Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer

Satoshi Wada, Christopher M. Jackson, Kiyoshi Yoshimura, Hung Rong Yen, Derese Getnet, Timothy J. Harris, Monica V. Goldberg, Tullia C. Bruno, Joseph F. Grosso, Nicholas Durham, George J. Netto, Andrew Mark Pardoll, Charles G. Drake

Research output: Contribution to journalArticle

Abstract

Background: The FDA recently approved an anti-CTLA-4 antibody (Iplimumab) for the treatment of metastatic melanoma. This decision was based on Phase III results, which demonstrate that blocking this immune checkpoint provides a survival advantage in patients with advanced disease. As a single agent, ipilimumab is also being clinically evaluated in advanced (metastatic, castrate-resistant) prostate cancer and two randomized, placebo-controlled Phase III studies have recently completed accrual.Methods: We used a well-described genetically engineered mouse (GEM), autochronous prostate cancer model (Pro-TRAMP) to explore the relative sequencing and dosing of anti-CTLA-4 antibody when combined with a cell-based, GM-CSF-secreting vaccine (GVAX).Results: Our results show that combined treatment results in a dramatic increase in effector CD8 T cells in the prostate gland, and enhanced tumor-antigen directed lytic function. These effects are maximized when CTLA-4 blockade is applied after, but not before, vaccination. Additional experiments, using models of metastatic disease, show that incorporation of low-dose cyclophosphamide into this combined treatment regimen results in an additional pre-clinical benefit.Conclusions: Together these studies define a combination regimen using anti-CTLA-4/GVAX immunotherapy and low-dose chemotherapy for potential translation to a clinical trial setting.

Original languageEnglish (US)
Article number89
JournalJournal of Translational Medicine
Volume11
Issue number1
DOIs
StatePublished - Apr 4 2013

Fingerprint

Immunotherapy
Prostatic Neoplasms
Chemotherapy
T-cells
Antibodies
Neoplasm Antigens
Granulocyte-Macrophage Colony-Stimulating Factor
Cyclophosphamide
Prostate
Melanoma
Vaccination
Therapeutics
Placebos
Clinical Trials
T-Lymphocytes
Drug Therapy
Survival
Experiments
GVAX vaccine
ipilimumab

Keywords

  • CTLA-4
  • Immunotherapy
  • Lymphocyte
  • Prostate cancer
  • Treg

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Wada, S., Jackson, C. M., Yoshimura, K., Yen, H. R., Getnet, D., Harris, T. J., ... Drake, C. G. (2013). Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer. Journal of Translational Medicine, 11(1), [89]. https://doi.org/10.1186/1479-5876-11-89

Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer. / Wada, Satoshi; Jackson, Christopher M.; Yoshimura, Kiyoshi; Yen, Hung Rong; Getnet, Derese; Harris, Timothy J.; Goldberg, Monica V.; Bruno, Tullia C.; Grosso, Joseph F.; Durham, Nicholas; Netto, George J.; Pardoll, Andrew Mark; Drake, Charles G.

In: Journal of Translational Medicine, Vol. 11, No. 1, 89, 04.04.2013.

Research output: Contribution to journalArticle

Wada, S, Jackson, CM, Yoshimura, K, Yen, HR, Getnet, D, Harris, TJ, Goldberg, MV, Bruno, TC, Grosso, JF, Durham, N, Netto, GJ, Pardoll, AM & Drake, CG 2013, 'Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer', Journal of Translational Medicine, vol. 11, no. 1, 89. https://doi.org/10.1186/1479-5876-11-89
Wada, Satoshi ; Jackson, Christopher M. ; Yoshimura, Kiyoshi ; Yen, Hung Rong ; Getnet, Derese ; Harris, Timothy J. ; Goldberg, Monica V. ; Bruno, Tullia C. ; Grosso, Joseph F. ; Durham, Nicholas ; Netto, George J. ; Pardoll, Andrew Mark ; Drake, Charles G. / Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer. In: Journal of Translational Medicine. 2013 ; Vol. 11, No. 1.
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