Glioblastoma (GBM), the most common type of primary brain tumor, is characterized by high mortality rate, short lifespan, and poor prognosis with a high tendency of recurrence. Functional therapeutics, including PRMT5 inhibitors, radiosensitizers, and emerging chimeric antigen receptor (CAR)-T immunotherapy, have been developed to treat GBM. However, the existence of physiological blood-brain barrier (BBB) or blood-brain-tumor barrier has impeded the efficient delivery of such promising therapeutics into the brain and limited their therapeutic efficacy.
Xiaoping Bao,
Purdue University
Given the native ability of neutrophils to cross BBB and penetrate the brain parenchyma, here we tested the therapeutic concept that neutrophils could be engineered with synthetic CARs to specifically target GBM and effectively deliver chemo-drugs to brain tumor as a novel dual chemoimmunotherapy for the first time. We genetically engineered human pluripotent stem cells with different chlorotoxin (CLTX) CARs and differentiated them into functional CAR-neutrophils. As compared to CAR-natural killer (NK) cells, systemically administered hPSC-derived CLTX CAR-neutrophils significantly reduced tumor burden in xenograft mouse models and extended their lifespan, suggesting superior abilities of neutrophils in crossing BBB and penetrating GBM xenograft in mice. We also loaded hypoxia-activated prodrug tirapazamine (TPZ) into CAR-neutrophils using silica nanoparticles with rough surfaces (R-SiO2-TPZ) and demonstrated their enhanced antitumor activities in xenograft mouse models, serving as a novel dual chemoimmunotherapy against GBM.
To bypass the expensive ex vivo cell engineering process, we recently engineered neutrophil-targeting exosomes to deliver synthetic modified mRNA (modRNA) into circulating neutrophils and directly produced CAR-neutrophils in vivo for GBM treatment. Our results established that CAR neutrophil engineering may provide an effective strategy for specific targeting of brain tumors and potentially other solid tumors.
Dr. Bao is currently the William K. Luckow Associate Professor at the Davidson School of Chemical Engineering and an active member of Purdue Institute for Cancer Research as well as Purdue Institute for Drug Discovery. His research program at Purdue focuses on stem cell bioengineering and immunoengineering. Dr. Bao earned his B.S. degree from Tsinghua University, China in 2011 and his Ph.D. from University of Wisconsin-Madison in 2016.
Prior to Purdue, Dr. Bao was an American Heart Association (AHA) post-doc fellow at the University of California-Berkeley (2016 to 2018). His research program at Purdue focuses on stem cell bioengineering, immunoengineering, genome editing and drug delivery, and develops innovative cell and gene therapies to treat currently incurable diseases, including brain cancers and disorders. Dr. Bao has published over 60 peer-reviewed papers and 10 pending/issued patents, some of which were licensed to AstraZeneca and Astheneia Bio. His research program is currently funded by American Cancer Society, NIH and NSF. Dr. Bao was recent awardees of American Cancer Society Research Scholar Award, 2025 Purdue College of Engineering (COE) Faculty Excellence Award for Early Career Research, 2023 BMES-CMBE Rising Star Junior Faculty Award, NSF CAREER Award, NIH Stephen Katz Early Stage Investigator Research Project Award, Showalter Research Trust Young Investigator Award, and Purdue Cancer Center Robbers New Investigator Award, etc.