Abstract SY24-01: Use of imaging to guide the development of immune cell therapies
Authors: Contag Christopher H. 
Published: August 2012

Abstract
Advances in in vivo imaging have enabled the study of cellular and molecular biology in living animals models of human disease. When integrated with thorough studies in cell culture and directed ex vivo analyses, these tools can reveal the nuances of cellular mechanisms and the subtlety of therapeutic responses. This is leading to the identification and interrogation of molecular targets at a level that was not previously possible, and is refining and accelerating the study of novel therapeutic strategies directed at these targets. The impact of molecular imaging has been most dramatic in preclinical studies of animal models and is moving into clinical studies. With these tools we have a unique opportunity to ask, and answer, hard questions about disease processes and novel therapies in the context of living tissues. By preserving the tissue structure and cellular function in these studies we can gain more information that is more relevant to the disease processes. The advances in stem cell biology and transgenic sciences are creating animal models that are more relevant to human disease and response to therapy, and imaging is accelerating the study of these more predictive models. Molecular imaging is leading to new insights, and enabling new approaches in the emerging fields of stem cell therapy, nanotechnology and regenerative medicine. This is leading to dramatic changes in the way we screen and develop new drugs. It is likely that these visible animal models of human biology and disease comprise one of the most important contributions of molecular imaging to human health as they serve to accelerate and refine the analyses of mammalian biology and offer a rapid readout for the development of new therapies. Using imaging we have developed a combination of two well-developed biotherapies that together maximize delivery, and improve efficacy in preclinical models of ovarian cancer. The dual biotherapy is comprised of immunotherapy with cytokine induced killer (CIK) cells, and oncolytic virotherapy with an attenuated vaccinia virus. These two therapies have a proven safety record with decades of clinical evaluation of each individual biotherapy, but alone the therapies lack efficacy. The limitations of each therapy are well understood and explain the lack of efficacy. In considering these limitations we proposed and tested the combination therapy and demonstrated a complementarity that overcomes the limitations of each individual therapy and creates a therapeutic synergy that is highly efficacious in preclinical studies. Transporting cytotoxic agents to tumor targets has been the goal of cell-mediated delivery, however, immune cells can also i) produce their own tumoricidal effect, ii) conceal a payload from an immune response, iii) amplify a selective agent at the target site and iv) facilitate an antitumor immune response. Integrating the biology of a cellular delivery vehicle with that of the therapeutic payload, vaccinia virus, leads to enhanced antitumor effects. Both of the agents display broad tumor-targeting potential and possess unique tumor killing mechanisms, together the therapies are able to recognize and destroy a far greater number and diversity of malignant cells within the heterogeneous tumor than either agent alone. Effective cancer therapy will require recognition and elimination of the root of the disease, the cancer stem cell, and this combination has this potential. The tumor-selectivity of oncolytic viruses is due to modifications that take advantage of the unique biology of the cancer cell, and similar modifications for integration into the delivery vehicle increases the safety and improves therapeutic outcome. In this dose escalation trail the cell numbers will be fixed and the dose of virus increased, and we will use imaging methods as rapid measures of treatment response to asses efficacy and guide future development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY24-01. doi:1538-7445.AM2012-SY24-01