The promise of 4-1BB (CD137)-mediated immunomodulation and the immunotherapy of cancer.

The continuing efforts in biomedical research to develop new therapies for cancer are entering an exciting new phase. Research over the past two to three decades has yielded a much more detailed understanding of the complexities of the cellular and molecular interactions involved in the generation and regulation of immune responses. We are also gaining insights into the mechanisms by which tumors evade or escape immune recognition and by which they become resistant to various existing chemotherapeutic and/or radiotherapeutic strategies. A clear conclusion that can be drawn from these studies is that effective treatments of cancer will become much more multifaceted and will include immunotherapeutic approaches. The identification and molecular cloning of genes encoding the receptors and ligands that play crucial roles in the generation and regulation of immune responses provides exciting new opportunities to induce and enhance effective endogenous immune responses to cancer. In this regard, the genes that comprise the tumor necrosis factor and tumor necrosis factor receptor superfamilies show particular promise. One receptor:ligand pair (4-1BB/CD137 and 4-1BBL/CD137L) is emerging as a target with important potential in its ability to enhance the generation of effective tumor-specific immune responses in situ. The results of the studies cited in this review highlight the potentials of 4-1BB-mediated immunotherapy.