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 leukaemia treatment, CAR T cell therapy holds high anticipation in curing cancers.
By contrast, clinical evaluation using CAR T cells for solid tumours are inferior to those for haematological malignancies. The solid tumour hosts a unique microenvironment to hamper the anti-tumour 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 tumours. “Breaking the physical barrier is the key point for CAR T therapy to combat solid tumors,” says Zhen Gu.
The researchers developed a porous microneedle that accommodates CAR T cells for in situ application in solid tumours. The team evaluated the mechanical strength of the microneedle and showed that the porous microneedle could be readily inserted into the tumour 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 tumours,” 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 tumour in a xenograft human melanoma mouse model. Comparing with a restricted distribution around the applied region by intratumour injection, CAR T cells delivered via the porous microneedle patch showed a more prominent tumour 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 tumour 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 tumour activity of the porous microneedle-assisted CAR T cells delivery strategy in a human melanoma model and an orthotopic human pancreatic tumour model. Besides the anti-solid tumour treatment, the microneedle platform for live cell delivery could also be extended in treating other diseases.
Source: Science China Press
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