Ohio State researchers evaluating one of AstraZeneca’s cancer therapy candidates

Biomedical Engineering Associate Professor Aleksander Skardal leads a multidisciplinary team of Ohio State University researchers who have entered into a research collaboration with AstraZeneca to assess the preclinical activity of one of the company’s novel CAR-T cell therapy candidates in targeting four types of cancer.

Chimeric antigen receptor T cells (CAR-T) are engineered immune cells that aim to remove disease-causing or dysfunctional cells while leaving healthy cells unaffected. CAR-T cell therapy has become an effective therapeutic for some cancers, but a crucial component is knowing which target to genetically engineer T cells to recognize.

The Ohio State team will conduct preclinical lab tests on the activity of one of AstraZeneca’s novel CAR-T cell therapy candidates in four distinct solid tumors that may share a common druggable target. Subtypes of these cancers lack reliable research models that accurately represent the disease, Skardal said, which hinders the development of new targeted therapies.

Their work will utilize Skardal’s innovative patient-derived tumor organoid (PTO) technology to assess the CAR-T cell therapy. Made from patient tumor tissue, PTO technology can be a better test platform than animal models that differ from human physiology and cell lines that fail to simulate the complex cellular architecture and heterogeneity found in tumors, Skardal said.

“Human tumor organoid and tumor-on-a-chip platforms cannot replace animal studies, which despite their limitations remain a gold standard,” he explained. “However, human-based in vitro models can provide important insights towards human-specific outcomes that might not be observed in animal models or even 2D human cell cultures, as we have shown in liver, lung, and cardiac models.”

Patient-derived tumor organoids have been deployed in a wide variety of cancer types for chemotherapy screening and even prediction of clinical outcomes in some patients. Skardal and his colleagues have extensive experience generating organoids for numerous tumor types and developed the first patient-derived tumor organoid model of adrenocortical carcinoma.

“Our team is uniquely positioned to address this problem in the field as we have successfully demonstrated the capability to generate viable PTOs from several cancer types that have been long considered difficult to maintain in in vitro settings,” Skardal said. “Moreover, we have been successful in describing approaches to screen immunotherapies such as T cell therapies in PTOs.”

The research team includes co-principal investigators Dr. Priya Dedhia and Dr. Joal Beane, assistant professors of surgical oncology at Ohio State. Dr. Casey Cosgrove, assistant professor of gynecologic oncology, is a co-investigator.

“Our goal is to deploy our PTO platform technology to test the efficacy of a novel CAR-T therapy in a physiologically relevant human-based platform, supplementing AstraZeneca’s internal studies and bolstering their eventual goal to enter human clinical trials,” Skardal said.

Skardal and Dr. Dedhia are co-founders and co-directors of the Ohio State Organoid Technology Program, made up of more than 30 faculty members from across the university who utilize organoid and organ-on-a-chip technologies or complementary technologies. The collaboration has advanced Ohio State’s expertise in this area and contributed to multiple research projects, including a $400,000 National Cancer Institute project to create accurate preclinical research models for the progression of adrenocortical carcinoma, and several awards from the National Institutes of Health, Department of Defense and private foundations.

by Candi Clevenger, College of Engineering Communications, clevenger.87@osu.edu