Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins

Catherine M. Bollard, Stephen Gottschalk, Vicky Torrano, Oumar Diouf, Stephanie Ku, Yasmin Hazrat, George Carrum, Carlos Ramos, Luis Fayad, Elizabeth J. Shpall, Barbara Pro, Hao Liu, Meng Fen Wu, Daniel Lee, Andrea M. Sheehan, Youli Zu, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, Cliona M. Rooney

Research output: Contribution to journalArticle

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Abstract

Purpose: Tumor cells from approximately 40% of patients with Hodgkin or non-Hodgkin lymphoma express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2, which represent attractive targets for immunotherapy. Because T cells specific for these antigens are present with low frequency and may be rendered anergic by the tumors that express them, we expanded LMP-cytotoxic T lymphocytes (CTLs) from patients with lymphoma using autologous dendritic cells and EBV-transformed B-lymphoblastoid cell lines transduced with an adenoviral vector expressing either LMP2 alone (n = 17) or both LMP2 and ΔLMP1 (n = 33). Patients and Methods: These genetically modified antigen-presenting cells expanded CTLs that were enriched for specificity against type II latency LMP antigens. When infused into 50 patients with EBV-associated lymphoma, the expanded CTLs did not produce infusional toxicities. Results: Twenty-eight of 29 high-risk or multiple-relapse patients receiving LMP-CTLs as adjuvant therapy remained in remission at a median of 3.1 years after CTL infusion. None subsequently died as a result of lymphoma, but nine succumbed to complications associated with extensive prior chemoradiotherapy, including myocardial infarction and secondary malignancies. Of 21 patients with relapsed or resistant disease at the time of CTL infusion, 13 had clinical responses, including 11 complete responses. T cells specific for LMP as well as nonviral tumor-associated antigens (epitope spreading) could be detected in the peripheral blood within 2 months after CTL infusion, but this evidence for epitope spreading was seen only in patients achieving clinical responses. Conclusion: Autologous T cells directed to the LMP2 or LMP1 and LMP2 antigens can induce durable complete responses without significant toxicity. Their earlier use in the disease course may reduce delayed treatment-related mortality.

Original languageEnglish (US)
Pages (from-to)798-808
Number of pages11
JournalJournal of Clinical Oncology
Volume32
Issue number8
DOIs
StatePublished - Mar 10 2014
Externally publishedYes

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Cytotoxic T-Lymphocytes
Human Herpesvirus 4
Lymphoma
Membrane Proteins
Antigens
T-Lymphocytes
Epitopes
Neoplasms
Chemoradiotherapy
Neoplasm Antigens
Antigen-Presenting Cells
Hodgkin Disease
Non-Hodgkin's Lymphoma
Immunotherapy
Dendritic Cells
Myocardial Infarction
Recurrence
Cell Line
Mortality
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. / Bollard, Catherine M.; Gottschalk, Stephen; Torrano, Vicky; Diouf, Oumar; Ku, Stephanie; Hazrat, Yasmin; Carrum, George; Ramos, Carlos; Fayad, Luis; Shpall, Elizabeth J.; Pro, Barbara; Liu, Hao; Wu, Meng Fen; Lee, Daniel; Sheehan, Andrea M.; Zu, Youli; Gee, Adrian P.; Brenner, Malcolm K.; Heslop, Helen E.; Rooney, Cliona M.

In: Journal of Clinical Oncology, Vol. 32, No. 8, 10.03.2014, p. 798-808.

