, Miklos, Cathomas, Richard, Hilbe, Wolfgang, Pall, Georg, Wehler, Thomas, Alt, Jürgen, Bischoff, Helge, Geissler, Michael, Griesinger, Frank, Kollmeier, Jens, Papachristofilou, Alexandros, Doener, Fatma, Fotin-Mleczek, Mariola, Hipp, Madeleine, Hong, Henoch S., Kallen, Karl-Josef, Klinkhardt, Ute, Stosnach, Claudia, Scheel, Birgit, Schroeder, Andreas, Seibel, Tobias, Gnad-Vogt, Ulrike, Zippelius, Alfred, Park, Ha-Ram, Ahn, Yong-Oon, Kim, Tae Min, Kim, Soyeon, Kim, Seulki, Lee, Yu Soo, Keam, Bhumsuk, Kim, Dong-Wan, Heo, Dae Seog, Pilon-Thomas, Shari, Weber, Amy, Morse, Jennifer, Kodumudi, Krithika, Liu, Hao, Mullinax, John, Sarnaik, Amod A., Pike, Luke, Bang, Andrew, Balboni, Tracy, Taylor, Allison, Spektor, Alexander, Wilhite, Tyler, Krishnan, Monica, Cagney, Daniel, Alexander, Brian, Aizer, Ayal, Buchbinder, Elizabeth, Awad, Mark, Ghandi, Leena, Schoenfeld, Jonathan, Lessey-Morillon, Elizabeth, Ridnour, Lisa, Segal, Neil H., Sharma, Manish, Le, Dung T., Ferris, Robert L., Zelenetz, Andrew D., Levy, Ronald, Lossos, Izidore S., Jacobson, Caron, Ramchandren, Radhakrishnan, Godwin, John, Colevas, A. Dimitrios, Meier, Roland, Krishnan, Suba, Gu, Xuemin, Neely, Jaclyn, Timmerman, John, Vanpouille-Box, Claire I., Formenti, Silvia C., Demaria, Sandra, Wennerberg, Erik, Mediero, Aranzazu, Cronstein, Bruce N., Gustafson, Michael P., DiCostanzo, AriCeli, Wheatley, Courtney, Kim, Chul-Ho, Bornschlegl, Svetlana, Gastineau, Dennis A., Johnson, Bruce D., Dietz, Allan B., MacDonald, Cameron, Bucsek, Mark, Qiao, Guanxi, Hylander, Bonnie, Repasky, Elizabeth, Turbitt, William J., Xu, Yitong, Mastro, Andrea, Rogers, Connie J., Withers, Sita, Wang, Ziming, Khuat, Lam T., Dunai, Cordelia, Blazar, Bruce R., Longo, Dan, Rebhun, Robert, Grossenbacher, Steven K., Monjazeb, Arta, Murphy, William J., Rowlinson, Scott, Agnello, Giulia, Alters, Susan, Lowe, David, Scharping, Nicole, Menk, Ashley V., Whetstone, Ryan, Zeng, Xue, Delgoffe, Greg M., Santos, Patricia M., Shi, Jian, Delgoffe, Greg, Nagasaka, Misako, Sukari, Ammar, Byrne-Steele, Miranda, Pan, Wenjing, Hou, Xiaohong, Brown, Brittany, Eisenhower, Mary, Han, Jian, Collins, Natalie, Manguso, Robert, Pope, Hans, Shrestha, Yashaswi, Boehm, Jesse, Haining, W. Nicholas, Cron, Kyle R., Sivan, Ayelet, Aquino-Michaels, Keston, Orecchioni, Marco, Bedognetti, Davide, Hendrickx, Wouter, Fuoco, Claudia, Spada, Filomena, Sgarrella, Francesco, Cesareni, Gianni, Marincola, Francesco, Kostarelos, Kostas, Bianco, Alberto, Delogu, Lucia, Roelands, Jessica, Boughorbel, Sabri, Decock, Julie, Presnell, Scott, Wang, Ena, Marincola, Franco M., Kuppen, Peter, Ceccarelli, Michele, Rinchai, Darawan, Chaussabel, Damien, Miller, Lance, Nguyen, Andrew, Sanborn, J. Zachary, Vaske, Charles, Rabizadeh, Shahrooz, Niazi, Kayvan, Benz, Steven, Patel, Shashank, Restifo, Nicholas, White, James, Angiuoli, Sam, Sausen, Mark, Jones, Sian, Sevdali, Maria, Simmons, John, Velculescu, Victor, Diaz, Luis, Zhang, Theresa, Sims, Jennifer