Pilot study of interleukin-2 and lymphokine-activated killer cells combined with immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a in patients with metastatic melanoma and renal cell carcinoma

Mario Sznol, Jeffrey W. Clark, John W. Smith, Ronald G. Steis, Walter J. Urba, Lawrence V. Rubinstein, Louis A. Vandermolen, John Edward Janik, William H. Sharfman, Robert G. Fenton, Stephen P. Creekmore, Peter Kremers, Kevin Conlon, Jean Hersey, Joy Beveridge, Dan L. Longo

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Abstract

Background: Experiments in animal tumor models suggest that the antitumor effects of interleukin-2 (IL-2) or IL-2 in combination with lymphokine-activated killer (LAK) cells can be enhanced by chemotherapy agents such as cyclo-phosphamide or doxorubicin or by the biologic agent interferon α. Purpose: We determined the toxicity and clinical response rate of an IL-2-LAK cell regimen modified by the addition of moderate, immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a (IFN α-2a) in patients with metastatic melanoma and renal cell carcinoma. Methods: IL-2(3-6 million units/m2 per day) was administered by continuous infusion on days 0-5 and days 11-16. LAK cells were infused on days 11 and 12 or on days 11, 12, and 14. Low doses of cyclophosphamide (300 mg/ m2) and doxorubicin (25 mg/m2) were given on day 9 before the LAK cell infusions. Following the IL-2-LAK cell infusion, IFN α-2a (12 million units/m2) was administered for a total of nine doses to complete a cycle of treatment. A total of 89 patients were enrolled in the study. Results: For each histology, there were eight partial responses in 40 assessable patients, for an overall response rate of 20% (90% confidence interval = 10%-33%). The median response duration was 5 months, although two patients with renal cell carcinoma and one patient with metastatic melanoma had almost complete disappearance of tumor and are still responding after 26+, 22+, and 26+ months, respectively. Toxic effects were severe in patients receiving the highest dose of IL-2 administered in this study and similar to those reported with other high-dose IL-2-LAK cell regimens. Although toxic effects were completely reversible in most patients, there were four treatment-related deaths. Conclusions: This regimen is active in patients with metastatic melanoma and renal cell carcinoma and produces meaningful responses in a small percentage of these patients; however, it is not clear whether cyclophosphamide, doxorubicin, and IFN a-2α as used in this protocol appreciably augmented the antitumor activity of the IL-2-LAK cell regimen.

Original languageEnglish (US)
Pages (from-to)929-937
Number of pages9
JournalJournal of the National Cancer Institute
Volume84
Issue number12
DOIs
StatePublished - Jun 17 1992

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Lymphokine-Activated Killer Cells
Renal Cell Carcinoma
Interleukin-2
Melanoma
Drug Therapy
Doxorubicin
Poisons
Cyclophosphamide
Dimethoate
interferon alfa-2a
Interleukin-3
Biological Factors
Interferons
Neoplasms
Histology
Animal Models
Confidence Intervals

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Pilot study of interleukin-2 and lymphokine-activated killer cells combined with immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a in patients with metastatic melanoma and renal cell carcinoma. / Sznol, Mario; Clark, Jeffrey W.; Smith, John W.; Steis, Ronald G.; Urba, Walter J.; Rubinstein, Lawrence V.; Vandermolen, Louis A.; Janik, John Edward; Sharfman, William H.; Fenton, Robert G.; Creekmore, Stephen P.; Kremers, Peter; Conlon, Kevin; Hersey, Jean; Beveridge, Joy; Longo, Dan L.

In: Journal of the National Cancer Institute, Vol. 84, No. 12, 17.06.1992, p. 929-937.

Research output: Contribution to journalArticle

Sznol, M, Clark, JW, Smith, JW, Steis, RG, Urba, WJ, Rubinstein, LV, Vandermolen, LA, Janik, JE, Sharfman, WH, Fenton, RG, Creekmore, SP, Kremers, P, Conlon, K, Hersey, J, Beveridge, J & Longo, DL 1992, 'Pilot study of interleukin-2 and lymphokine-activated killer cells combined with immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a in patients with metastatic melanoma and renal cell carcinoma', Journal of the National Cancer Institute, vol. 84, no. 12, pp. 929-937. https://doi.org/10.1093/jnci/84.12.929
Sznol, Mario ; Clark, Jeffrey W. ; Smith, John W. ; Steis, Ronald G. ; Urba, Walter J. ; Rubinstein, Lawrence V. ; Vandermolen, Louis A. ; Janik, John Edward ; Sharfman, William H. ; Fenton, Robert G. ; Creekmore, Stephen P. ; Kremers, Peter ; Conlon, Kevin ; Hersey, Jean ; Beveridge, Joy ; Longo, Dan L. / Pilot study of interleukin-2 and lymphokine-activated killer cells combined with immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a in patients with metastatic melanoma and renal cell carcinoma. In: Journal of the National Cancer Institute. 1992 ; Vol. 84, No. 12. pp. 929-937.
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abstract = "Background: Experiments in animal tumor models suggest that the antitumor effects of interleukin-2 (IL-2) or IL-2 in combination with lymphokine-activated killer (LAK) cells can be enhanced by chemotherapy agents such as cyclo-phosphamide or doxorubicin or by the biologic agent interferon α. Purpose: We determined the toxicity and clinical response rate of an IL-2-LAK cell regimen modified by the addition of moderate, immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a (IFN α-2a) in patients with metastatic melanoma and renal cell carcinoma. Methods: IL-2(3-6 million units/m2 per day) was administered by continuous infusion on days 0-5 and days 11-16. LAK cells were infused on days 11 and 12 or on days 11, 12, and 14. Low doses of cyclophosphamide (300 mg/ m2) and doxorubicin (25 mg/m2) were given on day 9 before the LAK cell infusions. Following the IL-2-LAK cell infusion, IFN α-2a (12 million units/m2) was administered for a total of nine doses to complete a cycle of treatment. A total of 89 patients were enrolled in the study. Results: For each histology, there were eight partial responses in 40 assessable patients, for an overall response rate of 20{\%} (90{\%} confidence interval = 10{\%}-33{\%}). The median response duration was 5 months, although two patients with renal cell carcinoma and one patient with metastatic melanoma had almost complete disappearance of tumor and are still responding after 26+, 22+, and 26+ months, respectively. Toxic effects were severe in patients receiving the highest dose of IL-2 administered in this study and similar to those reported with other high-dose IL-2-LAK cell regimens. Although toxic effects were completely reversible in most patients, there were four treatment-related deaths. Conclusions: This regimen is active in patients with metastatic melanoma and renal cell carcinoma and produces meaningful responses in a small percentage of these patients; however, it is not clear whether cyclophosphamide, doxorubicin, and IFN a-2α as used in this protocol appreciably augmented the antitumor activity of the IL-2-LAK cell regimen.",
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TY - JOUR

