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Gert Riethmüller, P. Kufer, T. Raum, R. Lutterbuese, C. Klein, G. Schlimok*, K. Pantel, R.C. Bargou#, B. Doerken#
University of Munich
Munich, Germany
*Department of Central
Oncology, Augsburg
#Robert Roessle Hospital, MDC, Berlin
Adjuvant Cancer Therapy with Bioengineered Antibodies: A Change of Tools and Targets, Does It Make a Difference?
While active immunization strategies are presently in the limelight of public and scientific interest, the antibody field shows only slow recovery from a long and deep demise following a decade of high expectations. That period of unrestricted optimism began shortly after the introduction of the hybridoma technique, whose potential of generating pure monoclonal antibodies for cancer therapy had become rapidly evident. Subsequently, numerous clinical trials were initiated across the broad range of human tumors. A retrospective analysis of these trials reveals that, according to the rules of classical drug development, only patients with advanced or terminal stages of malignant disease were studied. Despite some remarkable and well-documented anecdotal successes, the overall outcome was bleak.
A comparison between trials on patients with solid tumors and those with lymphoma/leukemia reveals that objective remissions have occurred more frequently in the latter group. The hypothesis was raised that insufficient accessibility of cells in solid parenchyma and genomic instability resulting in antigenic heterogeneity and resistance accounted largely for the failure in solid tumors. A randomized trial on patients with early colorectal cancer treated with antibody after complete resection seems to support it. The recent 7-year survival analysis on 190 patients of this trial confirmed the significant and lasting effect on overall survival (increase of 32 %) and reduction of distant metastasis.
The minimal residual disease concept is now being tested in megatrials on >3000 patients with colon cancer. Also in residual B cell lymphoma, antibody treatment has led to the apparent eradication of malignant B cells, as judged by negative PCR test on bone marrow. The crux of minimal residual disease trials lies in the invisibility of remaining tumor cells that leads to inclusion of patients cured by surgery alone and, in addition, in the absence of an immediate therapeutic readout.
Information on the cellular targets, i.e., on remaining disseminated tumor cells, while critical for the further development of this strategy, is forthcoming only now. Bone marrow appears as a compartment where single epithelial tumor cells can be frequently identified in patients with minimal residual disease. Recent progress made in phenotypic and genotypic characterization of those disseminated cells has led to a deeper understanding of their malignant nature and biology. For a more rational therapy design, the assessment of antigenic heterogeneity displayed by micrometastatic cells can be used to select antibodies that optimally match the heterogeneously expressed antigens. Progress in PCR technology and the use of tumor specific probes will facilitate the introduction of novel surrogate endpoints. As an example, the specific use of RT-PCR is demonstrated for the detection of MAGE gene expression in bone marrow samples obtained from prostate cancer patents that show no other evidence of distant metastasis.
The direct effect on disseminated cells evaluated by quantitative assessment during therapy needs to be validated by clinical follow-up. Single-cell cDNA libraries now being used to analyze gene expression patterns in disseminated micrometastatic cells may yield information on cells that are refractory to immunotherapies. The power of this approach is demonstrated by hybridization of single cell cDNA libraries to arrays of multiple defined genes.
The new focus of antibody therapies on minimal residual disease is complemented by advances in protein engineering. Not only humanization of murine immunoglobulins but also direct selection of completely human antibodies is now already applied for therapeutic use. Thus, a novel human EpCAM (17-lA) antibody was generated from an unbiased human IgD library. Reduced immunogenicity, increased in vivo half-life, as well as improved cooperativity with natural effector mechanisms are strong arguments for new attempts along apparently old and trodden paths. The combination with novel bispecific single-chain antibodies may exploit the T cell cytotoxic potential in a full-house effector cell approach. Whether, in the end, immunotoxins or newer fusion proteins will be superior to intact and finely tuned recombinant human antibodies is difficult to predict. The establishment of valid surrogate markers in minimal residual cancer, however, clearly is critical for a faster and less risky development, not only of antibody-based strategies but for any adjuvant therapy.