A direct comparison of immunological and clinical effects of interleukin 2 with and without interferon-α in humans

Joan H. Schiller, Jacquelyn Hank, Barry Storer, Agnes A. Borchert, Karen Huseby Moore, Mark Albertini, Robin Bechhofer, Osvaldo Wesley, Raymond R. Brown, Ann Mrowca Bastin, Paul M. Sondel

Research output: Contribution to journalArticle

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Abstract

Interleukin 2 (IL-2) and interferon-α (IFN-α) are cytokines with synergistic antitumor effects in mouse models. The biological effects of this combination, however, have not been directly compared to each agent alone in humans. We conducted a Phase IB trial of IL-2 plus or minus IFN-α in 38 cancer patients. The objectives of this trial were to determine which doses of IFN-α and IL-2 maximally enhanced biological responses, and to determine whether the combined administration of IFN-α and IL-2 would result in a potentiation of biological responses over IL-2 alone. Patients received 4 days of IL-2 (1.5 × 106 units/m2/day or 3.0 × 106 units/m2/day) as a continuous infusion followed by a 3-day rest period, weekly for 3 weeks, with a 3-week rest period between 2 treatment courses. IFN-α (0.5 × 106 or 5 × 106 units/m2/day) was administered s.c. on days 1-4 weekly for 3 weeks with one of the 3-week courses. Patients were randomized to receive either IL-2 alone for course 1, followed by IL-2/ IFN-α for course 2, or IL-2/IFN-α in course 1, followed by IL-2 alone. Immunological parameters were evaluated before treatment, and 24 h after completion of the third week of IL-2. A statistically significant increase in the percentage of circulating natural killer cells (CD56), natural killer cells bearing the Fc receptor (CD16), and activated T cells (CD25) was observed following IL-2 alone, and following IL-2 plus IFN-α. Significant increases in lymphocyte-activated killer cell cytotoxicity, antibody cellular cytotoxicity, and serum IL-2 receptor were also observed following both IL-2 and IL-2 plus IFN-α. However, no significant differences were observed in the magnitude of the increase in the IL-2-alone group when compared to the IL-2 plus IFN-α group. The mean fluorescent intensity of monocytes positive for HLA-DR and Fc receptor expression also increased significantly in both groups, as did serum β2-microglobulin expression and indoleamine 2,3-dioxygenase activity. However, increases were not significantly different between patients receiving IL-2 alone and IL-2 plus IFN-α. No dose response effect for IFN-α was observed for any of the parameters assessed. Toxicities consisted primarily of constitutional toxicities, including fever, rigors, malaise, headache, anorexia, and a decrease in performance status. No clinically significant differences in toxicities were observed between courses consisting of IL-2 and those consisting of IFN-α and IL-2. Two patients had a partial response, and 5 patients had a minor response (partial plus minor response rate, 18%). In conclusion, we did not observe a difference in biological activity between IL-2 and IL-2 plus IFN-α in any of the immunological parameters we studied. Although this regimen was relatively well-tolerated, we cannot conclude that IFN-α adds significantly to the immunological or therapeutic activity of IL-2 alone.

Original languageEnglish (US)
Pages (from-to)1286-1292
Number of pages7
JournalCancer Research
Volume53
Issue number6
StatePublished - Mar 15 1993

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Interferons
Interleukin-2
Fc Receptors
Natural Killer Cells
Cytokine-Induced Killer Cells
Indoleamine-Pyrrole 2,3,-Dioxygenase
Interleukin-2 Receptors

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Schiller, J. H., Hank, J., Storer, B., Borchert, A. A., Moore, K. H., Albertini, M., ... Sondel, P. M. (1993). A direct comparison of immunological and clinical effects of interleukin 2 with and without interferon-α in humans. Cancer Research, 53(6), 1286-1292.

A direct comparison of immunological and clinical effects of interleukin 2 with and without interferon-α in humans. / Schiller, Joan H.; Hank, Jacquelyn; Storer, Barry; Borchert, Agnes A.; Moore, Karen Huseby; Albertini, Mark; Bechhofer, Robin; Wesley, Osvaldo; Brown, Raymond R.; Bastin, Ann Mrowca; Sondel, Paul M.

In: Cancer Research, Vol. 53, No. 6, 15.03.1993, p. 1286-1292.

Research output: Contribution to journalArticle

Schiller, JH, Hank, J, Storer, B, Borchert, AA, Moore, KH, Albertini, M, Bechhofer, R, Wesley, O, Brown, RR, Bastin, AM & Sondel, PM 1993, 'A direct comparison of immunological and clinical effects of interleukin 2 with and without interferon-α in humans', Cancer Research, vol. 53, no. 6, pp. 1286-1292.
Schiller JH, Hank J, Storer B, Borchert AA, Moore KH, Albertini M et al. A direct comparison of immunological and clinical effects of interleukin 2 with and without interferon-α in humans. Cancer Research. 1993 Mar 15;53(6):1286-1292.
Schiller, Joan H. ; Hank, Jacquelyn ; Storer, Barry ; Borchert, Agnes A. ; Moore, Karen Huseby ; Albertini, Mark ; Bechhofer, Robin ; Wesley, Osvaldo ; Brown, Raymond R. ; Bastin, Ann Mrowca ; Sondel, Paul M. / A direct comparison of immunological and clinical effects of interleukin 2 with and without interferon-α in humans. In: Cancer Research. 1993 ; Vol. 53, No. 6. pp. 1286-1292.
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AU - Schiller, Joan H.

AU - Hank, Jacquelyn

AU - Storer, Barry

AU - Borchert, Agnes A.

