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Abstract: Despite the enormous therapeutic potential of immune checkpoint blockade (ICB), it benefits only a small subset of patients. Some chemotherapeutics can switch 'immune-cold' tumours to 'immune-hot' to synergize with ICB. However, safe and universal therapeutic platforms implementing such immune effects remain scarce. We demonstrate that sphingomyelin-derived camptothecin nanovesicles (camptothesomes) elicit potent granzyme-B- and perforin-mediated cytotoxic T lymphocyte (CTL) responses, potentiating PD-L1/PD-1 co-blockade to eradicate subcutaneous MC38 adenocarcinoma with developed memory immunity. In addition, camptothesomes improve the pharmacokinetics and lactone stability of camptothecin, avoid systemic toxicities, penetrate deeply into the tumour and outperform the antitumour efficacy of Onivyde. Camptothesome co-load the indoleamine 2,3-dioxygenase inhibitor indoximod into its interior using the lipid-bilayer-crossing capability of the immunogenic cell death inducer doxorubicin, eliminating clinically relevant advanced orthotopic CT26-Luc tumours and late-stage B16-F10-Luc2 melanoma, and achieving complete metastasis remission when combined with ICB and folate targeting. The sphingomyelin-derived nanotherapeutic platform and doxorubicin-enabled transmembrane transporting technology are generalizable to various therapeutics, paving the way for transformation of the cancer immunochemotherapy paradigm.
Bio-sketch: Jianqin Lu, BPharm, PhD, is an Assistant Professor of Pharmaceutical Sciences in Pharmaceutics and Pharmacokinetics at R. Ken Coit College of Pharmacy (RKCCOP). The Lu research laboratory strives to develop innovative, safe, and efficacious therapeutics at the interface of drug delivery, synthetic chemistry, pharmaceutics, nanotechnology, biomaterials, and tumor immunology to address the pressing unmet needs in current cancer and other diseases therapy and prevention, particularly in the emerging field of combination immunochemotherapy. Recipient of the Norman R. and Priscilla A. Farnsworth Award at the University of Pittsburgh, the NIH/NCI Ruth L. Kirschstein Institutional National Research Service Award (T32) in Tumor Immunology, and the 2022 American Association of Colleges of Pharmacy (AACP) Pharmaceutics Research Award, Dr. Lu serves as the Director for Pharmaceutics and Pharmacokinetics Track at RKCCOP, the Secretary of Knowledge Management in AACP Pharmaceutics Section, and the Associate Editor for Frontiers in Medical Technology: Nano-Based Drug Delivery.
LOCATION
Harvill Room 305
PRESENTER
Dr. Jianqin Lu Professor, Department of Chemistry and Biochemistry, The University of Arizona