To circumvent the immunosuppressive effects of TGFβ in the tumor microenvironment of relapsed Hodgkin lymphoma, Bollard et al. engineered enriched EBV-specific T cells to express a dominant-negative TGFβ receptor type 2 (DNRII). When adoptively transferred without lymphodepletion into seven relapsed patients and one patient in remission, the cells expanded and persisted up to four years, yielding positive clinical responses, including two complete responses ongoing after four years.
Purpose Transforming growth factor-beta (TGF-beta) production in the tumor microenvironment is a potent and ubiquitous tumor immune evasion mechanism that inhibits the expansion and function of tumor-directed responses; therefore, we conducted a clinical study to discover the effects of the forced expression of a dominant-negative TGF-beta receptor type 2 (DNRII) on the safety, survival, and activity of infused tumor-directed T cells. Materials and Methods In a dose escalation study, eight patients with Epstein Barr virus-positive Hodgkin lymphoma received two to 12 doses of between 2 x 10(7) and 1.5 x 10(8) cells/m(2) of DNRII-expressing T cells with specificity for the Epstein Barr virus-derived tumor antigens, latent membrane protein (LMP)-1 and LMP-2 (DNRII-LSTs). Lymphodepleting chemotherapy was not used before infusion. Results DNRII-LSTs were resistant to otherwise inhibitory concentrations of TGF-beta in vitro and retained their tumor antigen-specific activity. After infusion, the signal from transgenic T cells in peripheral blood increased up to 100-fold as measured by quantitative polymerase chain reaction for the transgene, with a corresponding increase in the frequency of functional LMP-specific T cells. Expansion was not associated with any acute or long-term toxicity. DNRII-LSTs persisted for up to >/= 4 years. Four of the seven evaluable patients with active disease achieved clinical responses that were complete and ongoing in two patients at > 4 years, including in one patient who achieved only a partial response to unmodified tumor-directed T cells. Conclusion TGF-beta-resistant tumor-specific T cells safely expand and persist in patients with Hodgkin lymphoma without lymphodepleting chemotherapy before infusion. DNRII-LSTs can induce complete responses even in patients with resistant disease. Expression of DNRII may be useful for the many other tumors that exploit this potent immune evasion mechanism.
Author Info: (1) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen
Author Info: (1) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (2) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (3) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (4) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (5) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (6) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (7) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (8) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (9) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (10) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (11) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (12) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (13) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (14) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (15) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (16) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (17) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (18) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (19) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY. (20) Catherine M. Bollard, Tamara Tripic, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Houston Methodist Hospital, and Texas Children's Hospital; Catherine M. Bollard, Gianpietro Dotti, Stephen Gottschalk, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine, Houston, TX; Catherine M. Bollard, Conrad Russell Cruz, and Cecilia Barese, Children's National Health System, Washington, DC; Youli Zu and Daniel Y. Lee, Weill Medical College of Cornell University; and Owen O'Connor, Columbia University College of Physicians and Surgeons, The New York Presbyterian Hospital, New York, NY.
