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-Fc?R 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. While these strategies 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 that will effectively eliminate recurrences and thus result in long-term 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 in order to augment these immunotherapeutic strategies. Our preliminary results have indicated that anti-tumor Abs can elicit long-term cellular memory responses when appropriate Fc-Fc?R 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 augment these pathways to result in long-term memory responses.
Antibodies have emerged as a significant clinical modality in the treatment of metastatic disease. This proposal will study how tumor-specific antibodies elicit immune responses against tumor cells that can lead to long-term protection, will clarify the mechanisms of action of agonistic and antagonistic immunomodulatory antibodies that target the immune system to activate immune responses against tumors, and explore how the tumor microenvironment may be manipulated in order to augment these immunotherapeutic strategies. These studies will provide the required information for improving the efficacy and potency of antibody-based therapeutic agents to more effectively fight highly aggressive and currently incurable cancers that are refractory to most standard therapies.
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