Gene therapy of cancer

A pilot study of IL-4-gene-modified fibroblasts admixed with autologous tumor to elicit an immune response

M. T. Lotze, J. T. Rubin, S. Carty, H. Edington, P. Ferson, R. Landreneau, B. Pippin, M. Posner, D. Rosenfelder, C. Watson, T. Carlos, J. Kirkwood, B. Lembersky, Theodore Logan, M. Rosenstein, M. E. Rybak, T. Whiteside, E. Elder, R. C. Moen

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

BACKGROUND AND RATIONALE: Local therapies, such as surgery and radiation, rarely cure patients with disseminated cancer. Lamentably, our ability to alter the natural history of metastatic cancer using available chemotherapeutics is also limited and it is apparent that additional therapeutic strategies are needed. We, and others, have previously demonstrated that interleukin-2 (IL-2)-based immunotherapy induces clinically significant tumor regression in 20 to 30 percent of treated patients who have metastatic melanoma or renal cell carcinoma, respectively. Responses have been noted, albeit less frequently, among treated patients who have other malignancies including colon carcinoma, ovarian carcinoma, breast carcinoma and non-Hodgkin's lymphoma. The cost to the individual patient is significant toxicity. Few patients manifest durable clinical responses and significant benefit such as prolonged survival, cure or even palliation has yet to be clearly demonstrated. An alternative strategy for immunotherapy is suggested by in vitro and preclinical murine data showing that the cytokine microenvironment within tumors may determine the outcome of the immune response. In particular. the immunomodulatory cytokine interleukin-4 has a central role in the immune response to tumors in certain murine models. Implantation of the murine mastocytoma P815 into the anterior chamber of the eye results in progressive growth of this tumor while implantation into the subconjunctival sac of the eye results in tumor rejection. Cytolytic precursor cells residing in both sites secrete IL-2. However, only those isolated from the rejecting site (subconjunctival sac) elaborate IL-4 upon exposure to tumor. Bosco, et al, have injected IL-4 into the region of tumor-draining lymph nodes of mice bearing either a fibrosarcoma or a mammary adenocarcinoma. As little as 0.1 picogram per day induced tumor regression and protective immunity to subsequent tumor challenge. Tepper et al demonstrated that an invariably lethal murine B-cell lymphoma or a mammary adenocarcinoma, both transfected with the IL-4 gene, regressed after a brief period of growth. Golumbek et al have observed a similar effect with a spontaneous renal cell carcinoma (Renca) transfected with the gene for IL-4. They extended these observations by demonstrating both protective immunity against tumor rechallenge in mice vaccinated with these gene-modified tumors and tumor regression in a 6 to 9 day tumor model. In light of the demonstrated lack of therapeutic efficacy when administered systemically to patients with cancer, these studies suggest that the local production of IL-4 is associated with development of antitumor immunity that may translate to regression of established cancer.

Original languageEnglish (US)
Pages (from-to)41-55
Number of pages15
JournalHuman Gene Therapy
Volume5
Issue number1
StatePublished - 1994
Externally publishedYes

Fingerprint

Interleukin-4
Genetic Therapy
Fibroblasts
Genes
Neoplasms
Immunity
Renal Cell Carcinoma
Immunotherapy
Interleukin-2
Adenocarcinoma
Breast
Mastocytoma
Cytokines
Carcinoma
Tumor Microenvironment
Fibrosarcoma
Anterior Chamber
B-Cell Lymphoma
Growth
Non-Hodgkin's Lymphoma

ASJC Scopus subject areas

  • Genetics

Cite this

Lotze, M. T., Rubin, J. T., Carty, S., Edington, H., Ferson, P., Landreneau, R., ... Moen, R. C. (1994). Gene therapy of cancer: A pilot study of IL-4-gene-modified fibroblasts admixed with autologous tumor to elicit an immune response. Human Gene Therapy, 5(1), 41-55.

Gene therapy of cancer : A pilot study of IL-4-gene-modified fibroblasts admixed with autologous tumor to elicit an immune response. / Lotze, M. T.; Rubin, J. T.; Carty, S.; Edington, H.; Ferson, P.; Landreneau, R.; Pippin, B.; Posner, M.; Rosenfelder, D.; Watson, C.; Carlos, T.; Kirkwood, J.; Lembersky, B.; Logan, Theodore; Rosenstein, M.; Rybak, M. E.; Whiteside, T.; Elder, E.; Moen, R. C.

In: Human Gene Therapy, Vol. 5, No. 1, 1994, p. 41-55.

