Education:
BS 1980 Medical Biology - University of Amsterdam
MS (cum laude) 1983 Medical Biology - University of Amsterdam
PhD (cum laude) 1987 Medicine - University of Amsterdam
Postdoctoral Research Fellowship:
1987-1990 Netherlands Organization for Scientific Research
Started at USC: 2003
Research Topics: Immunology, Virology, Cancer Treatment
Research Description
My research is focussed on developing new and effective therapies for cervical cancer, prostate cancer and melanoma. These cancers express unique tumor-specific or tumor-associated antigens to which my lab directs T cell immune responses via DNA, RNA, protein or peptide based vaccines or by retroviral mediated transfer of T cell receptors. Vaccine components are delivered in their native form, by dendritic cells, by alpha viruses or by chimeric human papillomavirus virus-like-particles. This clinically oriented research is backed up by pre-clinical and basic research in both normal and transgenic animal models and in laboratory studies on patient material. Results from the pre-clinical studies have led to a variety of clinical trials for which I am the immunological coordinator.
Therapeutic vaccinations of cancer patients or cancer bearing animals is hampered by a variety of tumor immune escape mechanisms. My basic science research has recently identified some new mechanisms for such escapes that are induced by the activated ras oncogene and the cell fate determinant notch 1 and is exploring ways to counteract these escape mechanisms by pharmacological and immunotherapeutical means (multimodality treatment). Chances for successful immunotherapy of human cancer will also increase by the identification of new tumor (-associated) genes, antigens and epitopes and by understanding the basic biology of dendritic cells and Langerhans cells and the basic immunology of cancer causing viruses and therefore my lab also focuses on that.
A variety of techniques including advanced cell culture, cellular immunology, molecular biology, immunochemistry and immunohistology is being used in my research. Overall the research in my lab will lead to a fundamental understanding of virus-host interactions, antigen presentation, tumor-immune system interactions and the design of effective immunotherapeutic approaches for the above mentioned cancers and possibly other types of cancer.
Legend to Figure and PowerPoint presentation:
This animated figure (for animation, open the PowerPoint presentation and click on the figure several times) describes the latest knowledge developed in our lab on how high risk human papilloma virus (HPV), the virus linked to several human cancers including cervical cancer, infects a human being and evades immediate recognition by the human immune system, allowing it to multiply itself and infect subsequent sexual partners. The process starts by the virus binding to a colonization receptor CD16 allowing the virus to stick around until a micro-wound allows it to gain access to the basal cell just above the basement membrane. Here the virus starts its lifecycle and while the basal cells differentiate and move upwards the different viral genes of HPV are expressed, finally resulting in the formation of new virus particles that can infect the next sexual partner. In the infection process the virus also interacts with Langerhans cells that change phenotype such that when they migrate to the lymph nodes they are able to switch of the T cell immune response against the virus allowing it more time to finish its replicative cycle.
Selected Publications
Song LL, Peng Y, Yun J, Rizzo P, Chaturvedi V, Weijzen S, Kast WM, Stone PJ, Santos L, Loredo A, Lendahl U, Sonenshein G, Osborne B, Qin JZ, Pannuti A, Nickoloff BJ, Miele L. - Notch-1 associates with IKKalpha and regulates IKK activity in cervical cancer cells. - Oncogene [ 2008 ] Jun 16; . PubMed
Chiriva-Internati M, Cobos E, Da Silva DM, Kast WM. - Sperm fibrous sheath proteins: a potential new class of target antigens for use in human therapeutic cancer vaccines. - Cancer Immun [ 2008 ] Apr 24;8:8 . PubMed
Gray A, Raff AB, Chiriva-Internati M, Chen SY, Kast WM. - A paradigm shift in therapeutic vaccination of cancer patients: the need to apply therapeutic vaccination strategies in the preventive setting. - Immunol Rev [ 2008 ] Apr;222:316-27 . PubMed
Garcia-Hernandez Mde L, Gray A, Hubby B, Klinger OJ, Kast WM. - Prostate stem cell antigen vaccination induces a long-term protective immune response against prostate cancer in the absence of autoimmunity. - Cancer Res [ 2008 ] Feb 1;68(3):861-9 . PubMed
Chiriva-Internati M, Ferrari R, Yu Y, Hamrick C, Gagliano N, Grizzi F, Frezza E, Jenkins MR, Hardwick F, D'Cunha N, Kast WM, Cobos E. - AKAP-4: a novel cancer testis antigen for multiple myeloma. - Br J Haematol [ 2008 ] Feb;140(4):465-8 . PubMed
Le Poole IC, Elmasri WM, Denman CJ, Kroll TM, Bommiasamy H, Lyons Eiben G, Kast WM. - Langerhans cells and dendritic cells are cytotoxic towards HPV16 E6 and E7 expressing target cells. - Cancer Immunol Immunother [ 2008 ] Jun;57(6):789-97 . PubMed
Janetzki S, Panageas KS, Ben-Porat L, Boyer J, Britten CM, Clay TM, Kalos M, Maecker HT, Romero P, Yuan J, Kast WM, Hoos A. - Results and harmonization guidelines from two large-scale international Elispot proficiency panels conducted by the Cancer Vaccine Consortium (CVC/SVI). - Cancer Immunol Immunother [ 2008 ] Mar;57(3):303-15 . PubMed
Wong RM, Scotland RR, Lau RL, Wang C, Korman AJ, Kast WM, Weber JS. - Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. - Int Immunol [ 2007 ] Oct;19(10):1223-34 . PubMed
Roman LD, Wilczynski S, Muderspach LI, Burnett AF, O'Meara A, Brinkman JA, Kast WM, Facio G, Felix JC, Aldana M, Weber JS. - A phase II study of Hsp-7 (SGN-00101) in women with high-grade cervical intraepithelial neoplasia. - Gynecol Oncol [ 2007 ] Sep;106(3):558-66 . PubMed
Daftarian PM, Mansour M, Pohajdak B, Fuentes-Ortega A, Korets-Smith E, Macdonald L, Weir G, Brown RG, Kast WM. - Rejection of large HPV-16 expressing tumors in aged mice by a single immunization of VacciMax encapsulated CTL/T helper peptides. - J Transl Med [ 2007 ] Jun 7;5:26 . PubMed
