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Research Focus

To determine whether specific antigens of the prostate are immunologically recognized and could potentially be explored as tumor vaccine antigens. In the past, we have explored whether patients with prostate cancer have immunological responses to known prostate cancer-associated antigens, including prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA) [1-3]. We have further extended these analyses to evaluate antigens in an unbiased way recognized by serum IgG using SEREX, a methodology by which cDNA expression libraries from normal prostate tissue were screened with sera from patients with a variety of clinical conditions [4-7]. These conditions included patients with chronic prostatitis, and patients with prostate cancer treated with immune-modulating therapies. This has led to a list of prostate tissue-associated and prostate cancer-associated antigens that could potentially be pursued as targets for vaccine approaches. Since 2005 we have identified and/or prioritized three potential target antigens with different features: 
        1) PAP, a prostate-specific protein [2, 8]; 
        2) the androgen receptor, a protein critical to the development and progression of prostate cancer [3];
        3) SSX-2, an antigen specifically expressed in prostate cancer rather than normal prostate cells [9, 10].

Recent and ongoing efforts are continuing studies of antigen identification as above, and we are developing these three antigens as immunotherapeutic targets, with the following aims:
    1) To identify HLA-A2 specific epitopes derived from the amino acid sequences of PAP, AR ligand-binding domain (AR LBD), and SSX-2 [11]
    2) To determine whether cytolytic T cells (CTL) specific for these HLA-A2 epitopes can be cultured from the peripheral blood of HLA-A2-expressing patients with prostate cancer, and whether these lyse prostate cancer cell in vitro [11]
    3) To determine whether concurrent treatment with other agents can increase the susceptibility of prostate cancer cells to CTL-mediated lysis with CTL lines specific for PAP, ARLBD or SSX2.

The identification of IgG specific for prostate-associated antigens, and prostate-cancer associated antigens, further suggests that these might be used diagnostically for the detection of cancer or cancer recurrence, or for the evaluation of prostate-directed immune responses resulting from non-antigen-specific immunotherapies. We had previously demonstrated as proof-of-principle that a panel of cancer-testis antigens could be used for this purpose [12]. Using a larger panel of prostate tissue-associated antigens that we have identified, we have found that patients with prostate cancer or chronic prostatitis, relative to men without known prostate disease, have IgG responses to many of these antigens [13]. We are currently evaluating whether IgG responses occur to these antigens following immune-based therapies, and thus whether they might be developed as diagnostic antigens [14].

To develop models to evaluate antigen-specific DNA vaccines. The use of plasmid DNA alone as a means of in vivo gene delivery by direct injection was first described by Dr. Jon Wolff at the University of Wisconsin in 1990. In animal studies, plasmid DNA has been demonstrated to be taken up, and encoded genes expressed, by antigen-presenting cells directly, leading to antigen presentation through naturally processed epitopes. The directed expression of antigen by host cells, including MHC class I expressing bystander cells, can lead to vigorous CD8+ CTL responses specific for the targeted antigen. The ease of manufacturing plasmid DNA provides a significant advantage over protein- or viral-based vaccines. In addition, while viral vaccines are immunologically potent, DNA vaccines avoid the inherent problem of co-immunization with multiple foreign viral proteins that could potentially interfere with antigen-specific immunization. The efficacy of a DNA vaccine encoding tyrosinase for the treatment of canine melanoma, delivered with GM-CSF as a vaccine adjuvant, was USDA approved in early 2010 based on the results of randomized clinical studies in dogs – the first anti-tumor vaccine approved for use in the U.S. Thus, this approach bears further investigation in human clinical trials. In published studies we have found that repetitive immunization of rats with a vaccinia virus encoding human PAP did not result in a PAP-specific immune responses [15]. In contrast, animals immunized with a DNA vaccine encoding PAP developed PAP-specific CD8+ T-cell responses, and these responses could be “boosted” with repetitive immunizations [15, 16]. We are currently studying DNA vaccines encoding PAP, as well as AR and SSX-2, and evaluating methods to increase the efficiency and efficacy of immunization.

To translate laboratory findings to early human clinical trials. The ultimate goal of this research is to develop vaccines for patients with prostate cancer, and to begin to evaluate whether there are preferred target antigens for prostate cancer immunotherapy. We believe that the simplicity and preclinical efficacy of DNA vaccines will permit us to evaluate this specific question in early phase human clinical trials. We have completed one trial using a DNA vaccine encoding PAP [17, 18]. In that trial, patients with early recurrent prostate cancer were treated with one of three doses of a DNA vaccine encoding PAP in combination with GM-CSF. We found that several patients developed PAP-specific CD8+ T-cell responses, and did not identify safety concerns. Several individuals developed long-term immune responses that were associated with favorable changes in PSA kinetics [19]. We are currently conducting a trial evaluating different schedules of vaccine administration, and planning a larger phase II trial.


