There have been a number of significant advances in biological therapies for malignant disease, and several have gone to the clinical trial stage. Here we combine two well-developed biotherapies to maximize delivery, efficacy and safety and evaluate this new combination therapy using molecular imaging. Using an immune cell therapy based on cytokine induced killer (CIK) cells, we have demonstrated efficacy in clinical trials, and revealed, in preclinical trials, that these cells traffic to tumor sites and destroy cells from a variety of cancer types. The tempo of CIK cell trafficking to the tumor in these models suggested that in addition to their tumoricidal activity, they might be useful as a delivery vehicle for oncolytic viruses to enhance virotherapy. Here we propose a combination biotherapy, where the tumoricidal CIK cells are used to deliver replication competent, but modified, oncolytic vaccinia viruses to tumor targets. The modifications in the viruses have disabled them such that they are only capable of an effective infection cycle in tumor cells. Several of these vaccinia strains will be entering clinical trials within the next 3-9 months. Since immunotherapy is limited by the need for repeated cell infusions to achieve sufficient tumor cell killing, and the greatest problem for virotherapy is achieving successful systemic delivery of the virus to the tumor, the combination therapy is complementary and addresses the limitations of each individual therapy. We hypothesize that the infection of CIK cells with vaccinia virus immediately prior to their use in a tumor-bearing host will enable the CIK cells to act as a carrier vehicle, delivering an amplified payload of virus directly to the tumor. Preliminary results indicate that vaccinia undergoes an uncharacteristic replication cycle in CIK cells, releasing virus at the time these cells reach their tumor target, and that this tempo of replication can be utilized to deliver virotherapy to tumors in living subjects. The objective of this project therefore is to use advanced imaging approaches to refine this combination therapy in preclinical models and use this data to design and implement a Phase I clinical trial. This will be accomplished through three specific aims. First, we will characterize vaccinia-CIK cell interactions in culture to optimize the timing of infection of the effector cells and delivery of combined therapies. Second we will characterize immune cell trafficking patterns and viral infection in murine cancer models using imaging. Lastly, we will test the optimized conditions for this dual biotherapy in a limited clinical trial using PET imaging as an outcome measure. Imaging can greatly enhance the development of novel therapies and here we will optimize a novel combination of biotherapies using advanced molecular imaging.
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