Tumor-specific t-cells engineered to overcome tumor immune evasion induce clinical responses in patients with relapsed hodgkin lymphoma

Catherine M. Bollard, Tamara Tripic, Conrad Russell Cruz, Gianpietro Dotti, Stephen Gottschalk, V. Torrano, Olga Dakhova, G. Carrum, C. A. Ramos, Hao Liu, Meng Fen Wu, Andrea N. Marcogliese, Cecilia Barese, Youli Zu, Daniel Y. Lee, O. O’Connor, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, Cliona M. Rooney

Research output: Contribution to journalArticle

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Abstract

Purpose Transforming growth factor-b (TGF-b) 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-b 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 3 10 7 and 1.5 3 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-b 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-b–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.

Original languageEnglish (US)
Pages (from-to)1128-1139
Number of pages12
JournalJournal of Clinical Oncology
Volume36
Issue number11
DOIs
StatePublished - Apr 10 2018
Externally publishedYes

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Tumor Escape
Hodgkin Disease
T-Lymphocytes
Transforming Growth Factors
Neoplasms
Membrane Proteins
T-Cell Antigen Receptor Specificity
Immune Evasion
Drug Therapy
Tumor Microenvironment
Growth Factor Receptors
Neoplasm Antigens
Transgenes
Safety
Polymerase Chain Reaction
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tumor-specific t-cells engineered to overcome tumor immune evasion induce clinical responses in patients with relapsed hodgkin lymphoma. / Bollard, Catherine M.; Tripic, Tamara; Cruz, Conrad Russell; Dotti, Gianpietro; Gottschalk, Stephen; Torrano, V.; Dakhova, Olga; Carrum, G.; Ramos, C. A.; Liu, Hao; Wu, Meng Fen; Marcogliese, Andrea N.; Barese, Cecilia; Zu, Youli; Lee, Daniel Y.; O’Connor, O.; Gee, Adrian P.; Brenner, Malcolm K.; Heslop, Helen E.; Rooney, Cliona M.

In: Journal of Clinical Oncology, Vol. 36, No. 11, 10.04.2018, p. 1128-1139.

Research output: Contribution to journalArticle

Bollard, CM, Tripic, T, Cruz, CR, Dotti, G, Gottschalk, S, Torrano, V, Dakhova, O, Carrum, G, Ramos, CA, Liu, H, Wu, MF, Marcogliese, AN, Barese, C, Zu, Y, Lee, DY, O’Connor, O, Gee, AP, Brenner, MK, Heslop, HE & Rooney, CM 2018, 'Tumor-specific t-cells engineered to overcome tumor immune evasion induce clinical responses in patients with relapsed hodgkin lymphoma', Journal of Clinical Oncology, vol. 36, no. 11, pp. 1128-1139. https://doi.org/10.1200/JCO.2017.74.3179
Bollard, Catherine M. ; Tripic, Tamara ; Cruz, Conrad Russell ; Dotti, Gianpietro ; Gottschalk, Stephen ; Torrano, V. ; Dakhova, Olga ; Carrum, G. ; Ramos, C. A. ; Liu, Hao ; Wu, Meng Fen ; Marcogliese, Andrea N. ; Barese, Cecilia ; Zu, Youli ; Lee, Daniel Y. ; O’Connor, O. ; Gee, Adrian P. ; Brenner, Malcolm K. ; Heslop, Helen E. ; Rooney, Cliona M. / Tumor-specific t-cells engineered to overcome tumor immune evasion induce clinical responses in patients with relapsed hodgkin lymphoma. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 11. pp. 1128-1139.
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abstract = "Purpose Transforming growth factor-b (TGF-b) 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-b 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 3 10 7 and 1.5 3 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-b 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-b–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 = "Bollard, {Catherine M.} and Tamara Tripic and Cruz, {Conrad Russell} and Gianpietro Dotti and Stephen Gottschalk and V. Torrano and Olga Dakhova and G. Carrum and Ramos, {C. A.} and Hao Liu and Wu, {Meng Fen} and Marcogliese, {Andrea N.} and Cecilia Barese and Youli Zu and Lee, {Daniel Y.} and O. O’Connor and Gee, {Adrian P.} and Brenner, {Malcolm K.} and Heslop, {Helen E.} and Rooney, {Cliona M.}",
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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, Hao

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 K.

AU - Heslop, Helen E.

AU - Rooney, Cliona M.

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N2 - Purpose Transforming growth factor-b (TGF-b) 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-b 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 3 10 7 and 1.5 3 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-b 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-b–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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