References:

1. McNeel D. G., Nguyen L. D., Storer B. E., Vessella R., Lange P. H., and Disis M. L. (2000) "Antibody immunity to prostate cancer-associated antigens can be detected in the serum of patients with prostate cancer." J. Urol. 164:1825-1829.

2. McNeel D. G., Nguyen L. D., Ellis W. J., Higano C. S., Lange P. H., and Disis M. L. (2001) "Naturally occurring prostate cancer antigen-specific T cell responses of a Th1 phenotype can be detected in patients with prostate cancer." Prostate 47:222-229.

3. Olson B. M. and McNeel D. G. (2007) "Antibody and T-cell responses specific for the androgen receptor in patients with prostate cancer." Prostate 67:1729-1739.

4. Dunphy E. J., Eickhoff J. C., Muller C. H., Berger R. E., and McNeel D. G. (2004) "Identification of antigen-specific IgG in sera from patients with chronic prostatitis." J. Clin. Immunol. 24:492-501.

5. Mooney C. J., Dunphy E. J., Stone B., and McNeel D. G. (2006) "Identification of autoantibodies elicited in a patient with prostate cancer presenting as dermatomyositis." Int J Urol 13:211-217.

6. Hoeppner L. H., Dubovsky J. A., Dunphy E. J., and McNeel D. G. (2006) "Humoral immune responses to testis antigens in sera from patients with prostate cancer." Cancer Immun 6:1-7.

7. Dunphy E. J., Johnson L. E., Olson B. M., Frye T. P., and McNeel D. G. (2006) "New approaches to identification of antigenic candidates for future prostate cancer immunotherapy." Update Canc. Ther. 22:273-284.

8. McNeel D. G., Nguyen L. D., and Disis M. L. (2001) "Identification of T helper epitopes from prostatic acid phosphatase." Cancer Res. 61:5161-5167.

9. Dubovsky J. A. and McNeel D. G. (2007) "Inducible expression of a prostate cancer-testis antigen, SSX-2, following treatment with a DNA methylation inhibitor." Prostate 67:1781-1790.

10. Smith H. A. and McNeel D. G. (2010) "The SSX family of cancer-testis antigens as target proteins for tumor therapy." Clin Dev Immunol 2010:150591.

11. Olson B. M., Frye T. P., Johnson L. E., Fong L., Knutson K. L., Disis M. L., and McNeel D. G. (2010) "HLA-A2-restricted T-cell epitopes specific for prostatic acid phosphatase." Cancer Immunol Immunother 59:943-953.

12. Dubovsky J. A., Albertini M. R., and McNeel D. G. (2007) "MAD-CT-2 identified as a novel melanoma cancer-testis antigen using phage immunoblot analysis." J Immunother 30:675-683.

13. Maricque B. B., Eickhoff J. C., and McNeel D. G. (2010) "Antibody responses to prostate-associated antigens in patients with prostatitis and prostate cancer." Prostate:(in press).

14. Smith H. A., Maricque B. B., Eberhardt J., Petersen B., Gulley J. L., Schlom J., and McNeel D. G. (2011) "IgG responses to tissue-associated antigens as biomarkers of immunological treatment efficacy." J Biomed Biotech. 454861.

15. Johnson L. E., Frye T. P., Chinnasamy N., Chinnasamy D., and McNeel D. G. (2007) "Plasmid DNA vaccine encoding prostatic acid phosphatase is effective in eliciting autologous antigen-specific CD8+ T cells." Cancer Immunol Immunother 56:885-895.

16. Johnson L. E., Frye T. P., Arnot A. R., Marquette C., Couture L. A., Gendron-Fitzpatrick A., and McNeel D. G. (2006) "Safety and immunological efficacy of a prostate cancer plasmid DNA vaccine encoding prostatic acid phosphatase (PAP)." Vaccine24:293-303.

17. Zlotocha S., Staab M. J., Horvath D., Straus J., Dobratz J., Oliver K., Wasielewski S., Alberti D., Liu G., Wilding G., Eickhoff J., and McNeel D. G. (2005) "A phase I study of a DNA vaccine targeting prostatic acid phosphatase in patients with stage D0 prostate cancer." Clin Genitourin Cancer 4:215-218.

18. McNeel D. G., Dunphy E. J., Davies J. G., Frye T. P., Johnson L. E., Staab M. J., Horvath D. L., Straus J., Alberti D., Marnocha R., Liu G., Eickhoff J. C., and Wilding G. (2009) "Safety and immunological efficacy of a DNA vaccine encoding prostatic acid phosphatase in patients with stage D0 prostate cancer." J Clin Oncol 27:4047-4054.

19. Becker J. T., Olson B. M., Johnson L. E., Davies J. G., Dunphy E. J., and McNeel D. G. (2010) "DNA vaccine encoding prostatic acid phosphatase (PAP) elicits long-term T-cell responses in patients with recurrent prostate cancer." J Immunother33:639-647.
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