Penn State researchers have successfully 3D bioprinted cancerous breast tumors and treated them in a groundbreaking study to better understand the disease that is one of the leading killers worldwide.

A scientific first, this achievement lays the foundation for precision manufacturing of tumor models. The advancement will allow the future study and development of cancer therapies without the use of “in vivo” -; or “in the animal” -; experimentation.

This will help us understand how human immune cells interact with solid tumors. We have developed a tool that serves as a clinical test platform for the safety and accurate evaluation of experimental therapies. It is also a research platform for immunologists and biologists to understand how tumor grows, how it interacts with human cells, and how it metastasizes and spreads in the body.


Ibrahim Ozbolat, professor of engineering science and mechanics, biomedical engineering and neurosurgery at Penn State and lead author of the study

Ozbolat’s laboratory specializes in 3D printing to create a range of fabrics for human health. Two journal articles about the lab’s work using 3D bioprinting to aid in the study of breast cancer were recently published in Advanced functional materials and Biomanufacturing.

The researchers used a relatively new technique called suction-assisted bioprinting to precisely locate the tumors in three dimensions and create the tissue. The researchers then trained the tissue into a multiscale vascularized breast tumor model with blood vessels, which they found responded to chemotherapy and cellular immunotherapy.

The team first validated the accuracy of their tumor model by treating it with doxorubicin, an anthracycline-based chemotherapy drug commonly used to treat breast cancer. Finding that the bioprinted tumor responded to chemotherapy, the researchers then tested a cell-based immunotherapeutic treatment on the tumor in collaboration with Jackson Laboratory immunologist Dr. Derya Unutmaz.

The researchers used human CAR-T cells that were engineered through gene editing to recognize and fight an aggressive form of breast cancer cells. After 72 hours of circulating the edited CAR-T cells through the tumor, the researchers found that the bioprinted tumor cells had generated a positive immune response and were fighting the cancer cells.

“Our model is made from human cells, but what we’re making is a very simplified version of the human body,” Ozbolat said. “There are many details that exist in the native microenvironment that we are not able to replicate, or even consider replicating. We aim for simplicity within complexity. We want to have a fundamental understanding of how these systems work – and we need the growth process to be streamlined because we don’t have time to wait for tumors to grow at their natural rate.”

Ozbolat explained that despite remarkable advances in cancer treatment, there is a lack of preclinical platforms to study experimental anti-cancer agents. Having to rely on clinical trials to test the efficacy of treatments ultimately limits the successful clinical translation of cancer therapeutics, he said. The development of bioprinted models could open the door to entirely new ways of understanding the tumor microenvironment and the body’s immune response.

“Immunotherapy has already shown to be a promising treatment for hematological malignancies,” Ozbolat said. “Essentially, the patient’s immune cells are removed and genetically modified to be cytotoxic to cancer cells and then reintroduced into the patient’s bloodstream. effective type of circulation does not exist, so we built our model to try to better understand how tumors respond to immunotherapy.”

Ozbolat and her colleagues are now working with tumors taken from real breast cancer patients. Researchers will apply immunotherapy to patient-derived tumors to see how they respond.

“This is an important step in understanding the intricacies of the disease, which is essential if we are to develop novel therapies and targeted cancer therapies,” Ozbolat said.

Other study collaborators are Madhuri Dey, Myoung Hwan Kim, Momoka Nagamine, Ece Karhan, and Nazmiye Celik of Penn State, and Mikail Dogan, Lina Kozhaya, and Derya Unutmaz of the Jackson Laboratory for Genomic Medicine.

Immune cells for research were purchased commercially from an IRB-approved private company, which provides leucopaks from healthy adults in an anonymized form for research purposes. The work was supported by the National Cancer Institute, National Science Foundation, HG Barsumian, MD Memorial Fund and TUBITAK.

Source:

Journal reference:

Dey, M. et al. (2022) CAR-T cell-based chemotherapy and immunotherapeutic screening in a 3D bioprinted vascularized breast tumor model. Advanced functional materials. doi.org/10.1002/adfm.202203966.