Use of T-cell growth factors (interleukins 2, 4, 7, 10, and 12) in the evaluation of T-cell reactivity to melanoma

Michael T. Lotze, Herbert J. Zeh, Elaine M. Elder, Quan Cai, Barbara A. Pippin, Maury M. Rosenstein, Theresa L. Whiteside, Ronald Herberman

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Melanoma represents the single best example of a human tumor that has been shown to elicit specific T-cell reactivity. The responsiveness of some patients with metastatic melanoma to treatment with the prototypic T-cell growth factor (TCGF), interleukin-2 (IL-2), indicates that T cells play a role in antitumor immunity. Interleukin-4 (IL-4), another TCGF that has been administered clinically to humans, was not associated with tumor response in our trials conducted at the Surgery Branch of the National Cancer Institute. Combination trials of IL-2 with IL-4 have shown no increase in responsiveness of melanoma or other tumors when compared to IL-2 alone. However, enhanced expansion of tumor-infiltrating lymphocytes (TILs) in vitro has been observed with combinations of low-dose IL-2 and IL-4. We have begun a study evaluating the trafficking of such expanded lymphocytes following their adoptive transfer in association with systemic administration of IL-2 and IL-4. We have established several TIL cultures from fresh tumor samples, maintained them in long-term culture, and marked them with the neomycin phosphotransferase gene using the LNL6 retroviral vector. Such TILs appear to demonstrate no notable alterations in phenotype or cytolytic activity when compared to their nontransduced counterparts. In addition to IL-2 and IL-4, there are a variety of other novel TCGFs that are now available for evaluation in preclinical and clinical trials. IL-7 induces proliferation and lymphokine-activated killer (LAK) cell activity from human peripheral blood mononuclear cells. IL-7 also increases the proliferation of murine B and T cells located in the spleen and lymph nodes. Our studies of IL-7 reveal that expansion of TILs in combination with IL-2 is associated with the selective outgrowth of predominately CD4+ lymphocytes. IL-10 was originally defined as a factor inhibiting IL-2 and γ-interferon production by T-helper cells and thus termed cytokine synthesis inhibitory factor. Interestingly, murine IL-10 has been shown under certain circumstances to synergize with IL-2, IL-4, and IL-7 in the growth of thymic and peripheral T cells. A truncated version of IL-10 found within the Epstein- Barr virus genome (BCRF-2 or vIL-10) shares the cytokine synthesis inhibitory properties of IL-10 but does not appear to have TCGF activity. Interleukin-12 is a heterodimeric cytokine that enhances proliferation and cytolytic capacity of T cells and large granular lymphocytes. IL-12 synergizes with IL-2 in the induction of LAK cells, and induces the secretion of 7-interferon and tumor necrosis factor-α (TNF-α) from human peripheral blood mononuclear cells. IL-12 appears to be produced mainly by macrophages and B cells. Our initial studies demonstrate that IL-12 supports the growth of TILs previously cultured in IL-2. We have introduced both chains of the murine IL-12 gene into retroviral vectors and are beginning cytokine gene transfection studies. These studies will be combined with our ongoing evaluation of IL-2 and IL-4 transfection as a means to develop novel tumor vaccines.

Original languageEnglish (US)
Pages (from-to)212-217
Number of pages6
JournalJournal of Immunotherapy
Volume12
Issue number3
DOIs
StatePublished - Oct 1992
Externally publishedYes

Fingerprint

Interleukin-4
Interleukin-2
Melanoma
T-Lymphocytes
Tumor-Infiltrating Lymphocytes
Interleukin-12
Interleukin-7
Interleukin-10
Lymphokine-Activated Killer Cells
Lymphocytes
Cytokines
Interferons
Transfection
Blood Cells
Neoplasms
B-Lymphocytes
Kanamycin Kinase
Genes
Cancer Vaccines
National Cancer Institute (U.S.)

