A New Paradigm to Prevent and Treat Micrometastases

Abstract Metastsis is the direct cause of the majority of deaths in patients with solid tumors, thus representing a major unmet medical need. In some cancer types, microscopic metastases may have already occurred at the time of diagnosis. Because an established tumor microenvironment mediates therapeutic resistance through a variety of mechanisms, cancer cells are likely most vulnerable during their time in the bloodstream and early in the development of micrometastasis. Thus, effectively targeting those cells requires constant surveillance in order to “catch” them either in the circulation or in their early metastatic niche, before they have re-established a protective microenvironment. Currently FDA-approved systemic therapies for solid tumors are unable to adequate do so as they are intermittent; chemotherapy is given in cycles to allow recovery from toxicity to bone marrow and other organs, and even long-half-life antibodies result in peaks and troughs. Collectively, our available therapies likely fail to provide systemic tumor control of metastases in part because intermittent exposure not only kills only a percentage of cells during each treatment cycle, enabling surviving cells to develop cell-intrinsic drug resistance, but also due to the drug-free windows that enable cancer cells to spread. Our overarching hypothesis is that we can prevent and treat micrometastasis by leveraging gene therapy to provide constant, long-term, systemic immunologic pressure on cancer cells. We will test our hypothesis in models of neuroblastoma, the most common solid tumor in children outside of the brain, and Her2+ breast cancer, both of which have a poor prognosis when metastatic. We have developed an off-the-shelf strategy utilizing a single intravenous dose of recombinant adeno-associated virus (rAAV) to instruct normal cells to secrete bispecific T cell engagers into the bloodstream for long periods of time (rAAVrh74-aGD2-aCD3 and rAAVrh74-aHer2- aCD3), a platform we term “TransJoin.” Our specific aims are to: (1) Test the anti-metastasis efficacy of GD2 and Her2 TransJoins in preclinical models, (2) Test the safety of GD2 and Her2 TransJoins in preclinical models, and (3) Develop controllable expression of GD2 and Her2 and a kill switch. If successful, our data will support clinical translation of rAAVrh74-aGD2-aCD3 for neuroblastoma and rAAVrh74-aHer2-aCD3 for Her2+ breast cancer. Following a human phase I safety study, we envision clinical trials during post-induction therapy in the setting of minimal residual disease, to either prevent and/or treat micrometastases and improve long-term patient survival.