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51. Genome editing approaches for development of pan-population immunotherapies

Author

Legut, Mateusz

Abstract

Background - T-cell based immunotherapy is the greatest recent breakthrough in cancer treatment, and can induce complete lasting remission. T-cells are capable of responding to a vast diversity of antigens via their hypervariable T-cell receptor (TCR). However, current immunotherapies rely on αβ T-cells which are restricted to person-specific Human Leukocyte Antigen (HLA) molecules presenting peptides from cancer-specific antigens. Thus, a given αβ TCR therapy is applicable only to a minority of patients. In contrast, γδ T-cells, and some αβ T-cells, recognise diverse cancer types regardless of the HLA type. The aims of my thesis were to investigate the potential of using non-HLA restricted T-cells and their receptors for cancer immunotherapy, and to develop tools to facilitate the study of non-HLA restricted T-cells for cancer treatment.\ud Results – Initially, I developed a CRISPR/Cas9 method for generation of superior TCR transduced cells, in terms of their anticancer reactivity and antigen sensitivity, in comparison to TCR transduced cells generated by current clinical methodologies. Using this TCR replacement method I demonstrated that the anticancer reactivity of broadly cancer-reactive γδ T-cells derived from a variety of clinically relevant sources is dependent on their TCRs. I also used CRISPR/Cas9 genome editing to generate a panel of cancer cell lines deficient in known ligands of non-HLA restricted T-cells that can be used for initial dissection of their anticancer reactivity. Using this approach, I demonstrated that one of non-HLA restricted T-cell clones I procured recognised targets via CD1a. Finally, I developed a whole genome CRISPR/Cas9 pipeline for discovery of ligands and pathways essential for cancer cell recognition by non-HLA restricted T-cells.\ud Conclusions – My research demonstrated that TCRs from broadly cancer-reactive T-cells can be used to re-direct primary T-cells to many cancer types regardless of their HLA type, paving the way for pan-population immunotherapy. The discovery of non-HLA ligands for broadly cancer-reactive T-cells can be achieved using whole genome and targeted CRISPR/Cas9 gene editing technology.

52. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one

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

Subjects
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53. Genome editing approaches for development of pan-population immunotherapies

Author

Legut, Mateusz and Legut, Mateusz

Abstract

Background - T-cell based immunotherapy is the greatest recent breakthrough in cancer treatment, and can induce complete lasting remission. T-cells are capable of responding to a vast diversity of antigens via their hypervariable T-cell receptor (TCR). However, current immunotherapies rely on αβ T-cells which are restricted to person-specific Human Leukocyte Antigen (HLA) molecules presenting peptides from cancer-specific antigens. Thus, a given αβ TCR therapy is applicable only to a minority of patients. In contrast, γδ T-cells, and some αβ T-cells, recognise diverse cancer types regardless of the HLA type. The aims of my thesis were to investigate the potential of using non-HLA restricted T-cells and their receptors for cancer immunotherapy, and to develop tools to facilitate the study of non-HLA restricted T-cells for cancer treatment. Results – Initially, I developed a CRISPR/Cas9 method for generation of superior TCR transduced cells, in terms of their anticancer reactivity and antigen sensitivity, in comparison to TCR transduced cells generated by current clinical methodologies. Using this TCR replacement method I demonstrated that the anticancer reactivity of broadly cancer-reactive γδ T-cells derived from a variety of clinically relevant sources is dependent on their TCRs. I also used CRISPR/Cas9 genome editing to generate a panel of cancer cell lines deficient in known ligands of non-HLA restricted T-cells that can be used for initial dissection of their anticancer reactivity. Using this approach, I demonstrated that one of non-HLA restricted T-cell clones I procured recognised targets via CD1a. Finally, I developed a whole genome CRISPR/Cas9 pipeline for discovery of ligands and pathways essential for cancer cell recognition by non-HLA restricted T-cells. Conclusions – My research demonstrated that TCRs from broadly cancer-reactive T-cells can be used to re-direct primary T-cells to many cancer types regardless of their HLA type, paving the way for pan-pop

55. Ligand Identification for Orphan MHC-Agnostic T-Cell Receptors by Whole Genome CRISPR-Cas9 Screening.

Author

Crowther MD, Legut M, and Sewell AK

Subjects
Histocompatibility Antigens, Ligands, Major Histocompatibility Complex, CRISPR-Cas Systems, Receptors, Antigen, T-Cell genetics
Abstract

Killer T-cells play important roles in immunity to infection and cancer by detecting intracellular anomalies at the cell surface and destroying the cells that bear them. Conventional killer T-cells scan the intracellular proteome by sampling peptides presented at the cell surface by major histocompatibility complex (MHC) molecules. It is becoming apparent that some T-cells can also respond to pathogens and neoplasms by sensing intracellular changes through molecules other than MHC. We describe an unbiased methodology for T-cell receptor ligand discovery that requires no a priori knowledge regarding the nature of the antigen., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2022
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56. TCR-induced alteration of primary MHC peptide anchor residue.

