Dr. Sayers is a Senior Scientist with SAIC Frederick and works in collaboration with the Experimental Therapeutics Section (ETS), of the Laboratory of Experimental Immunology (LEI). Dr. Sayers obtained his Ph.D. in Biochemistry from the University of London and performed postdoctoral studies on purification of autoantigens at the Medical Clinic of the University of T bingen, Germany. He also worked as a lab-leader in the Department of Immunotherapy at the Sandoz Research Institute, Vienna, Austria before coming to the NCI. Dr. Wiltrout is the Head of ETS, LEI.
Biological therapy of cancer has not as yet provided significant therapeutic benefits for the majority of cancer patients. Nonetheless, some beneficial effects of immunotherapy have been seen in melanoma and renal cancer. These are assumed to be due to the activation of cells of the immune system. However, very little is known about how these cells or their products might mediate tumor cell destruction. Studies in our laboratory using several preclinical murine solid tumor models have determined that natural killer (NK) and T cells are critical for successful immunotherapy. These cells can mediate direct lysis of tumor target cells after cell-cell contact. Cytotoxic lymphocytes produce unique proteins such as the pore-forming protein perforin and a family of serine proteases (granzymes) which are thought to be involved in tumor cell lysis. These proteins are stored in intracellular granules that are released upon contact of effector lymphocytes with tumor targets. We have purified three of these granzymes to homogeneity and determined their enzyme specificities using synthetic substrates. Two of these enzymes were unique; therefore, we cloned and sequenced the cDNA for both rat and human versions of these enzymes. The biological role of these enzymes remains unclear. However, recent experiments with gene "knockout" mice for perforin or granzyme B suggest that combinations of these molecules are required to trigger target cell apoptosis. Furthermore, these mice are more susceptible to viral infections implicating cell-mediated cytotoxicity as an important component of anti-viral responses in vivo. Our current studies are concentrated on identifying the molecular events underlying tumor cell death, with a focus on the rapidly developing studies related to mechanism(s) of apoptosis. Several specific proteolytic events are required for apoptosis to proceed, and we are investigating whether the granzymes may mediate some of these events. Furthermore, the expression of several proteins in the apoptotic pathway (e.g. the ICE family of cysteine proteases, the bcl-2/bax family, p53) by tumor cells is being modified using DNA expression vectors or anti-sense constructs, to see how expression of these proteins effects susceptibility of tumor cells to chemotherapy, radiation therapy and immunotherapy in vivo and in vitro. Our overall goal is to better understand the molecular events operating during tumor cell death. This knowledge should be useful in the rational design of agents to trigger these "suicide" pathways in tumor cells. Key Words: Cancer immunotherapy, cytotoxicity, proteases, T lymphocytes.
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Updated: July 1, 1996