Generation of tumor-specific T lymphocytes for the treatment of posttransplant lymphoma

J. M. DiMaio, P. Van Trigt, J. W. Gaynor, R. D. Davis, E. Coveney, B. M. Clary, H. K. Lyerly

Research output: Contribution to journalArticle

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Abstract

Background: The incidence of lymphoproliferative disease, including B- cell lymphomas (BCL) in patients who have undergone heart or combined heart- lung transplants, has been reported to be as high as 15%. The majority of these tumors contain Epstein-Barr virus (EBV) DNA and regress when immunosuppressive agents are discontinued. This tumor regression is thought to be secondary to cytotoxic T lymphocytes (CTL) reactive to EBV-infected cells whose function is impaired in patients receiving immunosuppressive agents. We hypothesize that EBV-CTL expanded in the absence of these agents may demonstrate an antitumor effect against an EBV-expressing human BCL in vitro and in vivo. Methods and Results: An EBV-expressing BCL from a heart transplant recipient was isolated and expanded in culture. EBV-CTL were generated by stimulation of peripheral blood leukocytes with irradiated autologous tumor culls in low-dose interleukin-2. Autologous BCL, HLA- mismatched BCL, lymphokine-activated killer target cell line (Daudi), and the natural killer target cell line (K562) were used in a standard 4-hour cytotoxicity assay using 51CrO4 after 7, 14, and 28 days of stimulation. There was significant percent specific lysis of autologous BCL targets (78%) at all effector-to-target ratio as low as 20:1 as compared with control cells. EBV-CTL were then adoptively transferred into SCID mice (provided by Duke University Vivarium) that had been engrafted with autologous BCL 7 days before. There was a significant survival advantage to those mice engrafted with EBV-CTL as compared with control cells. Conclusions: The results indicate that ex vivo expansion of EBV-CTL in the absence of immunosuppressive agents results in a population that has significant antitumor activity. This strategy may be useful in the generation of EBV-CTL that might be effective antitumor agents in transplant recipients with EBV- associated lymphomas.

Original languageEnglish (US)
JournalCirculation
Volume92
Issue number9 SUPPL.
StatePublished - 1995

Fingerprint

Human Herpesvirus 4
Lymphoma
Cytotoxic T-Lymphocytes
B-Cell Lymphoma
T-Lymphocytes
Neoplasms
Immunosuppressive Agents
Therapeutics
Lymphokine-Activated Killer Cells
Cell Line
HLA-B Antigens
SCID Mice
Natural Killer Cells
Antineoplastic Agents
Interleukin-2
Leukocytes
Transplants
Lung
Survival
DNA

Keywords

  • cells
  • heart transplant
  • immunodeficiency
  • lymphocytes
  • lymphoma
  • transplantation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

DiMaio, J. M., Van Trigt, P., Gaynor, J. W., Davis, R. D., Coveney, E., Clary, B. M., & Lyerly, H. K. (1995). Generation of tumor-specific T lymphocytes for the treatment of posttransplant lymphoma. Circulation, 92(9 SUPPL.).

Generation of tumor-specific T lymphocytes for the treatment of posttransplant lymphoma. / DiMaio, J. M.; Van Trigt, P.; Gaynor, J. W.; Davis, R. D.; Coveney, E.; Clary, B. M.; Lyerly, H. K.

In: Circulation, Vol. 92, No. 9 SUPPL., 1995.

Research output: Contribution to journalArticle

DiMaio, JM, Van Trigt, P, Gaynor, JW, Davis, RD, Coveney, E, Clary, BM & Lyerly, HK 1995, 'Generation of tumor-specific T lymphocytes for the treatment of posttransplant lymphoma', Circulation, vol. 92, no. 9 SUPPL..
DiMaio JM, Van Trigt P, Gaynor JW, Davis RD, Coveney E, Clary BM et al. Generation of tumor-specific T lymphocytes for the treatment of posttransplant lymphoma. Circulation. 1995;92(9 SUPPL.).
DiMaio, J. M. ; Van Trigt, P. ; Gaynor, J. W. ; Davis, R. D. ; Coveney, E. ; Clary, B. M. ; Lyerly, H. K. / Generation of tumor-specific T lymphocytes for the treatment of posttransplant lymphoma. In: Circulation. 1995 ; Vol. 92, No. 9 SUPPL.
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AU - DiMaio, J. M.

AU - Van Trigt, P.

AU - Gaynor, J. W.

AU - Davis, R. D.

AU - Coveney, E.

AU - Clary, B. M.

AU - Lyerly, H. K.

PY - 1995

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AB - Background: The incidence of lymphoproliferative disease, including B- cell lymphomas (BCL) in patients who have undergone heart or combined heart- lung transplants, has been reported to be as high as 15%. The majority of these tumors contain Epstein-Barr virus (EBV) DNA and regress when immunosuppressive agents are discontinued. This tumor regression is thought to be secondary to cytotoxic T lymphocytes (CTL) reactive to EBV-infected cells whose function is impaired in patients receiving immunosuppressive agents. We hypothesize that EBV-CTL expanded in the absence of these agents may demonstrate an antitumor effect against an EBV-expressing human BCL in vitro and in vivo. Methods and Results: An EBV-expressing BCL from a heart transplant recipient was isolated and expanded in culture. EBV-CTL were generated by stimulation of peripheral blood leukocytes with irradiated autologous tumor culls in low-dose interleukin-2. Autologous BCL, HLA- mismatched BCL, lymphokine-activated killer target cell line (Daudi), and the natural killer target cell line (K562) were used in a standard 4-hour cytotoxicity assay using 51CrO4 after 7, 14, and 28 days of stimulation. There was significant percent specific lysis of autologous BCL targets (78%) at all effector-to-target ratio as low as 20:1 as compared with control cells. EBV-CTL were then adoptively transferred into SCID mice (provided by Duke University Vivarium) that had been engrafted with autologous BCL 7 days before. There was a significant survival advantage to those mice engrafted with EBV-CTL as compared with control cells. Conclusions: The results indicate that ex vivo expansion of EBV-CTL in the absence of immunosuppressive agents results in a population that has significant antitumor activity. This strategy may be useful in the generation of EBV-CTL that might be effective antitumor agents in transplant recipients with EBV- associated lymphomas.

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