Cancer cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer as vaccines for the treatment of genitourinary malignancies

William G. Nelson, Jonathan W. Simons, Bahar Mikhak, Ju Fay Chang, Angelo M. DeMarzo, Michael A. Carducci, Michael Kim, Christine E. Weber, Angelo A. Baccala, Marti A. Goeman, Shirley M. Clift, Dale G. Ando, Hyam I. Levitsky, Lawrence K. Cohen, Martin G. Sanda, Richard C. Mulligan, Alan W. Partin, H. Ballentine Carter, Steven Piantadosi, Fray F. Marshall

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

When irradiated and administered intradermally as vaccines, cancer cells engineered to secrete high levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) by gene transfer elicit potent anticancer immune responses in a variety of animal tumor models. Upon vaccination, antigens present in the cancer cells are phagocytosed and processed by skin dendritic cells. These dendritic cells then prime anticancer immune responses by presenting antigenic peptides to T cells. The immune responses generated are capable of eradicating small but lethal cancer cell inocula with minimal toxicity in preclinical animal tumor studies. To develop this vaccination strategy for the treatment of human genitourinary cancers, we have conducted phase I clinical trials using human genitourinary cancer cells as sources of cancer cell antigens. In the first human clinical trial of genetically engineered cancer cell vaccines, a phase I clinical trial of kidney cancer cell vaccines (n = 18), kidney cancer cells were removed at surgery, propagated briefly in vitro, and then genetically modified to secrete high levels of GM-CSF via ex vivo transduction with the retrovirus MFG-GM-CSF. After irradiation, the kidney cancer cells were administered as vaccines to 18 patients with advanced kidney cancers. Vaccine treatment, which caused few side effects, nonetheless appeared to trigger anticancer immune responses manifest as conversion of delayed-type hypersensitivity (DTH) skin responses against irradiated autologous cancer cells after vaccination. Biopsies of vaccine sites yielded findings reminiscent of biopsies from preclinical animal model studies, with evidence of vaccine cell recruitment of dendritic cells, T cells, and eosinophils. One patient with measurable kidney cancer metastases treated at the highest vaccine dose level experienced a partial treatment response. The bioactivity of GM-CSFsecreting autologous cancer cell vaccines was confirmed in a phase I clinical trial for prostate cancer (n=8). Vaccine cells were prepared from surgically harvested prostate tumors by ex vivo transduction with MFG-GM-CSF in a manner similar to that used for the kidney cancer trial. Vaccine treatment was well tolerated and associated with induction of anticancer immunity as assessed using DTH skin testing. In addition, new antiprostate cancer cell antibodies were detected in serum samples from treated men as a consequence of vaccination. These first clinical trials of GM-CSF-secreting cancer cell vaccines for the treatment of genitourinary cancers have demonstrated both safety and bioactivity, in that very few side effects have been seen and anticancer immune responses have been detected. Future clinical studies will be required to assess vaccine treatment efficacy, refine vaccination dose and schedule, define the appropriate clinical context for the use of such vaccines, and ascertain optimal combinations involving vaccines and other local or systemic anticancer treatments.

Original languageEnglish (US)
JournalCancer Chemotherapy and Pharmacology
Volume46
Issue numberSUPPL.
StatePublished - 2000
Externally publishedYes

Fingerprint

Gene transfer
Granulocyte-Macrophage Colony-Stimulating Factor
Vaccines
Cells
Kidney Neoplasms
Genes
Cancer Vaccines
Neoplasms
Urogenital Neoplasms
Vaccination
Clinical Trials, Phase I
Therapeutics
Tumors
Skin
Animals
T-cells
Biopsy
Delayed Hypersensitivity
Bioactivity
Dendritic Cells

Keywords

  • Gene transfer
  • Granulocyte-macrophage colony-stimulating factor
  • Kidney cancer
  • Prostate cancer
  • Vaccine

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Cancer cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer as vaccines for the treatment of genitourinary malignancies. / Nelson, William G.; Simons, Jonathan W.; Mikhak, Bahar; Chang, Ju Fay; DeMarzo, Angelo M.; Carducci, Michael A.; Kim, Michael; Weber, Christine E.; Baccala, Angelo A.; Goeman, Marti A.; Clift, Shirley M.; Ando, Dale G.; Levitsky, Hyam I.; Cohen, Lawrence K.; Sanda, Martin G.; Mulligan, Richard C.; Partin, Alan W.; Carter, H. Ballentine; Piantadosi, Steven; Marshall, Fray F.

