Cancer Antigen Discovery Program

Cancer Antigen Identification

LICR features prominently in the field of antigen discovery having cloned the first human tumor antigen, identified a substantial number of all known tumor antigens, and developed many highly successful techniques used for antigen discovery.

Introduction

The first step in developing cancer ‘immunotherapies’, therapies that harness the immune system, is to identify molecules that can be used to immunologically distinguish between cancer and normal cells, i.e. to identify cancer antigens.

Autologous Typing

In the late 1970’s, LICR Director Dr. Lloyd J. Old developed a system known as “autologous” serological typing to identify cancer antigens. The rationale was that antibodies in the serum from a cancer patient might react to antigens on tumor cells from the same patient. To develop a system that was as unambiguous as possible, the team restricted their tests to autologous reactions using cultured tumor cells, lymphocytes (T and B cells of the immune system), and sera from the same patient. To determine specificity, the team also analyzed normal cells, typically fibroblasts, from the same patient. Through autologous typing, the researchers found that a small subset of patients mounted a vigorous immune response to tumor cells but not normal cells. Although the team successfully identified some potential tumor targets, it was clear that most antigens remained undetected.

T cell Epitope Cloning

One member of the New York Branch team, and now an LICR Affiliate, Dr. Alexander Knuth, improved upon this technique by establishing the first cytotoxic (‘killer’) CD8+ T cell-defined autologous system in human melanoma cell lines. Using this system, Dr. Knuth was able to identify a melanoma patient whose CD8+ T cells specifically and rapidly destroyed her own cancer cells in vitro. Dr. Knuth then joined forces with Dr. Thierry Boon and his team at the Brussels Branch of the LICR, and, in a major break-through for the field of cancer immunology, they cloned the first human tumor antigen recognized by CD8+ T cells – MAGE (melanoma antigen).

Serological Typing Techniques

In 1995, the technique of SEREX (serological analysis of recombinant cDNA expression libraries), which is based on autologous typing and is able to rapidly analyze thousands of proteins in a tumor specimen, was developed by LICR Affiliate Dr. Michael Pfreundschuh. Shortly thereafter, LICR launched the ‘International SEREX Program’, a collaborative group that uses SEREX to identify potential cancer antigens. To date, researchers from the International SEREX Program have contributed nearly 2,000 sequences to the Cancer Immunome Database, the largest publicly-available database of cancer antigens, which was constructed, and is maintained, by the LICR Office of Information Technology.

Newer technologies for antigen identification continue to be developed and/or optimized by LICR. SADA (serum antibody detection arrays) was developed by Dr. Matthew Scanlan at the LICR New York Branch, and involves exposing hundreds of antigens immobilized on a tiny membrane surface to sera from a patient, and determining the frequency with which those antigens are reacting with components in the sera. SADA is of particular interest, as this type of screening shows potential for development as a diagnostic and prognostic tool for many cancer types. Finally, RAYS (recombinant antigen expression on yeast surface) is currently being developed by LICR Affiliate Dr. Christoph Renner in collaboration with the team at the LICR New York Branch.

Differential Expression Analyses

Committed to identifying all potential cancer antigens, LICR investigators are using the latest technologies to discover RNA and proteins that are differentially expressed in normal and cancer cells. Using a bioinformatics approach, potential ‘cancer/testis’ (CT) antigens are being discovered by identifying DNA sequences, in human DNA sequence data that are publicly-available and/or derived through LICR’s Cancer Genomics Program, that are commonly found in tumors and testes, but not other normal tissues (Gametogenic Program Induction in Cancer). To date, the LICR has identified over 1300 different DNA sequences that are potentially expressed only in tumors and germline tissues, and these ‘CT antigen-like sequences’ are now being further validated using standard laboratory techniques.

Key Publications