S., Barton, Sunjay M., Kadenhe-Chiweshe, Angela, Dela Cruz, Filemon, Turk, Andrew T., Mazzeo, Christopher F., Kung, Andrew L., Bruce, Jeffrey N., Yamashiro, Darrell J., Connolly, Eileen P., Baird, Jason, Crittenden, Marka, Friedman, David, Xiao, Hong, Leidner, Rom, Bell, Bryan, Young, Kristina, Gough, Michael, Bian, Zhen, Kidder, Koby, Liu, Yuan, Curran, Emily, Chen, Xiufen, Corrales, Leticia P., Kline, Justin, Aguilar, Ethan G., Guerriero, Jennifer, Sotayo, Alaba, Ponichtera, Holly, Pourzia, Alexandra, Schad, Sara, Carrasco, Ruben, Lazo, Suzan, Bronson, Roderick, Letai, Anthony, Kornbluth, Richard S., Gupta, Sachin, Termini, James, Guirado, Elizabeth, Stone, Geoffrey W., Meyer, Christina, Helming, Laura, Wilson, Nicholas, Hofmeister, Robert, Neubert, Natalie J., Tillé, Laure, Barras, David, Soneson, Charlotte, Baumgaertner, Petra, Rimoldi, Donata, Gfeller, David, Delorenzi, Mauro, Fuertes Marraco, Silvia A., Speiser, Daniel E., Abraham, Tara S., Xiang, Bo, Magee, Michael S., Waldman, Scott A., Snook, Adam E., Blogowski, Wojciech, Zuba-Surma, Ewa, Budkowska, Marta, Salata, Daria, Dolegowska, Barbara, Starzynska, Teresa, Chan, Leo, Somanchi, Srinivas, McCulley, Kelsey, Lee, Dean, Buettner, Nico, Shi, Feng, Myers, Paisley T., Curbishley, Stuart, Penny, Sarah A., Steadman, Lora, Millar, David, Speers, Ellen, Ruth, Nicola, Wong, Gabriel, Thimme, Robert, Adams, David, Cobbold, Mark, Thomas, Remy, Al-Muftah, Mariam, Wong, Michael KK, Morse, Michael, Clark, Joseph I., Kaufman, Howard L., Daniels, Gregory A., Hua, Hong, Rao, Tharak, Dutcher, Janice P., Kang, Kai, Saunthararajah, Yogen, Velcheti, Vamsidhar, Kumar, Vikas, Anwar, Firoz, Verma, Amita, Chheda, Zinal, Kohanbash, Gary, Sidney, John, Okada, Kaori, Shrivastav, Shruti, Carrera, Diego A., Liu, Shuming, Jahan, Naznin, Mueller, Sabine, Pollack, Ian F., Carcaboso, Angel M., Sette, Alessandro, Hou, Yafei, Okada, Hideho, Field, Jessica J., Zeng, Weiping, Shih, Vincent FS, Law, Che-Leung, Senter, Peter D., Gardai, Shyra J., Okeley, Nicole M., Abelin, Jennifer G., Saeed, Abu Z., Malaker, Stacy A., Shabanowitz, Jeffrey, Ward, Stephen T., Hunt, Donald F., Profusek, Pam, Wood, Laura, Shepard, Dale, Grivas, Petros, Kapp, Kerstin, Volz, Barbara, Oswald, Detlef, Wittig, Burghardt, Schmidt, Manuel, Sefrin, Julian P., Hillringhaus, Lars, Lifke, Valeria, Lifke, Alexander, Skaletskaya, Anna, Ponte, Jose, Chittenden, Thomas, Setiady, Yulius, Sivado, Eva, Thomas, Vincent, El Alaoui, Meddy, Papot, Sébastien, Dumontet, Charles, Dyson, Mike, McCafferty, John, El Alaoui, Said, Bommareddy, Praveen K., Zloza, Andrew, Kohlhapp, Frederick, Silk, Ann