Faculty Collaboration Database

Dual antigen target-based immunotherapy for prostate cancer eliminates the growth of established tumors in mice. Immunotherapy 2011 Jun;3(6):735-46

Date

06/15/2011

Pubmed ID

21668311

DOI

10.2217/imt.11.59

Scopus ID

2-s2.0-79959193683 (requires institutional sign-in at Scopus site)   20 Citations

Abstract

AIMS: We have previously shown that immunization with an adenovirus vector carrying an individual antigen induces antigen-specific CD8 T cells actively engaged in the destruction of tumor cells expressing the cognate antigen. In order to expand the range of antitumor responses beyond an individual antigen, we designed a recombinant adenovirus type 5 (rAd5) carrying a fusion construct of two full-length antigens. We used this adenovirus vector to test the concept that multiantigenic effector T cells could be generated simultaneously following a single immunization.

METHOD: To perform the rAd5 constructs, we selected a combination of prostate-specific antigen (PSA) and prostate stem cell antigen (PSCA) genes based on their restricted distribution within the prostate tissue and their association with the development and progression of prostate cancer.

RESULTS: Immunization of mice with rAd5 vector carrying a fusion construct of PSA and PSCA (Ad5-PSA/PSCA) simultaneously induced the expansion of anti-PSA and anti-PSCA CD8 T cells, as measured by intracellular cytokine staining for IFN-γ. The antigen-specific T-cell responses that developed were efficient in eliminating the target cells expressing cognate antigens measured by an in vivo cytotoxic T-cell assay. The in vivo tumor growth study showed that immunization of mice with Ad5-PSA/PSCA vaccine induced strong antitumor immunity when challenged with mouse prostate tumor cell lines (RM11) expressing human PSA (RM11/PSA). To further analyze the impact on therapeutic efficacy of Ad5-PSA/PSCA vaccine against the tumor cells expressing PSA and PSCA (RM11-PSA/PSCA) antigens, we injected mice with Ad5-PSA/PSCA vaccine. The vaccine inhibited the growth of established tumors with 80% of the mice becoming tumor free. These data provide useful information that antigen-specific effector T cells can be generated simultaneously and that their additive antitumor effect has the potential to eliminate the growth of established tumors. Therefore, the immunotherapy approach of using the simultaneous targeting of dual antigens associated with prostate cancer may have important implications for human clinical trials.

Author List

Karan D, Dubey S, Van Veldhuizen P, Holzbeierlein JM, Tawfik O, Thrasher JB

Author

Dev Karan PhD Associate Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenoviridae
Animals
Antigens, Neoplasm
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cancer Vaccines
Cell Line, Tumor
Cytotoxicity Tests, Immunologic
Dendritic Cells
Epitopes, T-Lymphocyte
GPI-Linked Proteins
Humans
Immunotherapy, Active
Interferon-gamma
Lymphocyte Activation
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Neoplasm Proteins
Ovalbumin
Prostate-Specific Antigen
Prostatic Neoplasms
Spleen
T-Lymphocytes, Cytotoxic
Transfection
Vaccines, DNA
Xenograft Model Antitumor Assays