Low dose subcutaneous interleukin-2 after autologous transplantation generates sustained in vivo natural killer cell activity

Jeffrey S. Miller, Jennifer Tessmer-Tuck, Bryce A. Pierson, Daniel Weisdorf, Philip McGlave, Bruce R. Blazar, Emmanuel Katsanis, Catherine Verfaillie, Jane Lebkowski, James Radford, Linda J. Burns

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Autologous transplantation can induce extended remission in some patients with advanced breast cancer and lymphoma yet nearly 80% and 50%, respectively, will ultimately relapse. In vitro studies suggest that activated natural killer cells (NK) mediate lyric activity against breast cancer and lymphoma cell lines. Therefore, immunotherapy with interleukin-2 (IL-2, Amgen) to activate NK may improve long-term disease-free survival when administered in a post-transplant minimal residual disease setting. To determine the feasibility of administering IL-2 and activation of NK post-transplant, twelve patients (6 breast cancer, 6 lymphoma) were enrolled on a phase I dose escalation study after autologous transplantation (median day + 94, range 50-166). IL-2 was self administered at 0.25 × 106 (n=6) or 0.5 × 106 (n=6) U/m2/day subcutaneously for 84 consecutive days. The best tolerated dose was 0.25 × 106 U/m2/day (75% of planned doses given vs. 48% at the higher dose). Dose limiting toxicity occurred in 6 patients (n=2 at 0.25 × 106 U/m2/day, n=4 at 0.5 × 106 U/m2/day) consisting of decreased performance status (n=2), thrombocytopenia (n=3, 1 at the lower dose), and mild neutropenia (n=1 at the lower dose). However, all symptoms resolved within a week following discontinuation of IL-2 and no patient required hospitalization. Circulating soluble IL-2 receptor levels were significantly increased in all patients receiving IL-2. Patients receiving at least 28 days of IL-2 exhibited a greater than 10-fold increment in circulating CD56+bright/CD3- NK. Furthermore, lytic function was increased against NK resistant targets, MCF-7 (breast cancer), and Raji (lymphoma). In vivo IL-2 primed NK cells obtained by lymphapheresis were activated in large-scale ex vivo incubation in high dose IL-2 (1,000 U/mL) at high cell density (10 × 106/mL), in gas permeable bags, and using serum-free media. NK lytic function against MCF-7 and Raji targets was further enhanced. We conclude that low dose subcutaneous IL-2 based immunotherapy is feasible, relatively safe, can be administered in an outpatient setting and hypothesize that additional ex vivo incubation in IL-2 may be used to generate NK cells with potent antitumor effects in vivo.

Original languageEnglish (US)
Pages (from-to)34-44
Number of pages11
JournalBiology of Blood and Marrow Transplantation
Volume3
Issue number1
StatePublished - Apr 1997
Externally publishedYes

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Autologous Transplantation
Natural Killer Cells
Interleukin-2
Lymphoma
Breast Neoplasms
Immunotherapy
Leukapheresis
Transplants
Interleukin-2 Receptors
Serum-Free Culture Media
Residual Neoplasm
Neutropenia
Interleukin-1
Disease-Free Survival
Hospitalization
Outpatients
Cell Count
Gases
Recurrence
Cell Line

ASJC Scopus subject areas

  • Transplantation

Cite this

Miller, J. S., Tessmer-Tuck, J., Pierson, B. A., Weisdorf, D., McGlave, P., Blazar, B. R., ... Burns, L. J. (1997). Low dose subcutaneous interleukin-2 after autologous transplantation generates sustained in vivo natural killer cell activity. Biology of Blood and Marrow Transplantation, 3(1), 34-44.

Low dose subcutaneous interleukin-2 after autologous transplantation generates sustained in vivo natural killer cell activity. / Miller, Jeffrey S.; Tessmer-Tuck, Jennifer; Pierson, Bryce A.; Weisdorf, Daniel; McGlave, Philip; Blazar, Bruce R.; Katsanis, Emmanuel; Verfaillie, Catherine; Lebkowski, Jane; Radford, James; Burns, Linda J.

In: Biology of Blood and Marrow Transplantation, Vol. 3, No. 1, 04.1997, p. 34-44.

Research output: Contribution to journalArticle

Miller, JS, Tessmer-Tuck, J, Pierson, BA, Weisdorf, D, McGlave, P, Blazar, BR, Katsanis, E, Verfaillie, C, Lebkowski, J, Radford, J & Burns, LJ 1997, 'Low dose subcutaneous interleukin-2 after autologous transplantation generates sustained in vivo natural killer cell activity', Biology of Blood and Marrow Transplantation, vol. 3, no. 1, pp. 34-44.
Miller, Jeffrey S. ; Tessmer-Tuck, Jennifer ; Pierson, Bryce A. ; Weisdorf, Daniel ; McGlave, Philip ; Blazar, Bruce R. ; Katsanis, Emmanuel ; Verfaillie, Catherine ; Lebkowski, Jane ; Radford, James ; Burns, Linda J. / Low dose subcutaneous interleukin-2 after autologous transplantation generates sustained in vivo natural killer cell activity. In: Biology of Blood and Marrow Transplantation. 1997 ; Vol. 3, No. 1. pp. 34-44.
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AU - McGlave, Philip

AU - Blazar, Bruce R.

AU - Katsanis, Emmanuel

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AU - Lebkowski, Jane

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AU - Burns, Linda J.

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N2 - Autologous transplantation can induce extended remission in some patients with advanced breast cancer and lymphoma yet nearly 80% and 50%, respectively, will ultimately relapse. In vitro studies suggest that activated natural killer cells (NK) mediate lyric activity against breast cancer and lymphoma cell lines. Therefore, immunotherapy with interleukin-2 (IL-2, Amgen) to activate NK may improve long-term disease-free survival when administered in a post-transplant minimal residual disease setting. To determine the feasibility of administering IL-2 and activation of NK post-transplant, twelve patients (6 breast cancer, 6 lymphoma) were enrolled on a phase I dose escalation study after autologous transplantation (median day + 94, range 50-166). IL-2 was self administered at 0.25 × 106 (n=6) or 0.5 × 106 (n=6) U/m2/day subcutaneously for 84 consecutive days. The best tolerated dose was 0.25 × 106 U/m2/day (75% of planned doses given vs. 48% at the higher dose). Dose limiting toxicity occurred in 6 patients (n=2 at 0.25 × 106 U/m2/day, n=4 at 0.5 × 106 U/m2/day) consisting of decreased performance status (n=2), thrombocytopenia (n=3, 1 at the lower dose), and mild neutropenia (n=1 at the lower dose). However, all symptoms resolved within a week following discontinuation of IL-2 and no patient required hospitalization. Circulating soluble IL-2 receptor levels were significantly increased in all patients receiving IL-2. Patients receiving at least 28 days of IL-2 exhibited a greater than 10-fold increment in circulating CD56+bright/CD3- NK. Furthermore, lytic function was increased against NK resistant targets, MCF-7 (breast cancer), and Raji (lymphoma). In vivo IL-2 primed NK cells obtained by lymphapheresis were activated in large-scale ex vivo incubation in high dose IL-2 (1,000 U/mL) at high cell density (10 × 106/mL), in gas permeable bags, and using serum-free media. NK lytic function against MCF-7 and Raji targets was further enhanced. We conclude that low dose subcutaneous IL-2 based immunotherapy is feasible, relatively safe, can be administered in an outpatient setting and hypothesize that additional ex vivo incubation in IL-2 may be used to generate NK cells with potent antitumor effects in vivo.

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