Research Interests:

In the broadest sense the group is interested in the interaction between human neoplasms and immune system. The understanding of tumor immunobiology is a prerequisite to develop new diagnostic and therapeutic tools in the fight against cancer. We focus on two main areas:

1. The identification and characterisation of new tumor antigens

2. The T cell response against tumor antigens and the development of cancer vaccines

1. The Identification and Characterization of Tumor Antigens

Tumor Antigens

Antigens are molecules that can be recognized by antibodies or T cells of the immune system either in the forms of an intact molecule, or as smaller, processed fragments. Tumor antigens fall into several different categories: Differentiation antigens, mutation and splice variant antigens, overexpressed/amplified antigen, viral antigens and CT antigens. CT antigens are proteins expressed only in normal ‘germline' tissues (testis, placenta, and embryonic and fetal ovary) and in cancer cells. Because germline cells do not express major histocompatibility complex (MHC) molecules, the cells are unable to present antigens on their surface, thus a cancer therapy would not target these normal cells. The SCP-1 antigen, discovered in Homburg by SEREX technique is a CT antigen; it is expressed in testis and in a variety of tumors such as pancreas, breast, liver, colon and lymphoma (Kubuschok 2004, Neumann 2005)

Cancer Associated Expression

Effective cancer vaccines must be able to induce broad, robust, long-lasting immune responses directed toward cancer antigens expressed in human tumors. Thus, once a cancer antigen has been identified, it is characterized to satisfy vaccine requirements based upon tumor-specific expression criteria, and immunogenicity. Cancer antigen expression is evaluated through extensive molecular biological and immunohistochemical (IHC) analyses of various human cancers and their corresponding normal tissues (Kubuschok, Neumann 2004-2006). Restricted tissue expression is important to ensure that a vaccine does not induce the immune system to attack healthy normal tissues that also express the cancer antigen.

2. The T cell Response against Tumor Antigens and Development of Cancer Vaccines

Immunogenicity

Further selection of clinically relevant antigens is based upon the analysis of the immune response against them in cancer patients. Detection of pre-existing or spontaneous immunity provides a basis for determining an antigen's inherent immunogenicity. We developed methodologies for assessing both antibody and T cell antigen-specific immune responses (Immune Monitoring). For example, analyses of spontaneous immunity in patients with tumors expressing the SCP-1 cancer antigen indicate the co-existence of SCP-1-specific antibody, CD8+ T cell and CD4+ T cell responses. The observed ‘integrated' (antibody plus T cell) immune response to SCP-1 underscores this antigen's immunogenicity and significance in the development of defined cancer vaccines (Kubuschok, Neumann 2004-2006).

Characterization of Spontaneous Immunity

Characterization of the spontaneous immune response to defined cancer antigens has led to the identification of specific antigenic peptide ‘epitopes'; short protein sequences that are recognized by antigen-specific CD8+ T and CD4+ T cells (Kubuschok 2006, Neumann.2004, 2005). Knowledge gained from identifying peptide epitope sequences can be applied directly to the characterization of antigen-specific immune responses following immunization with cancer vaccines, and to the further development of peptide-based cancer vaccines.

Vaccine Development

Studies conducted by our group and others indicate that vaccine-induced CD8+ T cells, which can potentially eliminate tumor cells in cancer patients, can be induced using peptide-based vaccines. These peptide-based vaccines use antigenic sequences previously identified as the minimal CD8+ or CD4+ T cells ‘epitopes' (short protein sequences recognized by the T cells) (see above). These are combined with adjuvants or immunostimulatory compounds, such as granulocyte macrophage-colony stimulating factor (GM-CSF), or CpG (a specific nucleotide sequence), that stimulate the immune response to an antigen. Moreover, we evaluated, whether antigen-presenting cells, which were genetically modified to express tumor antigens, are able to elicit tumor-specific T cell responses in cancer patients (Kubuschok, 2000 and 2002)