Prostate cancer is the most common cancer amongst men in developed countries and in the United States alone over 180,000 new cases were diagnosed in 2008 1
. Treatment options for prostate cancer include surgery with radical prostatectomy, hormone therapy, chemotherapy 2
and radiation 3
. However, severe secondary effects are common amongst patients and there is no curative treatment once the primary tumor metastasizes 4
. The introduction of genetically-engineered oncolytic viruses as a new therapeutic avenue in the battle against cancer began with the use of oncolytic herpes simplex viruses (oHSV) 5
. Typically, oHSV carry mutations in the viral genome that enable them to replicate in and kill cancer cells, without harming normal tissue 6
. Amongst the benefits of oHSV vectors are that they are easily manipulated, can carry transgene inserts 7
and have already been safely used in human subjects with a variety of cancers 8, 9
. Another advantage of oHSV is that it can interact synergistically with other therapeutic modalities, including chemotherapeutic agents 10, 11
and radiotherapy 12
, thereby promoting better therapeutic outcomes by targeting more then one aspect of cancer biology.
Previous work from our laboratory and others has shown that oHSVs can be used as an in situ
vaccine to generate a tumor-specific host immune response 13-16
. Prostatic acid phosphatase (PAP) is a prostate-specific antigen that is expressed in both prostate cells and prostate cancer cells 17
as well as other adenocarcinomas 18
. However, as it is a self-antigen it is not immunogenic due presumably to tolerance. It has previously been shown that immunization of rats with human PAP (hPAP) generates a CTL response leading to tissue-specific prostatitis 19
. Furthermore, immunization of metastatic prostate cancer patients with recombinant mouse PAP (mPAP) loaded dendritic cells has been shown to result in an anti-tumor immune response and clinical stabilization of the disease, as indicated by a decreased rise of serum PSA levels 18
. This suggests that vaccination with a xenogeneic homolog can break tolerance to a self-antigen, human PAP (hPAP), inducing a Th1-type cytokine response to both mouse and human PAP antigens. Other studies have confirmed this concept of using a xenogenic form of an antigen to break anti-tumor tolerance to other proteins, such as: prostate stem cell antigen, where DNA vaccination induced anti-tumor immune responses against TRAMP-C1 tumors 19
, prostate-specific membrane antigen (PSMA) 20
, gp100 in melanoma 21
, HER2 expressed from a replication-deficient adenovirus vector in breast cancer 22
, and EGFR 23
. We therefore hypothesized that an oHSV expressing a xenogenic PAP could be used to treat prostate cancer.
In the present study we have combined the ability of oHSV to specifically replicate in and kill cancer cells with the immunogenic effects of in situ vaccination with a xenogeneic PAP protein to create a more powerful therapeutic strategy for prostate cancer. Our results show that this combined approach achieves improved inhibition of established tumor growth and animal survival compared to oHSV alone or when expressing syngeneic mPAP. These results represent an encouraging step towards the development of a viable therapy for prostate cancer and describe a novel approach that should be applicable to other oncolytic viruses.