Dosing of drugs ranging from cancer chemotherapeutics to anti-microbials to thrombolytics is limited by systemic toxic side effects. We propose to develop a new class of image-guided temporarily deployable, endovascular catheter- based medical devices that selectively remove specific drugs or other diagnostic or therapeutic agents from the blood stream in order to reduce systemic toxicities. The proposed ChemoFilters incorporate specialized membranes that bind target drugs in situ through a variety of mechanisms. During the clinically standard interventional radiology (IR) approach of x-ray fluoroscopically guided intraarterial chemotherapy (IAC) infusion to a target organ (e.g., a solid organ containing a tumor), excess drug that is not trapped in the target organ passes through to the veins draining the organ and then is circulated to the rest of the body, causing toxicities in distant locations. By temporarily deploying a ChemoFilter in the vein(s) draining the organ undergoing IAC, we seek to bind excess drug before it can escape to cause systemic toxicity. The ChemoFilter would then be removed in the IR suite shortly after the IAC procedure, thus removing excess drug from the patient. Although paired intraaterial infusion and venous filtration can theoretically be used for any drug that has its site of therapeutic action in one location and its site of dose-limiting toxicity in another location, the most compelling application for this technology is increasing efficacy and safety of locoregional cancer chemotherapy. Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Image-guided transarterial chemoembolization (TACE), a form of IAC, is performed in IR and is a standard of care for unresectable HCC. TACE cost- effectively increases survival in this population. Doxorubicin (Dox) is a low-cost, highly effective, chemotherapeutic agent frequently used in IAC. Dox use is limited by systemic toxicities, most importantly irreversible cardiac failure. Dox follows a therapeutic linear dose-response model, in which increasing dose linearly increases tumor cell kill, providing motivation for higher-dose Dox therapy. Established agents like Dox and cisplatinum (with known dose-limiting toxicities that are spatially removed from their site of action during selective organ IAC) and new agents like nanoparticles (with uncertain toxicities) are the most compelling first candidates for clinical translation of endovascular chemofiltration. Prototype ChemoFilter devices with specialized ionic or DNA oligonucleotide coated membranes will be modeled, built, validated in vitro for efficacy, and tested in vivo for efficacy and safety. Experienced teams from UCSF, UC Berkeley, Caltech, and ChemoFilter will undertake the following specific aims: (SA1) determine optimal geometry and chemistry for endovascular filtration devices, (SA2) validate optimized filter designs in vitro for capacity to capture drugs or therapeutic particles, (SA3) evaluate optimized filter designs in vivo for safety and capacity to capture drugs or therapeutic particles, and (SA4) test preclinical efficacy of optimized filter in vivo in a pig model of hepatic chemotherapy infusion. Achievement of these aims will create a family of minimally invasive medical devices that could markedly increase the efficacy of locoregional intraarterial chemotherapy by lowering systemic drug concentrations and reducing systemic toxicities, thus permitting dose escalation in any given IAC procedure and consequently better local tumor control in fewer IAC sessions.
We propose a paradigm shift in cancer therapy: ChemoFilter, an endovascular catheter-based medical device that will be inserted under image guidance into the veins of the body to directly filter specific chemotherapy drugs out of the blood stream after these drugs have had their effect on a tumor but before they have caused systemic toxic effects. ChemoFilter would help patients fight cancer by minimizing drug toxicity, allowing for high-dose therapy to better treat their disease and improve survival. Although patients suffering from liver cancer, the third leading cause of cancer death worldwide, and the fastest growing fatal cancer in the U.S., would be the first to benefit from this device, the ChemoFilter approach can be applied to drugs and agents treating many types of cancers and non-neoplastic conditions.
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