Research output: Contribution to journalArticle

Lotze, MT, Rubin, JT, Carty, S, Edington, H, Ferson, P, Landreneau, R, Pippin, B, Posner, M, Rosenfelder, D, Watson, C, Carlos, T, Kirkwood, J, Lembersky, B, Logan, T, Rosenstein, M, Rybak, ME, Whiteside, T, Elder, E & Moen, RC 1994, 'Gene therapy of cancer: A pilot study of IL-4-gene-modified fibroblasts admixed with autologous tumor to elicit an immune response', Human Gene Therapy, vol. 5, no. 1, pp. 41-55.
Lotze, M. T. ; Rubin, J. T. ; Carty, S. ; Edington, H. ; Ferson, P. ; Landreneau, R. ; Pippin, B. ; Posner, M. ; Rosenfelder, D. ; Watson, C. ; Carlos, T. ; Kirkwood, J. ; Lembersky, B. ; Logan, Theodore ; Rosenstein, M. ; Rybak, M. E. ; Whiteside, T. ; Elder, E. ; Moen, R. C. / Gene therapy of cancer : A pilot study of IL-4-gene-modified fibroblasts admixed with autologous tumor to elicit an immune response. In: Human Gene Therapy. 1994 ; Vol. 5, No. 1. pp. 41-55.
@article{3daab51225674b47b9411e1b24b6fe84,
title = "Gene therapy of cancer: A pilot study of IL-4-gene-modified fibroblasts admixed with autologous tumor to elicit an immune response",
abstract = "BACKGROUND AND RATIONALE: Local therapies, such as surgery and radiation, rarely cure patients with disseminated cancer. Lamentably, our ability to alter the natural history of metastatic cancer using available chemotherapeutics is also limited and it is apparent that additional therapeutic strategies are needed. We, and others, have previously demonstrated that interleukin-2 (IL-2)-based immunotherapy induces clinically significant tumor regression in 20 to 30 percent of treated patients who have metastatic melanoma or renal cell carcinoma, respectively. Responses have been noted, albeit less frequently, among treated patients who have other malignancies including colon carcinoma, ovarian carcinoma, breast carcinoma and non-Hodgkin's lymphoma. The cost to the individual patient is significant toxicity. Few patients manifest durable clinical responses and significant benefit such as prolonged survival, cure or even palliation has yet to be clearly demonstrated. An alternative strategy for immunotherapy is suggested by in vitro and preclinical murine data showing that the cytokine microenvironment within tumors may determine the outcome of the immune response. In particular. the immunomodulatory cytokine interleukin-4 has a central role in the immune response to tumors in certain murine models. Implantation of the murine mastocytoma P815 into the anterior chamber of the eye results in progressive growth of this tumor while implantation into the subconjunctival sac of the eye results in tumor rejection. Cytolytic precursor cells residing in both sites secrete IL-2. However, only those isolated from the rejecting site (subconjunctival sac) elaborate IL-4 upon exposure to tumor. Bosco, et al, have injected IL-4 into the region of tumor-draining lymph nodes of mice bearing either a fibrosarcoma or a mammary adenocarcinoma. As little as 0.1 picogram per day induced tumor regression and protective immunity to subsequent tumor challenge. Tepper et al demonstrated that an invariably lethal murine B-cell lymphoma or a mammary adenocarcinoma, both transfected with the IL-4 gene, regressed after a brief period of growth. Golumbek et al have observed a similar effect with a spontaneous renal cell carcinoma (Renca) transfected with the gene for IL-4. They extended these observations by demonstrating both protective immunity against tumor rechallenge in mice vaccinated with these gene-modified tumors and tumor regression in a 6 to 9 day tumor model. In light of the demonstrated lack of therapeutic efficacy when administered systemically to patients with cancer, these studies suggest that the local production of IL-4 is associated with development of antitumor immunity that may translate to regression of established cancer.",
author = "Lotze, {M. T.} and Rubin, {J. T.} and S. Carty and H. Edington and P. Ferson and R. Landreneau and B. Pippin and M. Posner and D. Rosenfelder and C. Watson and T. Carlos and J. Kirkwood and B. Lembersky and Theodore Logan and M. Rosenstein and Rybak, {M. E.} and T. Whiteside and E. Elder and Moen, {R. C.}",
year = "1994",
language = "English (US)",
volume = "5",
pages = "41--55",
journal = "Human Gene Therapy",
issn = "1043-0342",
publisher = "Mary Ann Liebert Inc.",
number = "1",

}

TY - JOUR

T1 - Gene therapy of cancer

T2 - A pilot study of IL-4-gene-modified fibroblasts admixed with autologous tumor to elicit an immune response

AU - Lotze, M. T.

AU - Rubin, J. T.

AU - Carty, S.

AU - Edington, H.

AU - Ferson, P.

AU - Landreneau, R.

AU - Pippin, B.

AU - Posner, M.

AU - Rosenfelder, D.

AU - Watson, C.

AU - Carlos, T.

AU - Kirkwood, J.

AU - Lembersky, B.

AU - Logan, Theodore

AU - Rosenstein, M.

AU - Rybak, M. E.

AU - Whiteside, T.

AU - Elder, E.

AU - Moen, R. C.