W., Jhawar, Sachin, Paneque, Tomas, Newman, Jenna, Beltran, Pedro, Cao, Felicia, Hong, Bang-Xing, Rodriguez-Cruz, Tania, Song, Xiao-Tong, Gottschalk, Stephen, Calderon, Hugo, Illingworth, Sam, Brown, Alice, Fisher, Kerry, Seymour, Len, Champion, Brian, Eriksson, Emma, Wenthe, Jessica, Hellström, Ann-Charlotte, Paul-Wetterberg, Gabriella, Loskog, Angelica, Milenova, Ioanna, Ståhle, Magnus, Jarblad-Leja, Justyna, Ullenhag, Gustav, Dimberg, Anna, Moreno, Rafael, Alemany, Ramon, Goyal, Sharad, Silk, Ann, Mehnert, Janice, Gabrail, Nashat, Bryan, Jennifer, Medina, Daniel, Mitchell, Leah, Yagiz, Kader, Lopez, Fernando, Mendoza, Daniel, Munday, Anthony, Gruber, Harry, Jolly, Douglas, Fuhrmann, Steven, Radoja, Sasa, Tan, Wei, Pourchet, Aldo, Frey, Alan, Mohr, Ian, Mulvey, Matthew, Andtbacka, Robert H. I., Ross, Merrick, Agarwala, Sanjiv, Grossmann, Kenneth, Taylor, Matthew, Vetto, John, Neves, Rogerio, Daud, Adil, Khong, Hung, Meek, Stephanie M., Ungerleider, Richard, Welden, Scott, Tanaka, Maki, Williams, Matthew, Hallmeyer, Sigrun, Fox, Bernard, Feng, Zipei, Paustian, Christopher, Bifulco, Carlo, Zafar, Sadia, Hemminki, Otto, Bramante, Simona, Vassilev, Lotta, Wang, Hongjie, Lieber, Andre, Hemmi, Silvio, de Gruijl, Tanja, Kanerva, Anna, Ansari, Tameem, Sundararaman, Srividya, Roen, Diana, Lehmann, Paul, Bloom, Anja C., Bender, Lewis H., Walters, Ian B., Berzofsky, Jay A., Chapelin, Fanny, Ahrens, Eric T., DeFalco, Jeff, Harbell, Michael, Manning-Bog, Amy, Scholz, Alexander, Zhang, Danhui, Baia, Gilson, Tan, Yann Chong, Sokolove, Jeremy, Kim, Dongkyoon, Williamson, Kevin, Chen, Xiaomu, Colrain, Jillian, Santo, Gregg Espiritu, Nguyen, Ngan, Volkmuth, Wayne, Greenberg, Norman, Robinson, William, Emerling, Daniel, Drake, Charles G., Petrylak, Daniel P., Antonarakis, Emmanuel S., Kibel, Adam S., Chang, Nancy N., Vu, Tuyen, Campogan, Dwayne, Haynes, Heather, Trager, James B., Sheikh, Nadeem A., Quinn, David I., Kirk, Peter, Addepalli, Murali, Chang, Thomas, Zhang, Ping, Konakova, Marina, Hagihara, Katsunobu, Pai, Steven, VanderVeen, Laurie, Obalapur, Palakshi, Kuo, Peiwen, Quach, Phi, Fong, Lawrence, Charych, Deborah H., Zalevsky, Jonathan, Langowski, John L., Kirksey, Yolanda, Nutakki, Ravi, Kolarkar, Shalini, Pena, Rhoneil, Hoch, Ute, Doberstein, Stephen K., Cha, John, Mallon, Zach, Perez, Myra, McDaniel, Amanda, Anand, Snjezana, Uecker, Darrin, Nuccitelli, Richard, Wieckowski, Eva, Muthuswamy, Ravikumar, Ravindranathan, Roshni, Renrick, Ariana N., Thounaojam, Menaka, Thomas, Portia, Pellom, Samuel, Shanker, Anil, Dudimah, Duafalia, Brooks, Alan, Su, Yu-Lin, Adamus, Tomasz, Zhang, Qifang, Nechaev, Sergey, Kortylewski, Marcin, Wei, Spencer, Anderson, Clark, Tang, Chad, Schoenhals, Jonathan, Tsouko, Efrosini, Heymach, John, de Groot, Patricia, Chang, Joe, Hess, Kenneth R., Diab, Adi, Sharma, Padmanee, Hong, David, Welsh, James, Parsons, Andrea J., Leleux, Jardin, Ascarateil, Stephane, Koziol, Marie