Keywords

  • Gene therapy
  • Interleukin-10
  • Interleukin-12
  • Interleukin-2
  • Interleukin-4
  • Interleukin-7
  • Tumor immunology

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

Cite this

Use of T-cell growth factors (interleukins 2, 4, 7, 10, and 12) in the evaluation of T-cell reactivity to melanoma. / Lotze, Michael T.; Zeh, Herbert J.; Elder, Elaine M.; Cai, Quan; Pippin, Barbara A.; Rosenstein, Maury M.; Whiteside, Theresa L.; Herberman, Ronald.

In: Journal of Immunotherapy, Vol. 12, No. 3, 10.1992, p. 212-217.

Research output: Contribution to journalArticle

Lotze, Michael T. ; Zeh, Herbert J. ; Elder, Elaine M. ; Cai, Quan ; Pippin, Barbara A. ; Rosenstein, Maury M. ; Whiteside, Theresa L. ; Herberman, Ronald. / Use of T-cell growth factors (interleukins 2, 4, 7, 10, and 12) in the evaluation of T-cell reactivity to melanoma. In: Journal of Immunotherapy. 1992 ; Vol. 12, No. 3. pp. 212-217.
@article{3d9b896bf73a4efbaaa9b13223fb7f62,
title = "Use of T-cell growth factors (interleukins 2, 4, 7, 10, and 12) in the evaluation of T-cell reactivity to melanoma",
abstract = "Melanoma represents the single best example of a human tumor that has been shown to elicit specific T-cell reactivity. The responsiveness of some patients with metastatic melanoma to treatment with the prototypic T-cell growth factor (TCGF), interleukin-2 (IL-2), indicates that T cells play a role in antitumor immunity. Interleukin-4 (IL-4), another TCGF that has been administered clinically to humans, was not associated with tumor response in our trials conducted at the Surgery Branch of the National Cancer Institute. Combination trials of IL-2 with IL-4 have shown no increase in responsiveness of melanoma or other tumors when compared to IL-2 alone. However, enhanced expansion of tumor-infiltrating lymphocytes (TILs) in vitro has been observed with combinations of low-dose IL-2 and IL-4. We have begun a study evaluating the trafficking of such expanded lymphocytes following their adoptive transfer in association with systemic administration of IL-2 and IL-4. We have established several TIL cultures from fresh tumor samples, maintained them in long-term culture, and marked them with the neomycin phosphotransferase gene using the LNL6 retroviral vector. Such TILs appear to demonstrate no notable alterations in phenotype or cytolytic activity when compared to their nontransduced counterparts. In addition to IL-2 and IL-4, there are a variety of other novel TCGFs that are now available for evaluation in preclinical and clinical trials. IL-7 induces proliferation and lymphokine-activated killer (LAK) cell activity from human peripheral blood mononuclear cells. IL-7 also increases the proliferation of murine B and T cells located in the spleen and lymph nodes. Our studies of IL-7 reveal that expansion of TILs in combination with IL-2 is associated with the selective outgrowth of predominately CD4+ lymphocytes. IL-10 was originally defined as a factor inhibiting IL-2 and γ-interferon production by T-helper cells and thus termed cytokine synthesis inhibitory factor. Interestingly, murine IL-10 has been shown under certain circumstances to synergize with IL-2, IL-4, and IL-7 in the growth of thymic and peripheral T cells. A truncated version of IL-10 found within the Epstein- Barr virus genome (BCRF-2 or vIL-10) shares the cytokine synthesis inhibitory properties of IL-10 but does not appear to have TCGF activity. Interleukin-12 is a heterodimeric cytokine that enhances proliferation and cytolytic capacity of T cells and large granular lymphocytes. IL-12 synergizes with IL-2 in the induction of LAK cells, and induces the secretion of 7-interferon and tumor necrosis factor-α (TNF-α) from human peripheral blood mononuclear cells. IL-12 appears to be produced mainly by macrophages and B cells. Our initial studies demonstrate that IL-12 supports the growth of TILs previously cultured in IL-2. We have introduced both chains of the murine IL-12 gene into retroviral vectors and are beginning cytokine gene transfection studies. These studies will be combined with our ongoing evaluation of IL-2 and IL-4 transfection as a means to develop novel tumor vaccines.",
keywords = "Gene therapy, Interleukin-10, Interleukin-12, Interleukin-2, Interleukin-4, Interleukin-7, Tumor immunology",
author = "Lotze, {Michael T.} and Zeh, {Herbert J.} and Elder, {Elaine M.} and Quan Cai and Pippin, {Barbara A.} and Rosenstein, {Maury M.} and Whiteside, {Theresa L.} and Ronald Herberman",
year = "1992",
month = "10",
doi = "10.1097/00002371-199210000-00015",
language = "English (US)",
volume = "12",
pages = "212--217",
journal = "Journal of Immunotherapy",
issn = "1524-9557",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