In: Cancer Chemotherapy and Pharmacology, Vol. 46, No. SUPPL., 2000.

Research output: Contribution to journalArticle

Nelson, WG, Simons, JW, Mikhak, B, Chang, JF, DeMarzo, AM, Carducci, MA, Kim, M, Weber, CE, Baccala, AA, Goeman, MA, Clift, SM, Ando, DG, Levitsky, HI, Cohen, LK, Sanda, MG, Mulligan, RC, Partin, AW, Carter, HB, Piantadosi, S & Marshall, FF 2000, 'Cancer cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer as vaccines for the treatment of genitourinary malignancies', Cancer Chemotherapy and Pharmacology, vol. 46, no. SUPPL..
Nelson, William G. ; Simons, Jonathan W. ; Mikhak, Bahar ; Chang, Ju Fay ; DeMarzo, Angelo M. ; Carducci, Michael A. ; Kim, Michael ; Weber, Christine E. ; Baccala, Angelo A. ; Goeman, Marti A. ; Clift, Shirley M. ; Ando, Dale G. ; Levitsky, Hyam I. ; Cohen, Lawrence K. ; Sanda, Martin G. ; Mulligan, Richard C. ; Partin, Alan W. ; Carter, H. Ballentine ; Piantadosi, Steven ; Marshall, Fray F. / Cancer cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer as vaccines for the treatment of genitourinary malignancies. In: Cancer Chemotherapy and Pharmacology. 2000 ; Vol. 46, No. SUPPL.
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T1 - Cancer cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer as vaccines for the treatment of genitourinary malignancies

AU - Nelson, William G.

AU - Simons, Jonathan W.

AU - Mikhak, Bahar

AU - Chang, Ju Fay

AU - DeMarzo, Angelo M.

AU - Carducci, Michael A.

AU - Kim, Michael

AU - Weber, Christine E.

AU - Baccala, Angelo A.

AU - Goeman, Marti A.

AU - Clift, Shirley M.

AU - Ando, Dale G.

AU - Levitsky, Hyam I.

AU - Cohen, Lawrence K.

AU - Sanda, Martin G.

AU - Mulligan, Richard C.

AU - Partin, Alan W.

AU - Carter, H. Ballentine

AU - Piantadosi, Steven

AU - Marshall, Fray F.