Eve, Bai, Dina, Dai, Peihong, Wang, Weiyi, Yang, Ning, Shuman, Stewart, Deng, Liang, Dillon, Patrick, Petroni, Gina, Brenin, David, Bullock, Kim, Olson, Walter, Smolkin, Mark E., Smith, Kelly, Nail, Carmel, Slingluff, Craig L., Sharma, Meenu, Fa’ak, Faisal, Janssen, Louise, Khong, Hiep, Xiao, Zhilan, Hailemichael, Yared, Singh, Manisha, Vianden, Christina, Overwijk, Willem W., Facciabene, Andrea, Stefano, Pierini, Chongyung, Fang, Rafail, Stavros, Nielsen, Michael, Vanderslice, Peter, Woodside, Darren G., Market, Robert V., Biediger, Ronald J., Marathi, Upendra K., Hollevoet, Kevin, Geukens, Nick, Declerck, Paul, Joly, Nathalie, McIntosh, Laura, Paramithiotis, Eustache, Rizell, Magnus, Sternby, Malin, Andersson, Bengt, Karlsson-Parra, Alex, Kuai, Rui, Ochyl, Lukasz, Schwendeman, Anna, Moon, James, Deng, Weiwen, Hudson, Thomas E., Hanson, Bill, Rae, Chris S., Burrill, Joel, Skoble, Justin, Katibah, George, deVries, Michele, Lauer, Peter, Dubensky, Thomas W., Chen, Xin, Zhou, Li, Ren, Xiubao, Aggarwal, Charu, Mangrolia, Drishty, Cohen, Roger, Weinstein, Gregory, Morrow, Matthew, Bauml, Joshua, Kraynyak, Kim, Boyer, Jean, Yan, Jian, Lee, Jessica, Humeau, Laurent, Oyola, Sandra, Duff, Susan, Weiner, David, Yang, Zane, Bagarazzi, Mark, McNeel, Douglas G., Eickhoff, Jens, Jeraj, Robert, Staab, Mary Jane, Straus, Jane, Rekoske, Brian, Liu, Glenn, Melssen, Marit, Grosh, William, Varhegyi, Nikole, Galeassi, Nadejda, Deacon, Donna H., Gaughan, Elizabeth, Ghisoli, Maurizio, Barve, Minal, Mennel, Robert, Wallraven, Gladice, Manning, Luisa, Senzer, Neil, Nemunaitis, John, Ogasawara, Masahiro, Ota, Shuichi, Peace, Kaitlin M., Hale, Diane F., Vreeland, Timothy J., Jackson, Doreen O., Berry, John S., Trappey, Alfred F., Herbert, Garth S., Clifton, Guy T., Hardin, Mark O., Toms, Anne, Qiao, Na, Litton, Jennifer, Peoples, George E., Mittendorf, Elizabeth A., Ghamsari, Lila, Flano, Emilio, Jacques, Judy, Liu, Biao, Havel, Jonathan, Makarov, Vladimir, Chan, Timothy A., Flechtner, Jessica B., Facciponte, John, Ugel, Stefano, De Sanctis, Francesco, Coukos, George, Paris, Sébastien, Pottier, Agnes, Levy, Laurent, Lu, Bo, Cappuccini, Federica, Pollock, Emily, Bryant, Richard, Hamdy, Freddie, Hill, Adrian, Redchenko, Irina, Sultan, Hussein, Kumai, Takumi, Fesenkova, Valentyna, Celis, Esteban, Fernando, Ingrid, Palena, Claudia, David, Justin M., Gabitzsch, Elizabeth, Jones, Frank, Gulley, James L., Herranz, Mireia Uribe, Wada, Hiroshi, Shimizu, Atsushi, Osada, Toshihiro, Fukaya, Satoshi, Sasaki, Eiji, Abolhalaj, Milad, Askmyr, David, Lundberg, Kristina, Albrekt, Ann-Sofie, Greiff, Lennart, Lindstedt, Malin, Flies, Dallas B., Higuchi, Tomoe, Ornatowski, Wojciech, Harris, Jaryse, Adams, Sarah