Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice

J. P H Machiels, R. Todd Reilly, L. A. Emens, A. M. Ercolini, R. Y. Lei, D. Weintraub, F. I. Okoye, Elizabeth Jaffee

Research output: Contribution to journalArticle

Abstract

Tumor-specific immune tolerance limits the effectiveness of cancer vaccines. In addition, tumor vaccines alone have a limited potential for the treatment of measurable tumor burdens. This highlights the importance of identifying more potent cancer vaccine strategies for clinical testing. We tested immune-modulating doses of chemotherapy in combination with a granulocyte/macrophage-colony stimulating factor (GM-CSF)-secreting, HER-2/neu (neu)-expressing whole-cell vaccine as a means to treat existing mammary tumors in antigen-specific tolerized neu transgenic mice. Earlier studies have shown that neu transgenic mice exhibit immune tolerance to the neu-expressing tumors similar to what is observed in patients with cancer. We found that cyclophosphamide, paclitaxel, and doxorubicin, when given in a defined sequence with a GM-CSF-secreting, neu-expressing whole-cell vaccine, enhanced the vaccine's potential to delay tumor growth in neu transgenic mice. In addition, we showed that these drugs mediate their effects by enhancing the efficacy of the vaccine rather than via a direct cytolytic effect on cancer cells. Furthermore, paclitaxel and cyclophosphamide appear to amplify the T helper 1 neuspecific T-cell response. These findings suggest that the combined treatment with immune-modulating doses of chemotherapy and the GM-CSF-secreting neu vaccine can overcome immune tolerance and induce an antigen-specific antitumor immune response. These data provide the immunological rationale for testing immune-modulating doses of chemotherapy in combination with tumor vaccines in patients with cancer.

Original languageEnglish (US)
Pages (from-to)3689-3697
Number of pages9
JournalCancer Research
Volume61
Issue number9
StatePublished - May 1 2001

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Granulocyte-Macrophage Colony-Stimulating Factor
Paclitaxel
Doxorubicin
Cyclophosphamide
Cancer Vaccines
Vaccines
Immune Tolerance
Transgenic Mice
Neoplasms
Combination Drug Therapy
Th1 Cells
Neoplasm Antigens
Tumor Burden
Breast Neoplasms
Antigens
Drug Therapy
Therapeutics
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. / Machiels, J. P H; Todd Reilly, R.; Emens, L. A.; Ercolini, A. M.; Lei, R. Y.; Weintraub, D.; Okoye, F. I.; Jaffee, Elizabeth.

In: Cancer Research, Vol. 61, No. 9, 01.05.2001, p. 3689-3697.

Research output: Contribution to journalArticle

Machiels, J. P H ; Todd Reilly, R. ; Emens, L. A. ; Ercolini, A. M. ; Lei, R. Y. ; Weintraub, D. ; Okoye, F. I. ; Jaffee, Elizabeth. / Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. In: Cancer Research. 2001 ; Vol. 61, No. 9. pp. 3689-3697.
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