PY - 2000

Y1 - 2000

N2 - When irradiated and administered intradermally as vaccines, cancer cells engineered to secrete high levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) by gene transfer elicit potent anticancer immune responses in a variety of animal tumor models. Upon vaccination, antigens present in the cancer cells are phagocytosed and processed by skin dendritic cells. These dendritic cells then prime anticancer immune responses by presenting antigenic peptides to T cells. The immune responses generated are capable of eradicating small but lethal cancer cell inocula with minimal toxicity in preclinical animal tumor studies. To develop this vaccination strategy for the treatment of human genitourinary cancers, we have conducted phase I clinical trials using human genitourinary cancer cells as sources of cancer cell antigens. In the first human clinical trial of genetically engineered cancer cell vaccines, a phase I clinical trial of kidney cancer cell vaccines (n = 18), kidney cancer cells were removed at surgery, propagated briefly in vitro, and then genetically modified to secrete high levels of GM-CSF via ex vivo transduction with the retrovirus MFG-GM-CSF. After irradiation, the kidney cancer cells were administered as vaccines to 18 patients with advanced kidney cancers. Vaccine treatment, which caused few side effects, nonetheless appeared to trigger anticancer immune responses manifest as conversion of delayed-type hypersensitivity (DTH) skin responses against irradiated autologous cancer cells after vaccination. Biopsies of vaccine sites yielded findings reminiscent of biopsies from preclinical animal model studies, with evidence of vaccine cell recruitment of dendritic cells, T cells, and eosinophils. One patient with measurable kidney cancer metastases treated at the highest vaccine dose level experienced a partial treatment response. The bioactivity of GM-CSFsecreting autologous cancer cell vaccines was confirmed in a phase I clinical trial for prostate cancer (n=8). Vaccine cells were prepared from surgically harvested prostate tumors by ex vivo transduction with MFG-GM-CSF in a manner similar to that used for the kidney cancer trial. Vaccine treatment was well tolerated and associated with induction of anticancer immunity as assessed using DTH skin testing. In addition, new antiprostate cancer cell antibodies were detected in serum samples from treated men as a consequence of vaccination. These first clinical trials of GM-CSF-secreting cancer cell vaccines for the treatment of genitourinary cancers have demonstrated both safety and bioactivity, in that very few side effects have been seen and anticancer immune responses have been detected. Future clinical studies will be required to assess vaccine treatment efficacy, refine vaccination dose and schedule, define the appropriate clinical context for the use of such vaccines, and ascertain optimal combinations involving vaccines and other local or systemic anticancer treatments.

AB - When irradiated and administered intradermally as vaccines, cancer cells engineered to secrete high levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) by gene transfer elicit potent anticancer immune responses in a variety of animal tumor models. Upon vaccination, antigens present in the cancer cells are phagocytosed and processed by skin dendritic cells. These dendritic cells then prime anticancer immune responses by presenting antigenic peptides to T cells. The immune responses generated are capable of eradicating small but lethal cancer cell inocula with minimal toxicity in preclinical animal tumor studies. To develop this vaccination strategy for the treatment of human genitourinary cancers, we have conducted phase I clinical trials using human genitourinary cancer cells as sources of cancer cell antigens. In the first human clinical trial of genetically engineered cancer cell vaccines, a phase I clinical trial of kidney cancer cell vaccines (n = 18), kidney cancer cells were removed at surgery, propagated briefly in vitro, and then genetically modified to secrete high levels of GM-CSF via ex vivo transduction with the retrovirus MFG-GM-CSF. After irradiation, the kidney cancer cells were administered as vaccines to 18 patients with advanced kidney cancers. Vaccine treatment, which caused few side effects, nonetheless appeared to trigger anticancer immune responses manifest as conversion of delayed-type hypersensitivity (DTH) skin responses against irradiated autologous cancer cells after vaccination. Biopsies of vaccine sites yielded findings reminiscent of biopsies from preclinical animal model studies, with evidence of vaccine cell recruitment of dendritic cells, T cells, and eosinophils. One patient with measurable kidney cancer metastases treated at the highest vaccine dose level experienced a partial treatment response. The bioactivity of GM-CSFsecreting autologous cancer cell vaccines was confirmed in a phase I clinical trial for prostate cancer (n=8). Vaccine cells were prepared from surgically harvested prostate tumors by ex vivo transduction with MFG-GM-CSF in a manner similar to that used for the kidney cancer trial. Vaccine treatment was well tolerated and associated with induction of anticancer immunity as assessed using DTH skin testing. In addition, new antiprostate cancer cell antibodies were detected in serum samples from treated men as a consequence of vaccination. These first clinical trials of GM-CSF-secreting cancer cell vaccines for the treatment of genitourinary cancers have demonstrated both safety and bioactivity, in that very few side effects have been seen and anticancer immune responses have been detected. Future clinical studies will be required to assess vaccine treatment efficacy, refine vaccination dose and schedule, define the appropriate clinical context for the use of such vaccines, and ascertain optimal combinations involving vaccines and other local or systemic anticancer treatments.

KW - Gene transfer

KW - Granulocyte-macrophage colony-stimulating factor

KW - Kidney cancer

KW - Prostate cancer

KW - Vaccine

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