TY - JOUR
T1 - Tumor-specific t-cells engineered to overcome tumor immune evasion induce clinical responses in patients with relapsed hodgkin lymphoma
AU - Bollard, Catherine M.
AU - Tripic, Tamara
AU - Cruz, Conrad Russell
AU - Dotti, Gianpietro
AU - Gottschalk, Stephen
AU - Torrano, V.
AU - Dakhova, Olga
AU - Carrum, G.
AU - Ramos, C. A.
AU - Liu, H.
AU - Wu, Meng Fen
AU - Marcogliese, Andrea N.
AU - Barese, Cecilia
AU - Zu, Youli
AU - Lee, Daniel Y.
AU - O’Connor, O.
AU - Gee, Adrian P.
AU - Brenner, Malcolm
AU - Heslop, Helen
AU - Rooney, Cliona M.
N1 - Publisher Copyright:
© 2018 by American Society of Clinical Oncology. All rights reserved.
PY - 2018/4/10
Y1 - 2018/4/10
N2 - Purpose Transforming growth factor-β (TGF-β) 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-β 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 × 10
7 and 1.5 × 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-β 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-β-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.
AB - Purpose Transforming growth factor-β (TGF-β) 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-β 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 × 10
7 and 1.5 × 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-β 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-β-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.
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U2 - 10.1200/JCO.2017.74.3179
DO - 10.1200/JCO.2017.74.3179
M3 - Article
C2 - 29315015
AN - SCOPUS:85044231117
SN - 0732-183X
VL - 36
SP - 1128
EP - 1139
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 11
ER -