TY - JOUR

T1 - Use of T-cell growth factors (interleukins 2, 4, 7, 10, and 12) in the evaluation of T-cell reactivity to melanoma

AU - Lotze, Michael T.

AU - Zeh, Herbert J.

AU - Elder, Elaine M.

AU - Cai, Quan

AU - Pippin, Barbara A.

AU - Rosenstein, Maury M.

AU - Whiteside, Theresa L.

AU - Herberman, Ronald

PY - 1992/10

Y1 - 1992/10

N2 - Melanoma represents the single best example of a human tumor that has been shown to elicit specific T-cell reactivity. The responsiveness of some patients with metastatic melanoma to treatment with the prototypic T-cell growth factor (TCGF), interleukin-2 (IL-2), indicates that T cells play a role in antitumor immunity. Interleukin-4 (IL-4), another TCGF that has been administered clinically to humans, was not associated with tumor response in our trials conducted at the Surgery Branch of the National Cancer Institute. Combination trials of IL-2 with IL-4 have shown no increase in responsiveness of melanoma or other tumors when compared to IL-2 alone. However, enhanced expansion of tumor-infiltrating lymphocytes (TILs) in vitro has been observed with combinations of low-dose IL-2 and IL-4. We have begun a study evaluating the trafficking of such expanded lymphocytes following their adoptive transfer in association with systemic administration of IL-2 and IL-4. We have established several TIL cultures from fresh tumor samples, maintained them in long-term culture, and marked them with the neomycin phosphotransferase gene using the LNL6 retroviral vector. Such TILs appear to demonstrate no notable alterations in phenotype or cytolytic activity when compared to their nontransduced counterparts. In addition to IL-2 and IL-4, there are a variety of other novel TCGFs that are now available for evaluation in preclinical and clinical trials. IL-7 induces proliferation and lymphokine-activated killer (LAK) cell activity from human peripheral blood mononuclear cells. IL-7 also increases the proliferation of murine B and T cells located in the spleen and lymph nodes. Our studies of IL-7 reveal that expansion of TILs in combination with IL-2 is associated with the selective outgrowth of predominately CD4+ lymphocytes. IL-10 was originally defined as a factor inhibiting IL-2 and γ-interferon production by T-helper cells and thus termed cytokine synthesis inhibitory factor. Interestingly, murine IL-10 has been shown under certain circumstances to synergize with IL-2, IL-4, and IL-7 in the growth of thymic and peripheral T cells. A truncated version of IL-10 found within the Epstein- Barr virus genome (BCRF-2 or vIL-10) shares the cytokine synthesis inhibitory properties of IL-10 but does not appear to have TCGF activity. Interleukin-12 is a heterodimeric cytokine that enhances proliferation and cytolytic capacity of T cells and large granular lymphocytes. IL-12 synergizes with IL-2 in the induction of LAK cells, and induces the secretion of 7-interferon and tumor necrosis factor-α (TNF-α) from human peripheral blood mononuclear cells. IL-12 appears to be produced mainly by macrophages and B cells. Our initial studies demonstrate that IL-12 supports the growth of TILs previously cultured in IL-2. We have introduced both chains of the murine IL-12 gene into retroviral vectors and are beginning cytokine gene transfection studies. These studies will be combined with our ongoing evaluation of IL-2 and IL-4 transfection as a means to develop novel tumor vaccines.