Author

Madura F, Rizkallah PJ, Legut M, Holland CJ, Fuller A, Bulek A, Schauenburg AJ, Trimby A, Hopkins JR, Wells SA, Godkin A, Miles JJ, Sami M, Li Y, Liddy N, Jakobsen BK, Loveridge EJ, Cole DK, and Sewell AK

Subjects
Amino Acids, Antigen Presentation, Binding Sites, Cells, Cultured, Clone Cells, HLA-A2 Antigen chemistry, HLA-A2 Antigen metabolism, Humans, Lymphocyte Activation, MART-1 Antigen chemistry, Melanoma therapy, Peptides chemistry, Protein Binding, Protein Conformation, Receptors, Antigen, T-Cell genetics, T-Lymphocytes transplantation, Immunodominant Epitopes metabolism, Immunotherapy, Adoptive methods, MART-1 Antigen metabolism, Melanoma immunology, Peptides metabolism, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes immunology
Abstract

The HLA-A*02:01-restricted decapeptide EAAGIGILTV, derived from melanoma antigen recognized by T-cells-1 (MART-1) protein, represents one of the best-studied tumor associated T-cell epitopes, but clinical results targeting this peptide have been disappointing. This limitation may reflect the dominance of the nonapeptide, AAGIGILTV, at the melanoma cell surface. The decapeptide and nonapeptide are presented in distinct conformations by HLA-A*02:01 and TCRs from clinically relevant T-cell clones recognize the nonapeptide poorly. Here, we studied the MEL5 TCR that potently recognizes the nonapeptide. The structure of the MEL5-HLA-A*02:01-AAGIGILTV complex revealed an induced fit mechanism of antigen recognition involving altered peptide-MHC anchoring. This "flexing" at the TCR-peptide-MHC interface to accommodate the peptide antigen explains previously observed incongruences in this well-studied system and has important implications for future therapeutic approaches. Finally, this study expands upon the mechanisms by which molecular plasticity can influence antigen recognition by T cells., (© 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2019
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57. Optimized Peptide-MHC Multimer Protocols for Detection and Isolation of Autoimmune T-Cells.

Author

Dolton G, Zervoudi E, Rius C, Wall A, Thomas HL, Fuller A, Yeo L, Legut M, Wheeler S, Attaf M, Chudakov DM, Choy E, Peakman M, and Sewell AK

Abstract

Peptide-MHC (pMHC) multimers have become the "gold standard" for the detection and isolation of antigen-specific T-cells but recent evidence shows that normal use of these reagents can miss fully functional T-cells that bear T-cell receptors (TCRs) with low affinity for cognate antigen. This issue is particularly pronounced for anticancer and autoimmune T-cells as self-reactive T-cell populations are enriched for low-affinity TCRs due to the removal of cells with higher affinity receptors by immune tolerance mechanisms. Here, we stained a wide variety of self-reactive human T-cells using regular pMHC staining and an optimized technique that included: (i) protein kinase inhibitor (PKI), to prevent TCR triggering and internalization, and (ii) anti-fluorochrome antibody, to reduce reagent dissociation during washing steps. Lymphocytes derived from the peripheral blood of type 1 diabetes patients were stained with pMHC multimers made with epitopes from preproinsulin (PPI), insulin-β chain, glutamic acid decarboxylase 65 (GAD65), or glucose-6-phospate catalytic subunit-related protein (IGRP) presented by disease-risk allelles HLA A*02:01 or HLA*24:02. Samples from ankylosing spondylitis patients were stained with a multimerized epitope from vasoactive intestinal polypeptide receptor 1 (VIPR1) presented by HLA B*27:05. Optimized procedures stained an average of 40.5-fold ( p  = 0.01, range between 1.4 and 198) more cells than could be detected without the inclusion of PKI and cross-linking anti-fluorochrome antibody. Higher order pMHC dextramers recovered more cells than pMHC tetramers in parallel assays, and standard staining protocols with pMHC tetramers routinely recovered less cells than functional assays. HLA A*02:01-restricted PPI-specific and HLA B*27:05-restricted VIPR1-specific T-cell clones generated using the optimized procedure could not be stained by standard pMHC tetramer staining. However, these clones responded well to exogenously supplied peptide and endogenously processed and presented epitopes. We also showed that anti-fluorochrome antibody-conjugated magnetic beads enhanced staining of self-reactive T-cells that could not be stained using standard protocols, thus enabling rapid ex vivo isolation of autoimmune T-cells. We, therefore, conclude that regular pMHC tetramer staining is generally unsuitable for recovering self-reactive T-cells from clinical samples and recommend the use of the optimized protocols described herein.

