Recent progress of Wei Lu’s research group in the field of development of adjuvant formulation for cancer immunotherapy
Recently, Professor Wei Lu from School of Pharmacy, Fudan University, has used biomimetic technology to prepare an adjuvant for cancer vaccine. The work has been published entitled “Bacterium-Mimicking Vector with Enhanced Adjuvanticity for Cancer Immunotherapy and Minimized Toxicity” in Advanced Functional Materials.
Immunotherapy represents an emerging cancer therapeutic approach. In recent years, immunotherapy has achieved significantly clinical outcome, bringing new hope for the cure of cancer. The patient's immune system activated by the local injection of cancer vaccines generates specific tumor cell killing effect. Cancer vaccines are mainly composed of tumor specific antigens and immune adjuvants. The key to successful cancer vaccination is to develop immune adjuvants that can induce effective and durable anti-tumor immunity. However, the enhanced adjuvant potency often correlates with the elevated reactogenicity or adverse effects. For example, although complete Freund's adjuvant, mainly composed of heat-inactivated mycobacteria, is the gold standard respecting the adjuvanticity, it is restricted to use in human immunizations because of its serious toxicity. In the meanwhile, some clinical proved adjuvants are safe but significantly less effective than Freund's adjuvant. Therefore, development of adjuvant formulation with effective potency and minimized toxicity remains a challenge, but is of great clinical interest.
By mimicking the structure of the bacteria, the researchers integrated the active adjuvant ingredients from different cell structures in a single setting to orchestrate synergistic anti-tumor immunity. In such design, monophosphoryl lipid A, the detoxified form of the endotoxin lipopolysaccharides from Salmonella minnesota, and mifamurtide, a synthetic liposomal analog of muramyl dipeptide from mycobacteria, were intercalated into the phospholipid bilayer of a liposome to mimic the bacterial cell wall. Recombinant flagellin from Salmonella enterica was tethered to the surface of the liposome to mimic flagellum. DNA nanoparticles containing CpG motifs that were encapsulated into the liposomes to mimic the bacterial nucleoid. The bacterium-mimicking liposomes activated the immune system through multiple signaling pathways, and were more effective than Freund’s adjuvant in treating melanoma in mice with both therapeutic and prophylactic regimens. More importantly, the immune adjuvant combined with photothermal therapy was used as photothermal autovaccine. On one hand, photothermal therapy ablated the tumor cells from the patients. On the other hand, tumor specific antigens released from the dying cells, combined with the immune adjuvants, activated the immune system to eradicate the residual tumor cells so that the radical cure of tumor was achieved. The results demonstrated that the photothermal autovaccine cured 50% of melanoma in mice without recurrence.
The biomimetic liposomes produced slight, transient and reversible irritation after the administration. The adjuvant at the injection site was completely absorbed. In contrast, the paraffin oil in the Freund’s adjuvant was not degraded at the injection site, causing granuloma and resulting in long-term toxicity. The inactivated bacteria in the Freund’s adjuvant inevitably caused acute local irritations. The ingredients derived from the bacteria or their metabolites were not well clarified leading to the inconsistent quality between batches. Also, the potential toxicity was difficult to control. In comparison, the four adjuvant components of the reported biomimetic adjuvant were all synthetic molecules and have been proved to be safe in preclinical or clinical investigations. Liposomes are approved medical injection formulations. The bacterium-mimicking adjuvants are highly effective, absorbable and safe with controllable composition, thus showing a great promise for clinical translation.