F., Aguilera, Todd, Rafat, Marjan, Castellini, Laura, Shehade, Hussein, Kariolis, Mihalis, Jang, Dadi, vonEbyen, Rie, Graves, Edward, Ellies, Lesley, Rankin, Erinn, Koong, Albert, Giaccia, Amato, Ajina, Reham, Wang, Shangzi, Smith, Jill, Pierobon, Mariaelena, Jablonski, Sandra, Petricoin, Emanuel, Weiner, Louis M., Sherry, Lorcan, Waller, John, Anderson, Mark, Bigley, Alison, Bernatchez, Chantale, Haymaker, Cara, Kluger, Harriet, Tetzlaff, Michael, Jackson, Natalie, Gergel, Ivan, Tagliaferri, Mary, Hwu, Patrick, Snzol, Mario, Hurwitz, Michael, Barberi, Theresa, Martin, Allison, Suresh, Rahul, Barakat, David, Harris-Bookman, Sarah, Drake, Charles, Friedman, Alan, Berkey, Sara, Downs-Canner, Stephanie, Edwards, Robert P., Curiel, Tyler, Odunsi, Kunle, Bruno, Tullia C., Moore, Brandon, Squalls, Olivia, Ebner, Peggy, Waugh, Katherine, Mitchell, John, Franklin, Wilbur, Merrick, Daniel, McCarter, Martin, Palmer, Brent, Kern, Jeffrey, Vignali, Dario, Slansky, Jill, Chan, Anissa S. H., Qiu, Xiaohong, Fraser, Kathryn, Jonas, Adria, Ottoson, Nadine, Gordon, Keith, Kangas, Takashi O., Leonardo, Steven, Ertelt, Kathleen, Walsh, Richard, Uhlik, Mark, Graff, Jeremy, Bose, Nandita, Gupta, Ravi, Mandloi, Nitin, Paul, Kiran, Patil, Ashwini, Sathian, Rekha, Mohan, Aparna, Manoharan, Malini, Chaudhuri, Amitabha, Chen, Yu, Lin, Jing, Ye, Yun-bin, Xu, Chun-wei, Chen, Gang, Guo, Zeng-qing, Komarov, Andrey, Chenchik, Alex, Makhanov, Michael, Frangou, Costa, Zheng, Yi, Coltharp, Carla, Unfricht, Darryn, Dilworth, Ryan, Fridman, Leticia, Liu, Linying, Rajopadhye, Milind, Miller, Peter, Concha-Benavente, Fernando, Bauman, Julie, Trivedi, Sumita, Srivastava, Raghvendra, Ohr, James, Heron, Dwight, Duvvuri, Uma, Kim, Seungwon, Torrey, Heather, Mera, Toshi, Okubo, Yoshiaki, Vanamee, Eva, Foster, Rosemary, Faustman, Denise, Stack, Edward, Izaki, Daisuke, Beck, Kristen, Jia, Dan Tong, Armenta, Paul, White-Stern, Ashley, Marks, Douglas, Taback, Bret, Horst, Basil, Glickman, Laura Hix, Kanne, David B., Gauthier, Kelsey S., Desbien, Anthony L., Francica, Brian, Leong, Justin L., Sung, Leonard, Metchette, Ken, Kasibhatla, Shailaja, Pferdekamper, Anne Marie, Zheng, Lianxing, Cho, Charles, Feng, Yan, McKenna, Jeffery M., Tallarico, John, Bender, Steven, Ndubaku, Chudi, McWhirter, Sarah M., Gugel, Elena Gonzalez, Bell, Charles J. M., Munk, Adiel, Muniz, Luciana, Bhardwaj, Nina, Zhao, Fei, Evans, Kathy, Xiao, Christine, Holtzhausen, Alisha, Hanks, Brent A., Scholler, Nathalie, Yin, Catherine, Van der Meijs, Pien, Prantner, Andrew M., Krejsa, Cecile M., Smith, Leia, Johnson, Brian, Branstetter, Daniel, Stein, Paul L., Jaen, Juan C., Tan, Joanne BL, Chen, Ada, Park, Timothy, Powers, Jay P., Sexton, Holly, Xu, Guifen, Young, Steve W., Schindler, Ulrike, Deng, Wentao, Klinke, David John, Komar, Hannah M., Serpa, Gregory, Elnaggar, Omar, Hart, Philip, Schmidt, Carl, Dillhoff, Mary, Jin, Ming, Ostrowski, Michael