Gene transfer into humans - Immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction

Steven A. Rosenberg, Paul Aebersold, Kenneth Cornetta, Attan Kasid, Richard A. Morgan, Robert Moen, Evelyn M. Karson, Michael T. Lotze, James C. Yang, Suzanne Topalian, Maria J. Merino, Kenneth Culver, A. Dusty Miller, R. Michael Blaese, W. French Anderson

Research output: Contribution to journalArticle

Abstract

Background and Methods. Treatment with tumor-infiltrating lymphocytes (TIL) plus interleukin-2 can mediate the regression of metastatic melanoma in approximately half of patients. To optimize this treatment approach and define the in vivo distribution and survival of TIL, we used retroviral-mediated gene transduction to introduce the gene coding for resistance to neomycin into human TIL before their infusion into patients - thus using the new gene as a marker for the infused cells. Results. Five patients received the gene-modified TIL. All the patients tolerated the treatment well, and no side effects due to the gene transduction were noted. The presence and expression of the neomycin-resistance gene were demonstrated in TIL from all the patients with Southern blot analysis and enzymatic assay for the neomycin phosphotransferase coded by the bacterial gene. Cells from four of the five patients grew successfully in high concentrations of G418, a neomycin analogue otherwise toxic to eukaryotic cells. With polymerase-chain-reaction analysis, gene-modified cells were consistently found in the circulation of all five patients for three weeks and for as long as two months in two patients. Cells were recovered from tumor deposits as much as 64 days after cell administration. The procedure was safe according to all criteria, including the absence of infectious virus in TIL and in the patients. Conclusions. These studies demonstrate the feasibility and safety of using retroviral gene transduction for human gene therapy and have implications for the design of TIL with improved antitumor potency, as well as for the possible use of lymphocytes for the gene therapy of other diseases.

Original languageEnglish (US)
Pages (from-to)570-578
Number of pages9
JournalNew England Journal of Medicine
Volume323
Issue number9
StatePublished - Aug 30 1990
Externally publishedYes

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Tumor-Infiltrating Lymphocytes
Immunotherapy
Melanoma
Genes
Neomycin
Genetic Therapy
Kanamycin Kinase
Bacterial Genes
Poisons
Enzyme Assays
Feasibility Studies
Eukaryotic Cells
Southern Blotting
Interleukin-2
Therapeutics
Lymphocytes
Viruses
Safety
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Rosenberg, S. A., Aebersold, P., Cornetta, K., Kasid, A., Morgan, R. A., Moen, R., ... Anderson, W. F. (1990). Gene transfer into humans - Immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. New England Journal of Medicine, 323(9), 570-578.

Gene transfer into humans - Immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. / Rosenberg, Steven A.; Aebersold, Paul; Cornetta, Kenneth; Kasid, Attan; Morgan, Richard A.; Moen, Robert; Karson, Evelyn M.; Lotze, Michael T.; Yang, James C.; Topalian, Suzanne; Merino, Maria J.; Culver, Kenneth; Miller, A. Dusty; Blaese, R. Michael; Anderson, W. French.

In: New England Journal of Medicine, Vol. 323, No. 9, 30.08.1990, p. 570-578.

Research output: Contribution to journalArticle

Rosenberg, SA, Aebersold, P, Cornetta, K, Kasid, A, Morgan, RA, Moen, R, Karson, EM, Lotze, MT, Yang, JC, Topalian, S, Merino, MJ, Culver, K, Miller, AD, Blaese, RM & Anderson, WF 1990, 'Gene transfer into humans - Immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction', New England Journal of Medicine, vol. 323, no. 9, pp. 570-578.
Rosenberg, Steven A. ; Aebersold, Paul ; Cornetta, Kenneth ; Kasid, Attan ; Morgan, Richard A. ; Moen, Robert ; Karson, Evelyn M. ; Lotze, Michael T. ; Yang, James C. ; Topalian, Suzanne ; Merino, Maria J. ; Culver, Kenneth ; Miller, A. Dusty ; Blaese, R. Michael ; Anderson, W. French. / Gene transfer into humans - Immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. In: New England Journal of Medicine. 1990 ; Vol. 323, No. 9. pp. 570-578.
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abstract = "Background and Methods. Treatment with tumor-infiltrating lymphocytes (TIL) plus interleukin-2 can mediate the regression of metastatic melanoma in approximately half of patients. To optimize this treatment approach and define the in vivo distribution and survival of TIL, we used retroviral-mediated gene transduction to introduce the gene coding for resistance to neomycin into human TIL before their infusion into patients - thus using the new gene as a marker for the infused cells. Results. Five patients received the gene-modified TIL. All the patients tolerated the treatment well, and no side effects due to the gene transduction were noted. The presence and expression of the neomycin-resistance gene were demonstrated in TIL from all the patients with Southern blot analysis and enzymatic assay for the neomycin phosphotransferase coded by the bacterial gene. Cells from four of the five patients grew successfully in high concentrations of G418, a neomycin analogue otherwise toxic to eukaryotic cells. With polymerase-chain-reaction analysis, gene-modified cells were consistently found in the circulation of all five patients for three weeks and for as long as two months in two patients. Cells were recovered from tumor deposits as much as 64 days after cell administration. The procedure was safe according to all criteria, including the absence of infectious virus in TIL and in the patients. Conclusions. These studies demonstrate the feasibility and safety of using retroviral gene transduction for human gene therapy and have implications for the design of TIL with improved antitumor potency, as well as for the possible use of lymphocytes for the gene therapy of other diseases.",
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T1 - Gene transfer into humans - Immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction

