image: On the left, it is the schematic of porous microneedle patch fabrication, CAR T cell loading and implant of CAR T cell within the tumor bed after surgery. On the right, it is the distribution of CAR T cells (red) in the solid tumor with porous microneedle delivery or intratumor injection. Photo credit: Hongjun Li and Zhen Gu. view more
Credit: ©Science China Press
This study is led by Dr. Zhen Gu, professor in the College of Pharmaceutical Sciences at Zhejiang University, and Dr. Gianpietro Dotti in the Department of Microbiology and Immunology at the Univesity of North Carolina at Chapel Hill. Encouraged by its performance in leukemia treatment, CAR T cell therapy holds high anticipation in curing cancers. By contrast, clinical evaluation using CAR T cells for solid tumors are inferior to those for hematological malignancies. The solid tumor hosts a unique microenvironment to hamper the anti-tumor effects of CAR T therapy. Altogether, the dense extracellular matrix, abnormal vasculature, and interstitial fluid pressure knit a physical barrier preventing CAR T from entering the solid tumors. “Breaking the physical barrier is the key point for CAR T therapy to combat solid tumor,” says Zhen Gu.
The researchers developed a porous microneedle that accommodates CAR T cells for in situ application in solid tumor. The team evaluated the mechanical strength of the microneedle and showed that the porous microneedle could be readily inserted into the tumor matrix, while escorting approximately 20,000 CAR T cells per needle tip along with it. “Sufficient mechanical strength and loading capacity are prerequisite for the microneedle-based onsite CAR T cells seeding in solid tumors,” says Hongjun Li, the co-first author of this study and professor in the College of Pharmaceutical Sciences at Zhejiang University.
The team found that the killing and proliferation abilities of the CAR T cells loaded in the porous microneedle are comparable to the medium-cultured cells. “This is important, for the key challenge regarding cell delivery is avoiding disruption of its native functions and activities,” says Zejun Wang, the co-first author of this study and postdoctoral researcher in the Department of Bioengineering at UCLA.
The researchers also investigated the distribution of the CAR T cells in the solid tumor in a xenograft human melanoma mouse model. Comparing with a restricted distribution around the applied region by intratumor injection, CAR T cells delivered via the porous microneedle patch showed a more prominent tumor infiltration outcome, which provides the CAR T with more opportunities to encounter the cancer cells and initiate its activation and killing. “Benefiting from the enhanced tumor infiltration, the amplification of the CAR T cells in melanoma was significantly improved by delivery with the microneedle,” says Gianpietro Dotti.
The researchers also demonstrated the anti-solid tumor activity of the porous microneedle-assisted CAR T cells delivery strategy in a human melanoma model and an orthotopic human pancreatic tumor model. Besides the anti-solid tumor treatment, the microneedle platform for live cell delivery could also be extended in treating other diseases.
###
See the article: Scattered seeding of CAR T cells in solid tumors augments anticancer efficacy
https://doi.org/10.1093/nsr/nwab172
Journal
National Science Review