C., Koti, Madhuri, Au, Katrina, Peterson, Nichole, Truesdell, Peter, Reid-Schachter, Gillian, Graham, Charles, Craig, Andrew, Francis, Julie-Ann, Kotlan, Beatrix, Balatoni, Timea, Farkas, Emil, Toth, Laszlo, Ujhelyi, Mihaly, Savolt, Akos, Doleschall, Zoltan, Horvath, Szabolcs, Eles, Klara, Olasz, Judit, Csuka, Orsolya, Kasler, Miklos, Liszkay, Gabriella, Barnea, Eytan, Blakely, Collin, Flynn, Patrick, Goodman, Reid, Bueno, Raphael, Sugarbaker, David, Jablons, David, Broaddus, V. Courtney, West, Brian, Kunk, Paul R., Obeid, Joseph M., Winters, Kevin, Pramoonjago, Patcharin, Stelow, Edward B., Bauer, Todd W., Rahma, Osama E., Lamble, Adam, Kosaka, Yoko, Huang, Fei, Saser, Kate A., Adams, Homer, Tognon, Christina E., Laderas, Ted, McWeeney, Shannon, Loriaux, Marc, Tyner, Jeffery W., Druker, Brian J., Lind, Evan F., Liu, Zhuqing, Lu, Shanhong, Kane, Lawrence P., Shayan, Gulidanna, Femel, Julia, Lane, Ryan, Booth, Jamie, Lund, Amanda W., Rodriguez, Anthony, Engelhard, Victor H., Metelli, Alessandra, Wu, Bill X., Fugle, Caroline W., Saleh, Rachidi, Sun, Shaoli, Wu, Jennifer, Liu, Bei, Li, Zihai, Morris, Zachary S., Guy, Emily I., Heinze, Clinton, Kler, Jasdeep, Gressett, Monica M., Werner, Lauryn R., Gillies, Stephen D., Korman, Alan J., Loibner, Hans, Hank, Jacquelyn A., Rakhmilevich, Alexander L., Harari, Paul M., Sondel, Paul M., Huelsmann, Erica, Broucek, Joseph, Brech, Dorothee, Straub, Tobias, Irmler, Martin, Beckers, Johannes, Buettner, Florian, Schaeffeler, Elke, Schwab, Matthias, Noessner, Elfriede, Wolfreys, Alison, Da Costa, Andre, Silva, John, Crosby, Andrea, Staelens, Ludovicus, Craggs, Graham, Cauvin, Annick, Mason, Sean, Paterson, Alison M., Lake, Andrew C., Armet, Caroline M., O’Connor, Rachel W., Hill, Jonathan A., Normant, Emmanuel, Adam, Ammar, Biniszkiewicz, Detlev M., Chappel, Scott C., Palombella, Vito J., Holland, Pamela M., Becker, Annette, Leleti, Manmohan R., Newcomb, Eric, Tan, Joanne B. L., Rapisuwon, Suthee, Radfar, Arash, Gardner, Kellie, Gibney, Geoffrey, Atkins, Michael, Rennier, Keith R., Crowder, Robert, Wang, Ping, Pachynski, Russell K., Carrero, Rosa M. Santana, Rivas, Sarai, Beceren-Braun, Figen, Anthony, Scott, Schluns, Kimberly S., Sawant, Deepali, Chikina, Maria, Yano, Hiroshi, Workman, Creg, Salerno, Elise, Mauldin, Ileana, Deacon, Donna, Shea, Sofia, Pinczewski, Joel, Gajewski, Thomas, Spranger, Stefani, Horton, Brendan, Suzuki, Akiko, Leland, Pamela, Joshi, Bharat H., Puri, Raj K., Sweis, Randy F., Bao, Riyue, Luke, Jason, Theodoraki, Marie-Nicole, Mogundo, Frances-Mary, Won, Haejung, Moreira, Dayson, Gao, Chan, Zhao, Xingli, Duttagupta, Priyanka, Jones, Jeremy, D’Apuzzo, Massimo, and Pal, Sumanta

Published
2016
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7. In situ vaccination at a peripheral tumor site augments response against melanoma brain metastases.

Author

