Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans

D. H. Boldt, B. J. Mills, B. T. Gemlo, H. Holden, J. Mier, Elisabeth M. Paietta, J. D. McMannis, L. V. Escobedo, I. Sniecinski, A. A. Rayner, M. J. Hawkins, M. B. Atkins, N. Ciobanu, T. M. Ellis

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Adoptive immunotherapy with interleukin 2 (IL-2) and lymphokine-activated killer (LAK) cells (IL-2/LAK) is a technically demanding cancer therapy dependent upon large scale isolation and culture of lymphocytes. An important question is whether this technology can be accomplished routinely outside of highly specialized centers. In addition, no systematic examination of laboratory correlates of IL-2/LAK therapy in humans has been reported to date. The objectives of this report are to address two issues relevant to IL-2/LAK therapy. (a) Can IL-2/LAK therapy be accomplished outside of previously identified centers of expertise? (b) What are the relevant laboratory/clinical parameter correlations? The six institutions in the National Cancer Institute extramural trial treated 83 evaluable patients with renal cancer, malignant melanoma, or colon cancer with IL-2/LAK by a uniform protocol. Patients received 5 days of IL-2 priming, then daily leukaphereses for 5 days starting 48 h after IL-2 to harvest cells. Mononuclear cells were isolated, then cultured in roller bottles in 1-liter aliquots for 3 to 4 days at a cell density of 1.5 x 106 per ml with recombinant IL-2, 1500 units per ml. Cells were harvested and administered to patients with additional IL-2. Administration of IL-2 regularly induced lymphopenia and rebound lymphocytosis. Leukapheresis yields and numbers of LAK cells generated in culture and reinfused into patients correlated directly with peak lymphocyte counts achieved by IL-2 administration. Mean mononuclear cell recovery per 5 days of leukapheresis (± SEM) was 14.3 ± 0.8 x 1010. Average volume of cells cultured per patient was 95 liters (range, 41 to 235). Mean yield of cells harvested from cultures was 53%. Mean total number of LAK cells infused per patient was 7.6 ± 0.4 x 1010 (range, 2 to 15.2 x 1010). LAK activity was measured in vitro by lysis of 51Cr-labeled natural killer-resistant Daudi and fresh tumor targets. LAK effector cells regularly lysed these targets in vitro. Neither tumor reduction nor clinical toxicity correlated with dose or with cytolytic activity of LAK cells, or with other laboratory parameters including base-line lymphocyte count and IL-2-induced lymphocytosis. We conclude: (a) large quantities of LAK effector cells with tumoricidal activity can be generated routinely at different centers; (b) neither in vitro LAK activity nor numbers of LAK cells infused were predictive of clinical efficacy or toxicity. There is a need to identify other laboratory or clinical parameters more predictive of IL-2/LAK therapeutic efficacy or toxicity.

Original languageEnglish (US)
Pages (from-to)4409-4416
Number of pages8
JournalCancer Research
Volume48
Issue number15
StatePublished - 1988
Externally publishedYes

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Adoptive Immunotherapy
Lymphokine-Activated Killer Cells
Interleukin-2
Lymphokines
Leukapheresis
Lymphocytosis
Lymphocyte Count
Therapeutics
Neoplasms
Lymphopenia
National Cancer Institute (U.S.)
Kidney Neoplasms
Cell Size
Colonic Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Boldt, D. H., Mills, B. J., Gemlo, B. T., Holden, H., Mier, J., Paietta, E. M., ... Ellis, T. M. (1988). Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans. Cancer Research, 48(15), 4409-4416.

Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans. / Boldt, D. H.; Mills, B. J.; Gemlo, B. T.; Holden, H.; Mier, J.; Paietta, Elisabeth M.; McMannis, J. D.; Escobedo, L. V.; Sniecinski, I.; Rayner, A. A.; Hawkins, M. J.; Atkins, M. B.; Ciobanu, N.; Ellis, T. M.

In: Cancer Research, Vol. 48, No. 15, 1988, p. 4409-4416.

Research output: Contribution to journalArticle

Boldt, DH, Mills, BJ, Gemlo, BT, Holden, H, Mier, J, Paietta, EM, McMannis, JD, Escobedo, LV, Sniecinski, I, Rayner, AA, Hawkins, MJ, Atkins, MB, Ciobanu, N & Ellis, TM 1988, 'Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans', Cancer Research, vol. 48, no. 15, pp. 4409-4416.
Boldt, D. H. ; Mills, B. J. ; Gemlo, B. T. ; Holden, H. ; Mier, J. ; Paietta, Elisabeth M. ; McMannis, J. D. ; Escobedo, L. V. ; Sniecinski, I. ; Rayner, A. A. ; Hawkins, M. J. ; Atkins, M. B. ; Ciobanu, N. ; Ellis, T. M. / Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans. In: Cancer Research. 1988 ; Vol. 48, No. 15. pp. 4409-4416.
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T1 - Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans

AU - Boldt, D. H.

AU - Mills, B. J.

AU - Gemlo, B. T.

AU - Holden, H.

AU - Mier, J.

AU - Paietta, Elisabeth M.

AU - McMannis, J. D.

AU - Escobedo, L. V.

