Optimization of Prolonged Ex Vivo Animation of Human Tumor-bearing Liver

The ability to recapitulate the complexities of solid human tumors for the purposes of drug development and testing has been, and remains, a major obstacle in the progress of cancer care. Despite great efforts expended on pre-clinical optimization using existing models, most drugs simply fail to demonstrate efficacy when subjected to phase III clinical trial scrutiny. This is evidenced by the fact that 95% of oncology drugs fail to progress from phase I trials to FDA approval. Our interpretation is that the currently available model systems lack the appropriate clinical predictive power. The reasons for the inadequacies of these model systems, which are largely based upon cell lines, mouse models, or patient-derived xenografts, are myriad, but are almost certainly related to the absence of the human stromal component and its intricate relationship with tumor cells. Additionally, the human immune system and its complex interaction with the tumor is not recreated in any existing preclinical models. Modeling the multi-faceted interactions between human cancer cells and the multitude of various stromal components, including activated fibroblasts, immune cell infiltrate, and the abnormal vasculature is, at present, an impossibility. However, the potential exists for a new model of human malignancy using intact tumors removed from patients. Since 2005, ex vivo perfusion has been used to bridge organs from donation to transplantation. The bounds of these perfusion systems have recently been optimized and used to maintain whole human liver viable for one week.

Using existing treatment protocols at the NIH Clinical Center, we have already begun optimizing the system for use on tumor-bearing liver segments that are removed as part of standard treatment algorithms.  As a hepatobiliary oncologic surgeon, my lab has unparalleled access to tumor-bearing human tissue directly as it is removed from a patient’s body and transferred to the perfusion machine. Tumor-bearing human liver segments maintained ex-vivo recapitulate the complexities of a human tumor, supported by native stroma with preserved architectural relationships, surrounded by normal tissue under near-physiologic conditions because it is. Consequently, real-time tumor responses can be measured by serial biopsies during various drug delivery interventions which would allow development of rational novel drug combinations and/or use of sequential drugs.  Moreover, the perfusate is amenable to continuous sampling such that biomarker discovery will be greatly facilitated, with correlations actually relatable to real-time tumor obtained by biopsy. Additionally, drug metabolism and tumor penetration can be easily measured, which has been nearly impossible in patients. Finally, immunomodulatory agents will be directly assessed, which may provide a much-needed avenue of advancement our understanding about why some patients respond while others do not. We can envision a fundamental alteration in drug development such that efficacy is evaluated first, rather than last, with subsequent efforts focused on delivery techniques and minimization of toxicity.

A summer student will work with our multi-disciplinary team to further optimize the perfusion machines with

1. implementation of an in-line dialysis circuit,
2. placement of additional sensors for increased real-time hemodynamic and biochemical analysis,
3. design of cannulas to work with current pressure sensors and accommodate varying caliber of inflow vessels,
4. configuration of automated  infusion systems to simulate the homeostatic control of glucose delivery and
5. design software applications to assimilate the data. The BESIP student working in this area should have a background and interest in mechanical engineering, human physiology, and biochemistry. Through working closely with the interdisciplinary team, the BESIP intern will gain valuable hands-on experience with multiple procedures and technologies and can expect to gain experience in various areas of cancer and biomedical research.

To discuss more specifics of this summer project, please feel free to contact Dr. Jonathan Hernandez.