Combined alloreactive CTL cellular therapy with prodrug activator gene therapy in a model of breast cancer metastatic to the brain

Michelle J. Hickey, Colin C. Malone, Kate L. Erickson, Amy Lin, Horacio Soto, Edward T. Ha, Shuichi Kamijima, Akihito Inagaki, Masamichi Takahashi, Yuki Kato, Noriyuki Kasahara, Barbara M. Mueller, Carol A. Kruse

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Purpose: Individual or combined strategies of cellular therapy with alloreactive CTLs (alloCTL) and gene therapy using retroviral replicating vectors (RRV) encoding a suicide prodrug activating gene were explored for the treatment of breast tumors metastatic to the brain. Experimental Design: AlloCTL, sensitized to the HLA of MDA-MB-231 breast cancer cells, were examined in vitro for antitumor functionality toward breast cancer targets. RRV encoding the yeast cytosine deaminase (CD) gene was tested in vivo for virus spread, ability to infect, and kill breast cancer targets when exposed to 5-fluorocytosine (5-FC). Individual and combination treatments were tested in subcutaneous and intracranial xenograft models with 231BR, a brain tropic variant. Results: AlloCTL preparations were cytotoxic, proliferated, and produced IFN-g when coincubated with target cells displaying relevant HLA. In vivo, intratumorally placed alloCTL trafficked through one established intracranial 231BR focus to another in contralateral brain and induced tumor cell apoptosis. RRV-CD efficiently spread in vivo, infected 231BR and induced their apoptosis upon 5-FC exposure. Subcutaneous tumor volumes were significantly reduced in alloCTL and/or gene therapy-treated groups compared to control groups. Mice with established intracranial 231BR tumors treated with combined alloCTL and RRVCD had a median survival of 97.5 days compared with single modalities (50-83 days); all experimental treatment groups survived significantly longer than sham-treated groups (median survivals 31.5 or 40 days) and exhibited good safety/toxicity profiles. Conclusion: The results indicate combining cellular and suicide gene therapies is a viable strategy for the treatment of established breast tumors in the brain.

Original languageEnglish (US)
Pages (from-to)4137-4148
Number of pages12
JournalClinical Cancer Research
Volume19
Issue number15
DOIs
StatePublished - Aug 1 2013
Externally publishedYes

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Prodrugs
Genetic Therapy
Breast Neoplasms
Cytosine Deaminase
Brain
Flucytosine
Suicide
Apoptosis
HLA-DQ Antigens
Therapeutics
Aptitude
Tumor Burden
Heterografts
Brain Neoplasms
Genes
Research Design
Yeasts
Viruses
Safety
Control Groups

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Combined alloreactive CTL cellular therapy with prodrug activator gene therapy in a model of breast cancer metastatic to the brain. / Hickey, Michelle J.; Malone, Colin C.; Erickson, Kate L.; Lin, Amy; Soto, Horacio; Ha, Edward T.; Kamijima, Shuichi; Inagaki, Akihito; Takahashi, Masamichi; Kato, Yuki; Kasahara, Noriyuki; Mueller, Barbara M.; Kruse, Carol A.

In: Clinical Cancer Research, Vol. 19, No. 15, 01.08.2013, p. 4137-4148.

Research output: Contribution to journalArticle

Hickey, MJ, Malone, CC, Erickson, KL, Lin, A, Soto, H, Ha, ET, Kamijima, S, Inagaki, A, Takahashi, M, Kato, Y, Kasahara, N, Mueller, BM & Kruse, CA 2013, 'Combined alloreactive CTL cellular therapy with prodrug activator gene therapy in a model of breast cancer metastatic to the brain', Clinical Cancer Research, vol. 19, no. 15, pp. 4137-4148. https://doi.org/10.1158/1078-0432.CCR-12-3735
Hickey, Michelle J. ; Malone, Colin C. ; Erickson, Kate L. ; Lin, Amy ; Soto, Horacio ; Ha, Edward T. ; Kamijima, Shuichi ; Inagaki, Akihito ; Takahashi, Masamichi ; Kato, Yuki ; Kasahara, Noriyuki ; Mueller, Barbara M. ; Kruse, Carol A. / Combined alloreactive CTL cellular therapy with prodrug activator gene therapy in a model of breast cancer metastatic to the brain. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 15. pp. 4137-4148.
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T1 - Combined alloreactive CTL cellular therapy with prodrug activator gene therapy in a model of breast cancer metastatic to the brain

AU - Hickey, Michelle J.

AU - Malone, Colin C.

AU - Erickson, Kate L.

AU - Lin, Amy

AU - Soto, Horacio

AU - Ha, Edward T.

AU - Kamijima, Shuichi

AU - Inagaki, Akihito

AU - Takahashi, Masamichi

AU - Kato, Yuki

AU - Kasahara, Noriyuki

AU - Mueller, Barbara M.

AU - Kruse, Carol A.

PY - 2013/8/1

Y1 - 2013/8/1

N2 - Purpose: Individual or combined strategies of cellular therapy with alloreactive CTLs (alloCTL) and gene therapy using retroviral replicating vectors (RRV) encoding a suicide prodrug activating gene were explored for the treatment of breast tumors metastatic to the brain. Experimental Design: AlloCTL, sensitized to the HLA of MDA-MB-231 breast cancer cells, were examined in vitro for antitumor functionality toward breast cancer targets. RRV encoding the yeast cytosine deaminase (CD) gene was tested in vivo for virus spread, ability to infect, and kill breast cancer targets when exposed to 5-fluorocytosine (5-FC). Individual and combination treatments were tested in subcutaneous and intracranial xenograft models with 231BR, a brain tropic variant. Results: AlloCTL preparations were cytotoxic, proliferated, and produced IFN-g when coincubated with target cells displaying relevant HLA. In vivo, intratumorally placed alloCTL trafficked through one established intracranial 231BR focus to another in contralateral brain and induced tumor cell apoptosis. RRV-CD efficiently spread in vivo, infected 231BR and induced their apoptosis upon 5-FC exposure. Subcutaneous tumor volumes were significantly reduced in alloCTL and/or gene therapy-treated groups compared to control groups. Mice with established intracranial 231BR tumors treated with combined alloCTL and RRVCD had a median survival of 97.5 days compared with single modalities (50-83 days); all experimental treatment groups survived significantly longer than sham-treated groups (median survivals 31.5 or 40 days) and exhibited good safety/toxicity profiles. Conclusion: The results indicate combining cellular and suicide gene therapies is a viable strategy for the treatment of established breast tumors in the brain.

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