AU - Sniecinski, I.

AU - Rayner, A. A.

AU - Hawkins, M. J.

AU - Atkins, M. B.

AU - Ciobanu, N.

AU - Ellis, T. M.

PY - 1988

Y1 - 1988

N2 - Adoptive immunotherapy with interleukin 2 (IL-2) and lymphokine-activated killer (LAK) cells (IL-2/LAK) is a technically demanding cancer therapy dependent upon large scale isolation and culture of lymphocytes. An important question is whether this technology can be accomplished routinely outside of highly specialized centers. In addition, no systematic examination of laboratory correlates of IL-2/LAK therapy in humans has been reported to date. The objectives of this report are to address two issues relevant to IL-2/LAK therapy. (a) Can IL-2/LAK therapy be accomplished outside of previously identified centers of expertise? (b) What are the relevant laboratory/clinical parameter correlations? The six institutions in the National Cancer Institute extramural trial treated 83 evaluable patients with renal cancer, malignant melanoma, or colon cancer with IL-2/LAK by a uniform protocol. Patients received 5 days of IL-2 priming, then daily leukaphereses for 5 days starting 48 h after IL-2 to harvest cells. Mononuclear cells were isolated, then cultured in roller bottles in 1-liter aliquots for 3 to 4 days at a cell density of 1.5 x 106 per ml with recombinant IL-2, 1500 units per ml. Cells were harvested and administered to patients with additional IL-2. Administration of IL-2 regularly induced lymphopenia and rebound lymphocytosis. Leukapheresis yields and numbers of LAK cells generated in culture and reinfused into patients correlated directly with peak lymphocyte counts achieved by IL-2 administration. Mean mononuclear cell recovery per 5 days of leukapheresis (± SEM) was 14.3 ± 0.8 x 1010. Average volume of cells cultured per patient was 95 liters (range, 41 to 235). Mean yield of cells harvested from cultures was 53%. Mean total number of LAK cells infused per patient was 7.6 ± 0.4 x 1010 (range, 2 to 15.2 x 1010). LAK activity was measured in vitro by lysis of 51Cr-labeled natural killer-resistant Daudi and fresh tumor targets. LAK effector cells regularly lysed these targets in vitro. Neither tumor reduction nor clinical toxicity correlated with dose or with cytolytic activity of LAK cells, or with other laboratory parameters including base-line lymphocyte count and IL-2-induced lymphocytosis. We conclude: (a) large quantities of LAK effector cells with tumoricidal activity can be generated routinely at different centers; (b) neither in vitro LAK activity nor numbers of LAK cells infused were predictive of clinical efficacy or toxicity. There is a need to identify other laboratory or clinical parameters more predictive of IL-2/LAK therapeutic efficacy or toxicity.

AB - Adoptive immunotherapy with interleukin 2 (IL-2) and lymphokine-activated killer (LAK) cells (IL-2/LAK) is a technically demanding cancer therapy dependent upon large scale isolation and culture of lymphocytes. An important question is whether this technology can be accomplished routinely outside of highly specialized centers. In addition, no systematic examination of laboratory correlates of IL-2/LAK therapy in humans has been reported to date. The objectives of this report are to address two issues relevant to IL-2/LAK therapy. (a) Can IL-2/LAK therapy be accomplished outside of previously identified centers of expertise? (b) What are the relevant laboratory/clinical parameter correlations? The six institutions in the National Cancer Institute extramural trial treated 83 evaluable patients with renal cancer, malignant melanoma, or colon cancer with IL-2/LAK by a uniform protocol. Patients received 5 days of IL-2 priming, then daily leukaphereses for 5 days starting 48 h after IL-2 to harvest cells. Mononuclear cells were isolated, then cultured in roller bottles in 1-liter aliquots for 3 to 4 days at a cell density of 1.5 x 106 per ml with recombinant IL-2, 1500 units per ml. Cells were harvested and administered to patients with additional IL-2. Administration of IL-2 regularly induced lymphopenia and rebound lymphocytosis. Leukapheresis yields and numbers of LAK cells generated in culture and reinfused into patients correlated directly with peak lymphocyte counts achieved by IL-2 administration. Mean mononuclear cell recovery per 5 days of leukapheresis (± SEM) was 14.3 ± 0.8 x 1010. Average volume of cells cultured per patient was 95 liters (range, 41 to 235). Mean yield of cells harvested from cultures was 53%. Mean total number of LAK cells infused per patient was 7.6 ± 0.4 x 1010 (range, 2 to 15.2 x 1010). LAK activity was measured in vitro by lysis of 51Cr-labeled natural killer-resistant Daudi and fresh tumor targets. LAK effector cells regularly lysed these targets in vitro. Neither tumor reduction nor clinical toxicity correlated with dose or with cytolytic activity of LAK cells, or with other laboratory parameters including base-line lymphocyte count and IL-2-induced lymphocytosis. We conclude: (a) large quantities of LAK effector cells with tumoricidal activity can be generated routinely at different centers; (b) neither in vitro LAK activity nor numbers of LAK cells infused were predictive of clinical efficacy or toxicity. There is a need to identify other laboratory or clinical parameters more predictive of IL-2/LAK therapeutic efficacy or toxicity.

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