Published
2018
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58. Dual Molecular Mechanisms Govern Escape at Immunodominant HLA A2-Restricted HIV Epitope.

Author

Cole DK, Fuller A, Dolton G, Zervoudi E, Legut M, Miles K, Blanchfield L, Madura F, Holland CJ, Bulek AM, Bridgeman JS, Miles JJ, Schauenburg AJA, Beck K, Evavold BD, Rizkallah PJ, and Sewell AK

Abstract

Serial accumulation of mutations to fixation in the SLYNTVATL (SL9) immunodominant, HIV p17 Gag-derived, HLA A2-restricted cytotoxic T lymphocyte epitope produce the SLFNTIAVL triple mutant "ultimate" escape variant. These mutations in solvent-exposed residues are believed to interfere with TCR recognition, although confirmation has awaited structural verification. Here, we solved a TCR co-complex structure with SL9 and the triple escape mutant to determine the mechanism of immune escape in this eminent system. We show that, in contrast to prevailing hypotheses, the main TCR contact residue is 4N and the dominant mechanism of escape is not via lack of TCR engagement. Instead, mutation of solvent-exposed residues in the peptide destabilise the peptide-HLA and reduce peptide density at the cell surface. These results highlight the extraordinary lengths that HIV employs to evade detection by high-affinity TCRs with a broad peptide-binding footprint and necessitate re-evaluation of this exemplar model of HIV TCR escape.

Published
2017
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59. PD-1 + Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer.

Author

Donia M, Kjeldsen JW, Andersen R, Westergaard MCW, Bianchi V, Legut M, Attaf M, Szomolay B, Ott S, Dolton G, Lyngaa R, Hadrup SR, Sewell AK, and Svane IM

Subjects
Adult, Aged, Antigens, Neoplasm immunology, CD8-Positive T-Lymphocytes immunology, Female, Humans, Immunotherapy, Adoptive, Lymphocyte Activation immunology, Male, Melanoma genetics, Melanoma immunology, Melanoma pathology, Middle Aged, Programmed Cell Death 1 Ligand 2 Protein antagonists & inhibitors, Programmed Cell Death 1 Ligand 2 Protein immunology, Programmed Cell Death 1 Receptor antagonists & inhibitors, T-Lymphocytes, Cell- and Tissue-Based Therapy, Lymphocytes, Tumor-Infiltrating immunology, Melanoma therapy, Programmed Cell Death 1 Receptor immunology
Abstract

Purpose: Infusion of highly heterogeneous populations of autologous tumor-infiltrating lymphocytes (TIL) can result in tumor regression of exceptional duration. Initial tumor regression has been associated with persistence of tumor-specific TILs 1 month after infusion, but mechanisms leading to long-lived memory responses are currently unknown. Here, we studied the dynamics of bulk tumor-reactive CD8 + T-cell populations in patients with metastatic melanoma following treatment with TILs. Experimental Design: We analyzed the function and phenotype of tumor-reactive CD8 + T cells contained in serial blood samples of 16 patients treated with TILs. Results: Polyfunctional tumor-reactive CD8 + T cells accumulated over time in the peripheral lymphocyte pool. Combinatorial analysis of multiple surface markers (CD57, CD27, CD45RO, PD-1, and LAG-3) showed a unique differentiation pattern of polyfunctional tumor-reactive CD8 + T cells, with highly specific PD-1 upregulation early after infusion. The differentiation and functional status appeared largely stable for up to 1 year after infusion. Despite some degree of clonal diversification occurring in vivo within the bulk tumor-reactive CD8 + T cells, further analyses showed that CD8 + T cells specific for defined tumor antigens had similar differentiation status. Conclusions: We demonstrated that tumor-reactive CD8 + T-cell subsets that persist after TIL therapy are mostly polyfunctional, display a stable partially differentiated phenotype, and express high levels of PD-1. These partially differentiated PD-1 + polyfunctional TILs have a high capacity for persistence and may be susceptible to PD-L1/PD-L2-mediated inhibition. Clin Cancer Res; 23(19); 5779-88. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Published
2017
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