AB - Melanoma represents the single best example of a human tumor that has been shown to elicit specific T-cell reactivity. The responsiveness of some patients with metastatic melanoma to treatment with the prototypic T-cell growth factor (TCGF), interleukin-2 (IL-2), indicates that T cells play a role in antitumor immunity. Interleukin-4 (IL-4), another TCGF that has been administered clinically to humans, was not associated with tumor response in our trials conducted at the Surgery Branch of the National Cancer Institute. Combination trials of IL-2 with IL-4 have shown no increase in responsiveness of melanoma or other tumors when compared to IL-2 alone. However, enhanced expansion of tumor-infiltrating lymphocytes (TILs) in vitro has been observed with combinations of low-dose IL-2 and IL-4. We have begun a study evaluating the trafficking of such expanded lymphocytes following their adoptive transfer in association with systemic administration of IL-2 and IL-4. We have established several TIL cultures from fresh tumor samples, maintained them in long-term culture, and marked them with the neomycin phosphotransferase gene using the LNL6 retroviral vector. Such TILs appear to demonstrate no notable alterations in phenotype or cytolytic activity when compared to their nontransduced counterparts. In addition to IL-2 and IL-4, there are a variety of other novel TCGFs that are now available for evaluation in preclinical and clinical trials. IL-7 induces proliferation and lymphokine-activated killer (LAK) cell activity from human peripheral blood mononuclear cells. IL-7 also increases the proliferation of murine B and T cells located in the spleen and lymph nodes. Our studies of IL-7 reveal that expansion of TILs in combination with IL-2 is associated with the selective outgrowth of predominately CD4+ lymphocytes. IL-10 was originally defined as a factor inhibiting IL-2 and γ-interferon production by T-helper cells and thus termed cytokine synthesis inhibitory factor. Interestingly, murine IL-10 has been shown under certain circumstances to synergize with IL-2, IL-4, and IL-7 in the growth of thymic and peripheral T cells. A truncated version of IL-10 found within the Epstein- Barr virus genome (BCRF-2 or vIL-10) shares the cytokine synthesis inhibitory properties of IL-10 but does not appear to have TCGF activity. Interleukin-12 is a heterodimeric cytokine that enhances proliferation and cytolytic capacity of T cells and large granular lymphocytes. IL-12 synergizes with IL-2 in the induction of LAK cells, and induces the secretion of 7-interferon and tumor necrosis factor-α (TNF-α) from human peripheral blood mononuclear cells. IL-12 appears to be produced mainly by macrophages and B cells. Our initial studies demonstrate that IL-12 supports the growth of TILs previously cultured in IL-2. We have introduced both chains of the murine IL-12 gene into retroviral vectors and are beginning cytokine gene transfection studies. These studies will be combined with our ongoing evaluation of IL-2 and IL-4 transfection as a means to develop novel tumor vaccines.

KW - Gene therapy

KW - Interleukin-10

KW - Interleukin-12

KW - Interleukin-2

KW - Interleukin-4

KW - Interleukin-7

KW - Tumor immunology

UR - http://www.scopus.com/inward/record.url?scp=0026744872&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026744872&partnerID=8YFLogxK

U2 - 10.1097/00002371-199210000-00015

DO - 10.1097/00002371-199210000-00015

M3 - Article

C2 - 1359903

AN - SCOPUS:0026744872

VL - 12

SP - 212

EP - 217

JO - Journal of Immunotherapy

JF - Journal of Immunotherapy

SN - 1524-9557

IS - 3

ER -