Abstract
Engineered immune cells are at the forefront of adoptive cellular therapies but are limited to simple genetic manipulation of autologous cells. This project will explore a radical new approach – establishing a controllable but immortalized immune cell which can be used as a platform for cell therapies. This is a complex challenge since immortalization typically causes dysregulation and genetic instability. The student will meet this challenge by exploiting the molecular biology of natural immune cell malignancies along with high-throughput approaches to synthetic biology and systems biology. This cell therapy platform could form the basis for treatments of many disease types.
References
1. Rethinking Cancer Immunotherapy by Embracing and Engineering Complexity. Matthew H W Chin, Eileen Gentleman, Marc-Olivier Coppens, Richard M Day. Trends Biotechnol 2020 Oct;38(10):1054-1065. DOI: 10.1016/j.tibtech.2020.05.003
2. Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1-infected T cells. Toshiki Watanabe. Blood 2017 Mar 2;129(9):1071-1081. doi: 10.1182/blood-2016-09-692574.
3. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Waseem Qasim, Hong Zhan, Sujith Samarasinghe, Stuart Adams, Persis Amrolia, Sian Stafford, Katie Butler, Christine Rivat, Gary Wright, Kathy Somana, Sara Ghorashian, Danielle Pinner, Gul Ahsan, Kimberly Gilmour, Giovanna Lucchini, Sarah Inglott, William Mifsud, Robert Chiesa, Karl S Peggs, Lucas Chan, Farzin Farzeneh, Adrian J Thrasher, Ajay Vora, Martin Pule, Paul Veys. Sci Transl Med. 2017 Jan 25;9(374):eaaj2013. doi: 10.1126/scitranslmed.aaj2013.
4. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Marc R Mansour, Brian J Abraham, Lars Anders, Alla Berezovskaya, Alejandro Gutierrez, Adam D Durbin, Julia Etchin, Lee Lawton, Stephen E Sallan, Lewis B Silverman, Mignon L Loh, Stephen P Hunger, Takaomi Sanda, Richard A Young, A Thomas Look. Science 2014 Dec 12;346(6215):1373-7. doi: 10.1126/science.1259037.
5. JDP2: An oncogenic bZIP transcription factor in T cell acute lymphoblastic leukemia. Marc R Mansour, Shuning He, Zhaodong Li, Riadh Lobbardi, Brian J Abraham, Clemens Hug, Sunniyat Rahman, Theresa E Leon, You-Yi Kuang, Mark W Zimmerman, Traci Blonquist, Evisa Gjini, Alejandro Gutierrez, Qin Tang , Laura Garcia-Perez, Karin Pike-Overzet, Lars Anders, Alla Berezovskaya, Yi Zhou, Leonard I Zon, Donna Neuberg, Adele K Fielding, Frank J T Staal, David M Langenau, Takaomi Sanda, Richard A Young, A Thomas Look. Affiliations. J Exp Med 2018 Jul 2;215(7):1929-1945. doi: 10.1084/jem.20170484.