PY - 1994

Y1 - 1994

N2 - BACKGROUND AND RATIONALE: Local therapies, such as surgery and radiation, rarely cure patients with disseminated cancer. Lamentably, our ability to alter the natural history of metastatic cancer using available chemotherapeutics is also limited and it is apparent that additional therapeutic strategies are needed. We, and others, have previously demonstrated that interleukin-2 (IL-2)-based immunotherapy induces clinically significant tumor regression in 20 to 30 percent of treated patients who have metastatic melanoma or renal cell carcinoma, respectively. Responses have been noted, albeit less frequently, among treated patients who have other malignancies including colon carcinoma, ovarian carcinoma, breast carcinoma and non-Hodgkin's lymphoma. The cost to the individual patient is significant toxicity. Few patients manifest durable clinical responses and significant benefit such as prolonged survival, cure or even palliation has yet to be clearly demonstrated. An alternative strategy for immunotherapy is suggested by in vitro and preclinical murine data showing that the cytokine microenvironment within tumors may determine the outcome of the immune response. In particular. the immunomodulatory cytokine interleukin-4 has a central role in the immune response to tumors in certain murine models. Implantation of the murine mastocytoma P815 into the anterior chamber of the eye results in progressive growth of this tumor while implantation into the subconjunctival sac of the eye results in tumor rejection. Cytolytic precursor cells residing in both sites secrete IL-2. However, only those isolated from the rejecting site (subconjunctival sac) elaborate IL-4 upon exposure to tumor. Bosco, et al, have injected IL-4 into the region of tumor-draining lymph nodes of mice bearing either a fibrosarcoma or a mammary adenocarcinoma. As little as 0.1 picogram per day induced tumor regression and protective immunity to subsequent tumor challenge. Tepper et al demonstrated that an invariably lethal murine B-cell lymphoma or a mammary adenocarcinoma, both transfected with the IL-4 gene, regressed after a brief period of growth. Golumbek et al have observed a similar effect with a spontaneous renal cell carcinoma (Renca) transfected with the gene for IL-4. They extended these observations by demonstrating both protective immunity against tumor rechallenge in mice vaccinated with these gene-modified tumors and tumor regression in a 6 to 9 day tumor model. In light of the demonstrated lack of therapeutic efficacy when administered systemically to patients with cancer, these studies suggest that the local production of IL-4 is associated with development of antitumor immunity that may translate to regression of established cancer.

AB - BACKGROUND AND RATIONALE: Local therapies, such as surgery and radiation, rarely cure patients with disseminated cancer. Lamentably, our ability to alter the natural history of metastatic cancer using available chemotherapeutics is also limited and it is apparent that additional therapeutic strategies are needed. We, and others, have previously demonstrated that interleukin-2 (IL-2)-based immunotherapy induces clinically significant tumor regression in 20 to 30 percent of treated patients who have metastatic melanoma or renal cell carcinoma, respectively. Responses have been noted, albeit less frequently, among treated patients who have other malignancies including colon carcinoma, ovarian carcinoma, breast carcinoma and non-Hodgkin's lymphoma. The cost to the individual patient is significant toxicity. Few patients manifest durable clinical responses and significant benefit such as prolonged survival, cure or even palliation has yet to be clearly demonstrated. An alternative strategy for immunotherapy is suggested by in vitro and preclinical murine data showing that the cytokine microenvironment within tumors may determine the outcome of the immune response. In particular. the immunomodulatory cytokine interleukin-4 has a central role in the immune response to tumors in certain murine models. Implantation of the murine mastocytoma P815 into the anterior chamber of the eye results in progressive growth of this tumor while implantation into the subconjunctival sac of the eye results in tumor rejection. Cytolytic precursor cells residing in both sites secrete IL-2. However, only those isolated from the rejecting site (subconjunctival sac) elaborate IL-4 upon exposure to tumor. Bosco, et al, have injected IL-4 into the region of tumor-draining lymph nodes of mice bearing either a fibrosarcoma or a mammary adenocarcinoma. As little as 0.1 picogram per day induced tumor regression and protective immunity to subsequent tumor challenge. Tepper et al demonstrated that an invariably lethal murine B-cell lymphoma or a mammary adenocarcinoma, both transfected with the IL-4 gene, regressed after a brief period of growth. Golumbek et al have observed a similar effect with a spontaneous renal cell carcinoma (Renca) transfected with the gene for IL-4. They extended these observations by demonstrating both protective immunity against tumor rechallenge in mice vaccinated with these gene-modified tumors and tumor regression in a 6 to 9 day tumor model. In light of the demonstrated lack of therapeutic efficacy when administered systemically to patients with cancer, these studies suggest that the local production of IL-4 is associated with development of antitumor immunity that may translate to regression of established cancer.

UR - http://www.scopus.com/inward/record.url?scp=0028170348&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028170348&partnerID=8YFLogxK

M3 - Article

VL - 5

SP - 41

EP - 55

JO - Human Gene Therapy

JF - Human Gene Therapy

SN - 1043-0342

IS - 1

ER -