title: Combining T-cell immunotherapy and anti-androgen therapy for prostate cancer.
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.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sanchez
authors.forename: R
authors.initials: R
authors.lastname: Chan
authors.forename: P
authors.initials: P
authors.lastname: Bajgain
authors.forename: S
authors.initials: S
authors.lastname: Rambally
authors.forename: G
authors.initials: G
authors.lastname: Palapattu
authors.forename: M
authors.initials: M
authors.lastname: Mims
authors.forename: C M
authors.initials: CM
authors.lastname: Rooney
authors.forename: A M
authors.initials: AM
authors.lastname: Leen
authors.forename: M K
authors.initials: MK
authors.lastname: Brenner
authors.forename: J F
authors.initials: JF
authors.lastname: Vera
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003131:Combined Modality Therapy; D005485:Flutamide / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive; D008297:Male; D018396:Mucin-1 / Q000276:immunology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*; D019139:Tumor Escape
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; C060192:MUC1 protein, human; D018396:Mucin-1; D005485:Flutamide