AU - Moore, Karen Huseby

AU - Albertini, Mark

AU - Bechhofer, Robin

AU - Wesley, Osvaldo

AU - Brown, Raymond R.

AU - Bastin, Ann Mrowca

AU - Sondel, Paul M.

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N2 - Interleukin 2 (IL-2) and interferon-α (IFN-α) are cytokines with synergistic antitumor effects in mouse models. The biological effects of this combination, however, have not been directly compared to each agent alone in humans. We conducted a Phase IB trial of IL-2 plus or minus IFN-α in 38 cancer patients. The objectives of this trial were to determine which doses of IFN-α and IL-2 maximally enhanced biological responses, and to determine whether the combined administration of IFN-α and IL-2 would result in a potentiation of biological responses over IL-2 alone. Patients received 4 days of IL-2 (1.5 × 106 units/m2/day or 3.0 × 106 units/m2/day) as a continuous infusion followed by a 3-day rest period, weekly for 3 weeks, with a 3-week rest period between 2 treatment courses. IFN-α (0.5 × 106 or 5 × 106 units/m2/day) was administered s.c. on days 1-4 weekly for 3 weeks with one of the 3-week courses. Patients were randomized to receive either IL-2 alone for course 1, followed by IL-2/ IFN-α for course 2, or IL-2/IFN-α in course 1, followed by IL-2 alone. Immunological parameters were evaluated before treatment, and 24 h after completion of the third week of IL-2. A statistically significant increase in the percentage of circulating natural killer cells (CD56), natural killer cells bearing the Fc receptor (CD16), and activated T cells (CD25) was observed following IL-2 alone, and following IL-2 plus IFN-α. Significant increases in lymphocyte-activated killer cell cytotoxicity, antibody cellular cytotoxicity, and serum IL-2 receptor were also observed following both IL-2 and IL-2 plus IFN-α. However, no significant differences were observed in the magnitude of the increase in the IL-2-alone group when compared to the IL-2 plus IFN-α group. The mean fluorescent intensity of monocytes positive for HLA-DR and Fc receptor expression also increased significantly in both groups, as did serum β2-microglobulin expression and indoleamine 2,3-dioxygenase activity. However, increases were not significantly different between patients receiving IL-2 alone and IL-2 plus IFN-α. No dose response effect for IFN-α was observed for any of the parameters assessed. Toxicities consisted primarily of constitutional toxicities, including fever, rigors, malaise, headache, anorexia, and a decrease in performance status. No clinically significant differences in toxicities were observed between courses consisting of IL-2 and those consisting of IFN-α and IL-2. Two patients had a partial response, and 5 patients had a minor response (partial plus minor response rate, 18%). In conclusion, we did not observe a difference in biological activity between IL-2 and IL-2 plus IFN-α in any of the immunological parameters we studied. Although this regimen was relatively well-tolerated, we cannot conclude that IFN-α adds significantly to the immunological or therapeutic activity of IL-2 alone.

AB - Interleukin 2 (IL-2) and interferon-α (IFN-α) are cytokines with synergistic antitumor effects in mouse models. The biological effects of this combination, however, have not been directly compared to each agent alone in humans. We conducted a Phase IB trial of IL-2 plus or minus IFN-α in 38 cancer patients. The objectives of this trial were to determine which doses of IFN-α and IL-2 maximally enhanced biological responses, and to determine whether the combined administration of IFN-α and IL-2 would result in a potentiation of biological responses over IL-2 alone. Patients received 4 days of IL-2 (1.5 × 106 units/m2/day or 3.0 × 106 units/m2/day) as a continuous infusion followed by a 3-day rest period, weekly for 3 weeks, with a 3-week rest period between 2 treatment courses. IFN-α (0.5 × 106 or 5 × 106 units/m2/day) was administered s.c. on days 1-4 weekly for 3 weeks with one of the 3-week courses. Patients were randomized to receive either IL-2 alone for course 1, followed by IL-2/ IFN-α for course 2, or IL-2/IFN-α in course 1, followed by IL-2 alone. Immunological parameters were evaluated before treatment, and 24 h after completion of the third week of IL-2. A statistically significant increase in the percentage of circulating natural killer cells (CD56), natural killer cells bearing the Fc receptor (CD16), and activated T cells (CD25) was observed following IL-2 alone, and following IL-2 plus IFN-α. Significant increases in lymphocyte-activated killer cell cytotoxicity, antibody cellular cytotoxicity, and serum IL-2 receptor were also observed following both IL-2 and IL-2 plus IFN-α. However, no significant differences were observed in the magnitude of the increase in the IL-2-alone group when compared to the IL-2 plus IFN-α group. The mean fluorescent intensity of monocytes positive for HLA-DR and Fc receptor expression also increased significantly in both groups, as did serum β2-microglobulin expression and indoleamine 2,3-dioxygenase activity. However, increases were not significantly different between patients receiving IL-2 alone and IL-2 plus IFN-α. No dose response effect for IFN-α was observed for any of the parameters assessed. Toxicities consisted primarily of constitutional toxicities, including fever, rigors, malaise, headache, anorexia, and a decrease in performance status. No clinically significant differences in toxicities were observed between courses consisting of IL-2 and those consisting of IFN-α and IL-2. Two patients had a partial response, and 5 patients had a minor response (partial plus minor response rate, 18%). In conclusion, we did not observe a difference in biological activity between IL-2 and IL-2 plus IFN-α in any of the immunological parameters we studied. Although this regimen was relatively well-tolerated, we cannot conclude that IFN-α adds significantly to the immunological or therapeutic activity of IL-2 alone.

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