Molecular mechanisms of antibody-mediated immunotherapies

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ABSTRACT Our studies over the past two decades have focused on clarifying the mechanisms by which anti-tumor immunotherapies elicit their therapeutic effects. As a result of our studies, the importance of Fc-FcγR mediated effector pathways for the elimination of tumors has been elucidated, resulting in the optimization of these interactions in second-generation anti-tumor immunotherapeutics with improved clinical activity. One of the therapies developed as part of our previously funded NCI studies is now being tested across three clinical trials with early evidence of promising activity. While strategies improving antibody-based therapeutics through Fc engineering have resulted in more effective anti-tumor antibodies (Abs) with significantly improved survival, the long-term goal of immunotherapy is to develop therapeutic strategies that will elicit memory responses and effectively eliminate recurrences, resulting in improvements in overall survival. This current proposal aims to mechanistically investigate general strategies to accomplish this goal by focusing on 1) inducing tumor vaccination using anti-tumor monoclonal Abs (mAbs), 2) define the mechanisms by which agonistic and antagonistic immunomodulatory mAbs enhance anti-tumor vaccination, and 3) explore how the tumor microenvironment may be manipulated to improve these immunotherapeutic strategies. Our preliminary results have indicated that anti-tumor Abs can elicit long-term cellular memory responses when appropriate Fc-FcγR interactions are integrated into these Abs. Manipulating both the cellular effector responses and the tumor microenvironment through the use of Fc-optimized immunomodulatory Abs can further augment these pathways and result in long-term memory responses.