Clark PA, Sriramaneni RN, Jin WJ, Jagodinsky JC, Bates AM, Jaquish AA, Anderson BR, Le T, Lubin JA, Chakravarty I, Arthur IS, Heinze CM, Guy EI, Kler J, Klar KA, Carlson PM, Kim KM, Kuo JS, and Morris ZS

Subjects
Animals, Humans, Immune Checkpoint Inhibitors pharmacology, Male, Mice, Brain Neoplasms therapy, Immune Checkpoint Inhibitors therapeutic use, Melanoma, Experimental complications, Vaccination methods
Abstract

Background: Immune checkpoint inhibition (ICI) alone is not efficacious for a large number of patients with melanoma brain metastases. We previously established an in situ vaccination (ISV) regimen combining radiation and immunocytokine to enhance response to ICIs. Here, we tested whether ISV inhibits the development of brain metastases in a murine melanoma model., Methods: B78 (GD2 + ) melanoma 'primary' tumors were engrafted on the right flank of C57BL/6 mice. After 3-4 weeks, primary tumors were treated with ISV (radiation (12 Gy, day 1), α-GD2 immunocytokine (hu14.18-IL2, days 6-10)) and ICI (α-CTLA-4, days 3, 6, 9). Complete response (CR) was defined as no residual tumor observed at treatment day 90. Mice with CR were tested for immune memory by re-engraftment with B78 in the left flank and then the brain. To test ISV efficacy against metastases, tumors were also engrafted in the left flank and brain of previously untreated mice. Tumors were analyzed by quantitative reverse transcription-PCR, immunohistochemistry, flow cytometry and multiplex cytokine assay., Results: ISV+α-CTLA-4 resulted in immune memory and rejection of B78 engraftment in the brain in 11 of 12 mice. When B78 was engrafted in brain prior to treatment, ISV+α-CTLA-4 increased survival compared with ICI alone. ISV+α-CTLA-4 eradicated left flank tumors but did not elicit CR at brain sites when tumor cells were engrafted in brain prior to ISV. ISV+α-CTLA-4 increased CD8 + and CD4 + T cells in flank and brain tumors compared with untreated mice. Among ISV + α-CTLA-4 treated mice, left flank tumors showed increased CD8 + infiltration and CD8 + :FOXP3 + ratio compared with brain tumors. Flank and brain tumors showed minimal differences in expression of immune checkpoint receptors/ligands or Mhc-1 . Cytokine productions were similar in left flank and brain tumors in untreated mice. Following ISV+α-CTLA-4, production of immune-stimulatory cytokines was greater in left flank compared with brain tumor grafts., Conclusion: ISV augmented response to ICIs in murine melanoma at brain and extracranial tumor sites. Although baseline tumor-immune microenvironments were similar at brain and extracranial tumor sites, response to ISV+α-CTLA-4 was divergent with reduced infiltration and activation of immune cells in brain tumors. Additional therapies may be needed for effective antitumor immune response against melanoma brain metastases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Published
