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

J Transl Med. 2013 Apr 4;11:89. doi: 10.1186/1479-5876-11-89.

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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Antineoplastic Agents / therapeutic use
  • CD8-Positive T-Lymphocytes / cytology
  • CTLA-4 Antigen / antagonists & inhibitors*
  • Cancer Vaccines / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclophosphamide / therapeutic use
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Humans
  • Immunotherapy / methods*
  • Ipilimumab
  • Liver Neoplasms / pathology
  • Liver Neoplasms / therapy
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasm Metastasis
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / therapy*
  • Time Factors

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • CTLA-4 Antigen
  • Cancer Vaccines
  • Ipilimumab
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Cyclophosphamide