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CALIFORNIA SCIENTISTS James Binley Todd Braciak Yang D. Dai Joanna Davies Brigitte Dudouet Richard A. Houghten Tony Hugli Valeria Judkowski J. Patrick Kampf Sophia Khaldoyanidi Alan Kleinfeld Prasad Koka Vipin Kumar Eugene G. Levin David Loskutoff Adel Nefzi Ron Ogata Clemencia Pinilla Claudia Raja Gabaglia Roy Riblet Fahu Samad Sally Sarawar Eli Sercarz Ingrid Schraufstatter Darcy Wilson FLORIDA SCIENTISTS Christopher Armishaw Colette Dooley Marc Giulianotti Richard A. Houghten Jose Luis Medina-Franco Karina Martinez Mayorga

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Positions and Honors

• Predoctoral Fellow in Dept. of Biochemistry, Michigan State University, 1984-1985
• Research Assistant in Dept. of Immunology, Scripps Clinic & Research Institute, 1985-1989
• Predoctoral Fellow in Dept. of Pathology, McMaster University, with Dr.. J. Gauldie, 1989-1995
• Postdoctoral Fellow in Dept. of Microbiology & Molecular Genetics, University of California, Los Angeles, with Dr. E. Sercarz, 1996-1997
• Postdoctoral Fellow in Dept. of Immune Regulation, La Jolla Inst. All. & Immunology, 1997-2000
• Research Scientist in Dept. of Immune Regulation, La Jolla Inst. All. & Immunology, 2001-2002
• Assistant Member, Division of Immune Regulation Torrey Pines Institute for Molecular Studies, 2002-Present

Modifying Immune Response for the Treatment of Prostate Cancer Using Recombinant Adenovirus Vectors

Gene therapies designed for stable gene replacement have many inherent problems. In an alternative approach, our group is developing recombinant adenovirus vector therapies for transient gene transfer more suitable to the capabilities of this vector. One method of adenovirus gene therapy involves the use of such vectors to modulate immune response and change the nature of disease outcomes. In this regard, we have developed a recombinant adenovirus vector system designed to transiently and efficiently express therapeutic genes for the treatment of disease. Many of these molecules are cytokines (molecules that act in a similar fashion to hormones but affect cells of the immune system). We are also targeting antigens from foreign pathogens and cancers in vectors for therapeutic and vaccine design. The power of this form of gene therapy resides in the fact that long-term expression is not required in order to modify immune response and transient expression is actually preferred. This application of adenovirus vector technology expands the concept of what has normally been considered ‘gene therapy’, in that genetic material encoding foreign, or allowing over-expression of, ‘self’ immune modifying genes are delivered but expressed transiently to treat the individual.

Our current goal is to develop an effective therapeutic protocol for patients with localized prostate cancer (PC) or metastatic PC using multifaceted approaches in mice. We are focused on several important but poorly studied antigens associated with prostate cancer: one example is prostate stem cell antigen (PSCA). This antigen has the potential advantage as a target for cancer therapy because it is constitutively expressed in the primary tumor and its metastatic lesions. In our work, we are determining how best to induce an effective tumor killing immune response in mouse models of prostate cancer, while maintaining the goal of treating human patients. All of our procedures tested for in the mouse models may be applicable to the treatment of patients.

We are also concentrating efforts to discover the relationship between chronic inflammation and prostate cancer (PC). It would be predicted that just as in melanoma tumors, when successfully treated, display accompanying vitiligo as a sign that the therapy disposed of melanin-containing cells. We likewise suggest that the induction of a Th1 response by immunization with a prostate antigen should be followed by inflammation and determinant spreading. In this process, the induction of a response to a Th1-inducing determinant on a single antigen is followed by the establishment of a localized proinflammatory milieu that leads to enhanced visibility of poorly processed (previously “cryptic”) determinants. Thus, this process increases the ability of the immune system to kill tumor. It is our overall goal in this work to show that the inflammatory process can be recruited to the end of stimulating a therapeutic response

For this work, prostate antigens and cytokine will be delivered in adenovirus vector form. Adenovirus vectors are highly efficient as gene transfer vehicles for the delivery and transient expression of foreign genes in vivo and have been used successfully in the treatment of cancers [1-5, 10]. The first use of an adenovirus vector expressing a cytokine molecule for the purpose of immune modulation was our study in 1993 in a model we developed that we described as a “pseudo-transgenic” animal model [5]. Since the function of the cytokine to be tested was directed in a tissue specific manner in adult animals and expression was transient, this model allowed analysis of in vivo cytokine function under nearly physiologic conditions

The importance of using cytokine delivery in our prostate tumor therapy in conjunction with antigen-targeted modalities is becoming readily apparent. For example, there has been a recent expansion in the scientific literature on the immunosuppressive effects of IL-10 on T cell activation and on its effects on down-regulating MHC expression [6-8]. We have chosen to use the IL-2, IL-6, IL-12 and GM-CSF cytokine vectors to generate and/or enhance a Th1 microenvironment, which correlates to favorable outcomes in clinical situations for other tumors [9].