2020
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8. Tumor-Specific Inhibition of In Situ Vaccination by Distant Untreated Tumor Sites.

Author

Morris ZS, Guy EI, Werner LR, Carlson PM, Heinze CM, Kler JS, Busche SM, Jaquish AA, Sriramaneni RN, Carmichael LL, Loibner H, Gillies SD, Korman AJ, Erbe AK, Hank JA, Rakhmilevich AL, Harari PM, and Sondel PM

Subjects
Animals, CTLA-4 Antigen antagonists & inhibitors, CTLA-4 Antigen immunology, CTLA-4 Antigen metabolism, Cancer Vaccines therapeutic use, Cell Line, Tumor, Combined Modality Therapy, Disease Models, Animal, Humans, Immune Tolerance, Melanoma immunology, Melanoma metabolism, Melanoma pathology, Melanoma therapy, Mice, Neoplasms metabolism, Neoplasms pathology, Neoplasms therapy, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Vaccination, Xenograft Model Antitumor Assays, Cancer Vaccines immunology, Neoplasms immunology
Abstract

In situ vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an in situ vaccination effect when combining radiation (RT) with intratumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the "primary" tumor would induce a systemic antitumor response causing regression of the "secondary" tumor. To test this, mice bearing one or two syngeneic murine tumors of B78 melanoma and/or Panc02 pancreatic cancer were treated with combined external beam RT and IT-IC to the designated "primary" tumor only. Primary and secondary tumor response as well as animal survival were monitored. Immunohistochemistry and quantitative real-time PCR were used to quantify tumor infiltration with regulatory T cells (Treg). Transgenic "DEREG" mice or IgG2a anti-CTLA-4 were used to transiently deplete tumor Tregs. Contrary to our initial hypothesis, we observed that the presence of an untreated secondary tumor antagonized the therapeutic effect of RT + IT-IC delivered to the primary tumor. We observed reciprocal tumor specificity for this effect, which was circumvented if all tumors received RT or by transient depletion of Tregs. Primary tumor treatment with RT + IT-IC together with systemic administration of Treg-depleting anti-CTLA-4 resulted in a renewed in situ vaccination effect. Our findings show that untreated tumors can exert a tumor-specific, Treg-dependent, suppressive effect on the efficacy of in situ vaccination and demonstrate clinically viable approaches to overcome this effect. Untreated tumor sites antagonize the systemic and local antitumor immune response to an in situ vaccination regimen. This effect is radiation sensitive and may be mediated by tumor-specific regulatory T cells harbored in the untreated tumor sites. Cancer Immunol Res; 6(7); 825-34. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Published
2018
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