Combining T-cell immunotherapy and anti-androgen therapy for prostate cancer

Prostate Cancer Prostatic Dis. 2013 Jun;16(2):123-31, S1. doi: 10.1038/pcan.2012.49. Epub 2013 Jan 8.

Abstract

Background: Prostate cancer remains a significant health problem for men in the Western world. Although treatment modalities are available, these do not confer long-term benefit and are accompanied by substantial side effects. Adoptive immunotherapy represents an attractive alternative to conventional treatments as a means to control tumor growth.

Methods: To selectively target the tumor-expressed form of Muc1 we constructed a retroviral vector encoding a chimeric antigen receptor (CAR) directed against the aberrantly-expressed extracellular portion of Muc1 called the 'variable number of tandem repeats'.

Results: We now demonstrate that T cells can be genetically engineered to express a CAR targeting the tumor-associated antigen Muc1. CAR-Muc1 T cells were able to selectively kill Muc1-expressing human prostate cancer cells. However, we noted that heterogeneous expression of the Muc1 antigen on tumor cells facilitated immune escape and the outgrowth of target-antigen loss variants of the tumor. Given the importance of androgen ablation therapy in the management of metastatic prostate cancer, we therefore also tested the value of combining conventional (anti-androgen) and experimental (CAR-Muc1 T cells) approaches. We show that CAR-Muc1 T cells were not adversely impacted by anti-androgen therapy and subsequently demonstrate the feasibility of combining the approaches to produce additive anti-tumor effects in vitro.

Conclusions: Adoptive transfer of CAR-Muc1 T cells alone or in combination with other luteinizing hormone-releasing hormone analogs or antagonists should be tested in human clinical trials.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Antagonists / pharmacology
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Cell Line, Tumor
  • Coculture Techniques
  • Combined Modality Therapy
  • Flutamide / pharmacology*
  • HEK293 Cells
  • Humans
  • Immunotherapy, Adoptive
  • Male
  • Mucin-1 / immunology
  • Mucin-1 / metabolism
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / therapy*
  • T-Lymphocytes / immunology*
  • Tumor Escape

Substances

  • Androgen Antagonists
  • Antineoplastic Agents, Hormonal
  • MUC1 protein, human
  • Mucin-1
  • Flutamide