Research output: Contribution to journalArticle

Bollard, CM, Gottschalk, S, Torrano, V, Diouf, O, Ku, S, Hazrat, Y, Carrum, G, Ramos, C, Fayad, L, Shpall, EJ, Pro, B, Liu, H, Wu, MF, Lee, D, Sheehan, AM, Zu, Y, Gee, AP, Brenner, MK, Heslop, HE & Rooney, CM 2014, 'Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins', Journal of Clinical Oncology, vol. 32, no. 8, pp. 798-808. https://doi.org/10.1200/JCO.2013.51.5304
Bollard, Catherine M. ; Gottschalk, Stephen ; Torrano, Vicky ; Diouf, Oumar ; Ku, Stephanie ; Hazrat, Yasmin ; Carrum, George ; Ramos, Carlos ; Fayad, Luis ; Shpall, Elizabeth J. ; Pro, Barbara ; Liu, Hao ; Wu, Meng Fen ; Lee, Daniel ; Sheehan, Andrea M. ; Zu, Youli ; Gee, Adrian P. ; Brenner, Malcolm K. ; Heslop, Helen E. ; Rooney, Cliona M. / Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. In: Journal of Clinical Oncology. 2014 ; Vol. 32, No. 8. pp. 798-808.
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abstract = "Purpose: Tumor cells from approximately 40{\%} of patients with Hodgkin or non-Hodgkin lymphoma express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2, which represent attractive targets for immunotherapy. Because T cells specific for these antigens are present with low frequency and may be rendered anergic by the tumors that express them, we expanded LMP-cytotoxic T lymphocytes (CTLs) from patients with lymphoma using autologous dendritic cells and EBV-transformed B-lymphoblastoid cell lines transduced with an adenoviral vector expressing either LMP2 alone (n = 17) or both LMP2 and ΔLMP1 (n = 33). Patients and Methods: These genetically modified antigen-presenting cells expanded CTLs that were enriched for specificity against type II latency LMP antigens. When infused into 50 patients with EBV-associated lymphoma, the expanded CTLs did not produce infusional toxicities. Results: Twenty-eight of 29 high-risk or multiple-relapse patients receiving LMP-CTLs as adjuvant therapy remained in remission at a median of 3.1 years after CTL infusion. None subsequently died as a result of lymphoma, but nine succumbed to complications associated with extensive prior chemoradiotherapy, including myocardial infarction and secondary malignancies. Of 21 patients with relapsed or resistant disease at the time of CTL infusion, 13 had clinical responses, including 11 complete responses. T cells specific for LMP as well as nonviral tumor-associated antigens (epitope spreading) could be detected in the peripheral blood within 2 months after CTL infusion, but this evidence for epitope spreading was seen only in patients achieving clinical responses. Conclusion: Autologous T cells directed to the LMP2 or LMP1 and LMP2 antigens can induce durable complete responses without significant toxicity. Their earlier use in the disease course may reduce delayed treatment-related mortality.",
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T1 - Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins

AU - Bollard, Catherine M.

AU - Gottschalk, Stephen

AU - Torrano, Vicky

AU - Diouf, Oumar

AU - Ku, Stephanie

AU - Hazrat, Yasmin

AU - Carrum, George

AU - Ramos, Carlos

AU - Fayad, Luis

AU - Shpall, Elizabeth J.

AU - Pro, Barbara

AU - Liu, Hao

AU - Wu, Meng Fen

AU - Lee, Daniel

AU - Sheehan, Andrea M.

AU - Zu, Youli

AU - Gee, Adrian P.

AU - Brenner, Malcolm K.

AU - Heslop, Helen E.

AU - Rooney, Cliona M.

PY - 2014/3/10

Y1 - 2014/3/10

N2 - Purpose: Tumor cells from approximately 40% of patients with Hodgkin or non-Hodgkin lymphoma express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2, which represent attractive targets for immunotherapy. Because T cells specific for these antigens are present with low frequency and may be rendered anergic by the tumors that express them, we expanded LMP-cytotoxic T lymphocytes (CTLs) from patients with lymphoma using autologous dendritic cells and EBV-transformed B-lymphoblastoid cell lines transduced with an adenoviral vector expressing either LMP2 alone (n = 17) or both LMP2 and ΔLMP1 (n = 33). Patients and Methods: These genetically modified antigen-presenting cells expanded CTLs that were enriched for specificity against type II latency LMP antigens. When infused into 50 patients with EBV-associated lymphoma, the expanded CTLs did not produce infusional toxicities. Results: Twenty-eight of 29 high-risk or multiple-relapse patients receiving LMP-CTLs as adjuvant therapy remained in remission at a median of 3.1 years after CTL infusion. None subsequently died as a result of lymphoma, but nine succumbed to complications associated with extensive prior chemoradiotherapy, including myocardial infarction and secondary malignancies. Of 21 patients with relapsed or resistant disease at the time of CTL infusion, 13 had clinical responses, including 11 complete responses. T cells specific for LMP as well as nonviral tumor-associated antigens (epitope spreading) could be detected in the peripheral blood within 2 months after CTL infusion, but this evidence for epitope spreading was seen only in patients achieving clinical responses. Conclusion: Autologous T cells directed to the LMP2 or LMP1 and LMP2 antigens can induce durable complete responses without significant toxicity. Their earlier use in the disease course may reduce delayed treatment-related mortality.

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