Key References. 1-10

1. Addison, C. L. et al. Intratumoral injection of an adenovirus expressing interleukin 2 induces regression and immunity in a murine breast cancer model. Proc Natl Acad Sci U S A 92, 8522-8526. (1995).
2. Aruga, A. et al. Type 1 versus type 2 cytokine release by Vbeta T cell subpopulations determines in vivo antitumor reactivity: IL-10 mediates a suppressive role. J Immunol 159, 664-673. (1997).
3. Caruso, M. et al. Adenovirus-mediated interleukin-12 gene therapy for metastatic colon carcinoma. Proc Natl Acad Sci U S A 93, 11302-11306. (1996).
4. Bramson, J. L. et al. Direct intratumoral injection of an adenovirus expressing interleukin- 12 induces regression and long-lasting immunity that is associated with highly localized expression of interleukin-12. Hum Gene Ther 7, 1995-2002. (1996).
5. Braciak, T. A., Mittal, S. K., Graham, F. L., Richards, C. D. & Gauldie, J. Construction of recombinant human type 5 adenoviruses expressing rodent IL-6 genes. An approach to investigate in vivo cytokine function. J Immunol 151, 5145-5153. (1993).
6. Qin, Z., Noffz, G., Mohaupt, M. & Blankenstein, T. Interleukin-10 prevents dendritic cell accumulation and vaccination with granulocyte-macrophage colony-stimulating factor gene-modified tumor cells. J Immunol 159, 770-776. (1997).
7. Yao, M. et al. Interleukin-10 expression and cytotoxic-T-cell response in Epstein-Barr- virus-associated nasopharyngeal carcinoma. Int J Cancer 72, 398-402. (1997).
8. Yue, F. Y. et al. Interleukin-10 is a growth factor for human melanoma cells and down- regulates HLA class-I, HLA class-II and ICAM-1 molecules. Int J Cancer 71, 630-637. (1997).
9. Lowes, M. A., Bishop, G. A., Crotty, K., Barnetson, R. S. & Halliday, G. M. T helper 1 cytokine mRNA is increased in spontaneously regressing primary melanomas. J Invest Dermatol 108, 914-919. (1997).
10. Putzer, B. M. et al. Interleukin 12 and B7-1 costimulatory molecule expressed by an adenovirus vector act synergistically to facilitate tumor regression. Proc Natl Acad Sci U S A 94, 10889-10894. (1997).

Publications

1. Raja-Gabaglia, C., de Durana, Y., Graham, F., Gauldie, J., Sercarz, E., and Braciak, T. Attenuation of the glucocorticoid response during Ad5IL-12 adenovirus vector treatment enhances NK cell-mediated killing of MHC class I-negative LNCaP prostate tumors. Cancer Res. 67(5): 2290-7, 2007.

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2. Gabaglia, C.R., Sercarz, E.E., Diaz-De-Durana, Y., Hitt, M., Graham, F.L., Gauldie, J., Braciak, T.A. Life-long systemic protection in mice vaccinated with L. major and adenovirus IL-12 vector requires active infection, macrophages and intact lymph nodes. Vaccine 23:247-257, 2004.

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3. Braciak, T.A., Pedersen, B., Chin, J., Hsiao, C., Ward, E.S., Maricic, I., Jahng, A., Graham, F.L., Gauldie, J., Sercarz, E.E., Kumar, V. Protection against experimental autoimmune encephalomyelitis generated by a recombinant adenovirus vector expressing the Vβ8.2 TCR is disrupted by coadministration with vectors expressing either IL-4 or -10. J. Immunol. 170:765-774, 2003.

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4. Wilson, S.S., van den Elzen, P., Maverakis, E., Beech, J.T., Braciak, T.A., Kumar, V., Sercarz, E. Residual public repertoires to self. J. Neuroimmunol. 107:233-239, 2000.

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5. Gabaglia, C.R., Pedersen, B., Hitt. M., Burdin, N., Sercarz, E.E., Graham, F.L., Gauldie, J., Braciak, T.A. A single intramuscular injection with an adenovirus-expressing IL-12 protects BALB/c mice against Leishmania major infection, while treatment with an IL-4-expressing vector increases disease susceptibility in B10.D2 mice. J. Immunol. 162:753-760, 1999.

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6. Quinn, A., Gabaglia, C.R., Schneider, S.C., Braciak, T., Sercarz, E. Immune response. In: Encyclopedia of Immunology (2nd ed.)(Delves, P., Ed.), Academic Press, London, 1998.