Journal of Clinical and Cellular Immunology
Open Access
ISSN: 2155-9899
ISSN: 2155-9899
Holbrook E Kohrt
Stanford University, USA
Posters & Accepted Abstracts: J Clin Cell Immunol
Tumor targeting monoclonal antibody (mAb) therapy has changed the natural history of patients with B cell lymphomas, breast cancer and colorectal and head and neck cancers, respectively. Despite their promise, response rates are suboptimal at less than 25%, highlighting the need to enhance mAb activity. Natural killer (NK) cells are important effector cells mediating antibody dependent cell mediated cytotoxicity (ADCC), a primary antitumor mechanism of action of mAbs. Approaches that specifically augment NK cell function can thus complement and enhance mAb therapy. The co stimulatory molecule CD137 (4-1BB), a member of the tumor necrosis factor receptor super family is expressed following NK and memory T cell activation. We found that isolated human NK cells substantially increased expression of CD137 when exposed to tumor cells bound by their tumor targeting mAb, including rituximab coated CD20 expressing lymphoma, trastuzumab coated, HER2 expressing breast cancer and cetuximab coated, EGFR expressing head and neck and colorectal cancer cell lines. Furthermore, activation of CD137 with an agonistic mAb (anti CD137) enhanced NK cell degranulation and cytotoxicity. In multiple murine syngeneic and xenograft models, combined tumor targeting mAb and anti CD137 mAb administration was synergistic and led to complete tumor resolution and prolonged survival, which was dependent on the presence of NK cells. In patients receiving mAb therapy, the level of CD137 on circulating NK cells increased post mAb infusions. This sequential antibody strategy, combining a tumor targeting mAb with anti CD137 to activate the host innate immune system, may improve the therapeutic effects of tumor targeting mAbs and is now being investigated in clinical trials.