T1 - Pilot study of interleukin-2 and lymphokine-activated killer cells combined with immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a in patients with metastatic melanoma and renal cell carcinoma

AU - Sznol, Mario

AU - Clark, Jeffrey W.

AU - Smith, John W.

AU - Steis, Ronald G.

AU - Urba, Walter J.

AU - Rubinstein, Lawrence V.

AU - Vandermolen, Louis A.

AU - Janik, John Edward

AU - Sharfman, William H.

AU - Fenton, Robert G.

AU - Creekmore, Stephen P.

AU - Kremers, Peter

AU - Conlon, Kevin

AU - Hersey, Jean

AU - Beveridge, Joy

AU - Longo, Dan L.

PY - 1992/6/17

Y1 - 1992/6/17

N2 - Background: Experiments in animal tumor models suggest that the antitumor effects of interleukin-2 (IL-2) or IL-2 in combination with lymphokine-activated killer (LAK) cells can be enhanced by chemotherapy agents such as cyclo-phosphamide or doxorubicin or by the biologic agent interferon α. Purpose: We determined the toxicity and clinical response rate of an IL-2-LAK cell regimen modified by the addition of moderate, immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a (IFN α-2a) in patients with metastatic melanoma and renal cell carcinoma. Methods: IL-2(3-6 million units/m2 per day) was administered by continuous infusion on days 0-5 and days 11-16. LAK cells were infused on days 11 and 12 or on days 11, 12, and 14. Low doses of cyclophosphamide (300 mg/ m2) and doxorubicin (25 mg/m2) were given on day 9 before the LAK cell infusions. Following the IL-2-LAK cell infusion, IFN α-2a (12 million units/m2) was administered for a total of nine doses to complete a cycle of treatment. A total of 89 patients were enrolled in the study. Results: For each histology, there were eight partial responses in 40 assessable patients, for an overall response rate of 20% (90% confidence interval = 10%-33%). The median response duration was 5 months, although two patients with renal cell carcinoma and one patient with metastatic melanoma had almost complete disappearance of tumor and are still responding after 26+, 22+, and 26+ months, respectively. Toxic effects were severe in patients receiving the highest dose of IL-2 administered in this study and similar to those reported with other high-dose IL-2-LAK cell regimens. Although toxic effects were completely reversible in most patients, there were four treatment-related deaths. Conclusions: This regimen is active in patients with metastatic melanoma and renal cell carcinoma and produces meaningful responses in a small percentage of these patients; however, it is not clear whether cyclophosphamide, doxorubicin, and IFN a-2α as used in this protocol appreciably augmented the antitumor activity of the IL-2-LAK cell regimen.

AB - Background: Experiments in animal tumor models suggest that the antitumor effects of interleukin-2 (IL-2) or IL-2 in combination with lymphokine-activated killer (LAK) cells can be enhanced by chemotherapy agents such as cyclo-phosphamide or doxorubicin or by the biologic agent interferon α. Purpose: We determined the toxicity and clinical response rate of an IL-2-LAK cell regimen modified by the addition of moderate, immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a (IFN α-2a) in patients with metastatic melanoma and renal cell carcinoma. Methods: IL-2(3-6 million units/m2 per day) was administered by continuous infusion on days 0-5 and days 11-16. LAK cells were infused on days 11 and 12 or on days 11, 12, and 14. Low doses of cyclophosphamide (300 mg/ m2) and doxorubicin (25 mg/m2) were given on day 9 before the LAK cell infusions. Following the IL-2-LAK cell infusion, IFN α-2a (12 million units/m2) was administered for a total of nine doses to complete a cycle of treatment. A total of 89 patients were enrolled in the study. Results: For each histology, there were eight partial responses in 40 assessable patients, for an overall response rate of 20% (90% confidence interval = 10%-33%). The median response duration was 5 months, although two patients with renal cell carcinoma and one patient with metastatic melanoma had almost complete disappearance of tumor and are still responding after 26+, 22+, and 26+ months, respectively. Toxic effects were severe in patients receiving the highest dose of IL-2 administered in this study and similar to those reported with other high-dose IL-2-LAK cell regimens. Although toxic effects were completely reversible in most patients, there were four treatment-related deaths. Conclusions: This regimen is active in patients with metastatic melanoma and renal cell carcinoma and produces meaningful responses in a small percentage of these patients; however, it is not clear whether cyclophosphamide, doxorubicin, and IFN a-2α as used in this protocol appreciably augmented the antitumor activity of the IL-2-LAK cell regimen.

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