Document Detail


Combining T-cell immunotherapy and anti-androgen therapy for prostate cancer.
MedLine Citation:
PMID:  23295316     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
C Sanchez; R Chan; P Bajgain; S Rambally; G Palapattu; M Mims; C M Rooney; A M Leen; M K Brenner; J F Vera
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-01-08
Journal Detail:
Title:  Prostate cancer and prostatic diseases     Volume:  16     ISSN:  1476-5608     ISO Abbreviation:  Prostate Cancer Prostatic Dis.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-15     Completed Date:  2013-12-11     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9815755     Medline TA:  Prostate Cancer Prostatic Dis     Country:  England    
Other Details:
Languages:  eng     Pagination:  123-31, S1     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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,  metabolism
Prostatic Neoplasms / immunology,  metabolism,  therapy*
T-Lymphocytes / immunology*
Tumor Escape
Grant Support
ID/Acronym/Agency:
P01 CA094237/CA/NCI NIH HHS; P30 CA125123/CA/NCI NIH HHS; T32 HL092332/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Androgen Antagonists; 0/Antineoplastic Agents, Hormonal; 0/MUC1 protein, human; 0/Mucin-1; 76W6J0943E/Flutamide

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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