AU - Rosenberg, Steven A.

AU - Aebersold, Paul

AU - Cornetta, Kenneth

AU - Kasid, Attan

AU - Morgan, Richard A.

AU - Moen, Robert

AU - Karson, Evelyn M.

AU - Lotze, Michael T.

AU - Yang, James C.

AU - Topalian, Suzanne

AU - Merino, Maria J.

AU - Culver, Kenneth

AU - Miller, A. Dusty

AU - Blaese, R. Michael

AU - Anderson, W. French

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N2 - Background and Methods. Treatment with tumor-infiltrating lymphocytes (TIL) plus interleukin-2 can mediate the regression of metastatic melanoma in approximately half of patients. To optimize this treatment approach and define the in vivo distribution and survival of TIL, we used retroviral-mediated gene transduction to introduce the gene coding for resistance to neomycin into human TIL before their infusion into patients - thus using the new gene as a marker for the infused cells. Results. Five patients received the gene-modified TIL. All the patients tolerated the treatment well, and no side effects due to the gene transduction were noted. The presence and expression of the neomycin-resistance gene were demonstrated in TIL from all the patients with Southern blot analysis and enzymatic assay for the neomycin phosphotransferase coded by the bacterial gene. Cells from four of the five patients grew successfully in high concentrations of G418, a neomycin analogue otherwise toxic to eukaryotic cells. With polymerase-chain-reaction analysis, gene-modified cells were consistently found in the circulation of all five patients for three weeks and for as long as two months in two patients. Cells were recovered from tumor deposits as much as 64 days after cell administration. The procedure was safe according to all criteria, including the absence of infectious virus in TIL and in the patients. Conclusions. These studies demonstrate the feasibility and safety of using retroviral gene transduction for human gene therapy and have implications for the design of TIL with improved antitumor potency, as well as for the possible use of lymphocytes for the gene therapy of other diseases.

AB - Background and Methods. Treatment with tumor-infiltrating lymphocytes (TIL) plus interleukin-2 can mediate the regression of metastatic melanoma in approximately half of patients. To optimize this treatment approach and define the in vivo distribution and survival of TIL, we used retroviral-mediated gene transduction to introduce the gene coding for resistance to neomycin into human TIL before their infusion into patients - thus using the new gene as a marker for the infused cells. Results. Five patients received the gene-modified TIL. All the patients tolerated the treatment well, and no side effects due to the gene transduction were noted. The presence and expression of the neomycin-resistance gene were demonstrated in TIL from all the patients with Southern blot analysis and enzymatic assay for the neomycin phosphotransferase coded by the bacterial gene. Cells from four of the five patients grew successfully in high concentrations of G418, a neomycin analogue otherwise toxic to eukaryotic cells. With polymerase-chain-reaction analysis, gene-modified cells were consistently found in the circulation of all five patients for three weeks and for as long as two months in two patients. Cells were recovered from tumor deposits as much as 64 days after cell administration. The procedure was safe according to all criteria, including the absence of infectious virus in TIL and in the patients. Conclusions. These studies demonstrate the feasibility and safety of using retroviral gene transduction for human gene therapy and have implications for the design of TIL with improved antitumor potency, as well as for the possible use of lymphocytes for the gene therapy of other diseases.

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