PD-L1 immune checkpoint blockade has become an important treatment approach for lung adenocarcinoma, but the response rate is low. Combination CD47/PD-L1 blockade can increase response rates, but immune-related adverse events (IRAEs) brought on by off-target effects have a significant impact on clinical efficacy. Thus, decreasing IRAEs while increasing the response rate of immunotherapy is a critical scientific topic for enhancing immunotherapy's efficacy.
By directing the drug supply to a specific area of the body, or "target" rather than spreading it out, the drug's effects can be maximized. The shortcomings of regular drug delivery are addressed by the method, which uses carrier-mediated drug delivery. These vehicles transport drugs to areas of the body that contain only sick tissue, limiting their contact with healthy cells. The purpose of a targeted delivery system is to prolong, localize, and target the diseased tissue with a protected drug.
On May 3, 2023, Professor Zou Chang's team from the First Affiliated Hospital of Southern University of Science and Technology and the Microfluidics-Biomaterials Laboratory of the Department of Biomedical Engineering collaborated to publish online in the journal Advanced Science a research paper entitled "Microfluidics-enabled nano-vesicle delivers CD47/PD-L1 antibodies to enhance anti-tumor immunity and reduce immunotoxicity in lung adenocarcinoma", which proposes a microfluidics-enabled polymeric nano-vesicle for delivery of CD47/PD-L1 antibodies for tumor acid response in solid tumors. PD-L1 antibody for tumor acid response-activated immunotherapy, and verified in an animal model that it can reduce IRAEs such as anemia and tissue inflammation, promote TAM polarization to M1 and enhance T cell anti-tumor function, and significantly improve dual checkpoint blockade immunotherapy in lung adenocarcinoma.
Researchers made tumor acid-responsive nanovesicles to protect the delivery of CD47/PD-L1 antibodies to tumors and release them with precision using microfluidics. This was done to reduce the non-specific activation of immune checkpoint antibodies in normal tissues and improve their focal enrichment efficiency.
A one-step microfluidic method without the involvement of organic solvents induced the self-assembly of pH-hypersensitive polymers to form nanovesicles efficiently encapsulating CD47/PD-L1 antibodies. The nanovesicles can effectively respond to the extracellular acidic environment of tumors by releasing highly viable antibodies and activating tumor cell phagocytosis by bone marrow-derived macrophages.
In Lewis lung cancer mice, nanovesicles significantly increased the accumulation of CD47/PD-L1 antibodies in tumors to 50% compared to the approximately 20% efficiency of intratumoral delivery of free antibodies. Compared to only 40% partial remission with high-dose free antibody combination treatment, the nanovesicles delivered 40% partial remission and 60% complete remission of tumors in the high-dose antibody treatment group and effectively prolonged the survival of mice by more than 60 days.
Flow analysis showed that nanovesicular delivery of CD47/PD-L1 antibody promoted remodeling of tumor-associated macrophages to an anti-tumor state and increased infiltration of dendritic cells and cytotoxic T lymphocytes. In addition, in vivo experiments showed that the nanovesicular delivery strategy caused fewer IRAEs such as anemia, pneumonia, hepatitis, and small intestinal inflammation.
Overall, the team developed a dual immune checkpoint blockade therapy targeting the acidic tumor microenvironment to activate CD47/PD-L1, achieving reduced toxicity and increased efficacy of CD47/PD-L1 antibodies for the treatment of lung cancer, which is expected to provide a new strategy for precision therapy.