By Deborah Borfitz
September 27, 2021 | Rensselaer Polytechnic Institute and South Korean biotech Medical & Bio Decision Company Ltd. (MBD) are working on turning a biochip into a personalized immunotherapy platform for rapidly screening a wide range of treatment cocktails for individual cancer patients. The platform would be ideally suited for very small tumor biopsy samples, including those extracted by fine needle aspiration, to see how well different combinations of chemotherapeutic drugs and monoclonal antibodies work in concert with natural killer (NK) cells in the tumor microenvironment, according to Jonathan Dordick, professor of chemical and biological engineering at Rensselaer.
In a demonstration of the small microphysiological system in action, recently published in Communications Biology (DOI: 10.1038/s42003-021-02417-2), the surprise finding was that the monoclonal antibody trastuzumab (Herceptin) and NK cells together boost the effectiveness of the commonly used but highly toxic chemotherapy drug paclitaxel (Taxol) against cancer cell lines in a three-dimensional (3D) aggregate of cells, so-called tumor spheroids, he says. On its own, Taxol had little effect on two types of breast cancer cells as well as pancreatic cancer cells when in a spheroid culture.
Traditional, two-dimensional (2D) cell culture models are unable to precisely select a clinically active drug, says Dordick, which is why 3D culture systems are emerging that better simulate what happens in vivo. These include tumor spheroids, which on the inside are “almost dormant” due to a lack of oxygen and nutrients.
The new high-throughput model would allow clinicians to perform many screenings of different compounds and concentrations simultaneously to find the combination with the best selectivity for and activity against cancer cells within a day or two. It is the size of a microscope slide, making it space-conserving while still easy to handle, Dordick shares.
Merging two biochips, sandwich style, the platform contains 330 micropillars and 330 microwells that snap together in a modular fashion, he explains. The micropillars can house either 2D or 3D cultures that slip upside down into the microwell chip containing any number of anticancer compounds, antibodies, and NK cells.
Automated microarray spotting systems are being developed, but the screening process is simple even when done manually, continues Dordick. MBD has developed an easy-to-use, commercially available spotter along with the micropillar and microwell culture chips, he notes.
Decision Support Tool
The development team has been working with 3D cell cultures on a microscale for years now, Dordick says, and already had a biochip being used to rapidly determine when molecules were potentially toxic. Enlarging the platform’s role to include drug screening, factoring in the human innate immune system, was a deliberate move toward precision medicine.
“Cancer therapy right now is about as close to precision medicine as there is,” says Dordick, noting that tumor genotyping is now standard practice in oncology. But the biochip could move personalization from populations to individuals, including the impact of a therapeutic regimen on cells (cancerous and non-cancerous) in their body.
Research to date suggests the possibility of giving cancer patients lower concentrations of highly toxic chemotherapy drugs, Dordick says, and the same might hold true for monoclonal antibodies.
The biochip is envisioned as a clinical decision support tool that would need to be formally approved by the U.S. Food and Drug Administration. But first, he says, the platform needs to be tested on more types of tumor cells and its sensitivity and specificity as a diagnostic tool painstakingly measured in clinical trials.
While the pairing of Taxol and Herceptin is already happening clinically, NK cells would have to be administered via cell therapy much like the CAR-T process, Dordick notes. As such, “much more evidence” is needed to ensure the therapeutic approach is safe for patients.
Biopsy samples for clinical studies will be available from medical centers in South Korea with whom MBD is directly linked as well as collaborations now being forged with the Luxembourg Institute of Health in Luxembourg and the Icahn School of Medicine at Mount Sinai in New York City, Dordick says.
BoSung Ku, formerly one of Dordick’s Ph.D. students, started MBD and serves as the CEO. The company has been generating and selling biochips and related hardware for the past few years.
Rensselaer and MBD jointly own pending patents for the 3D tumor spheroid micropillar array for antibody dependent cell-mediated cytotoxicity assays, says Dordick.
The number of pillars and wells in the plastic biochip may ultimately climb a bit—“we’ve already done 532 and it works fine”—and won’t be difficult for MBD to manufacture at any configuration or scale, Dordick says. The idea is to hit a number low enough to accommodate a sufficiently large number of cancer cells and high enough to be considered a high-throughput technique.
Importantly, the platform would allow doctors to take multiple different samples from a given tumor to account for its heterogeneity despite the tiny size of individual biopsy samples, he says. This should reduce the risk of false-negative results when sampling small amounts of tissue.
Often, non-surgical treatment begins before a tumor is cut out of patients based on what can be gleaned from a minimally invasive fine needle aspiration or core needle biopsy. “Our platform is ideally suited for that because it is so small and doesn’t need many cells [to produce a signal].”