Researchers here explain that one of the challenges involved in the development of cancer vaccines lies in finding ways to provoke a sufficiently robust response from the immune system. The larger the number of distinct sensing mechanisms that can be triggered by a vaccine, the more roused the immune system becomes. But cancer vaccines tend to be based on a single antigen that identifies a distinctive cancer cell surface feature and single immune-provoking molecule that works via only one of the many possible immune activation pathways. Thus researchers here build and test a nanoparticle platform that allows for the assembly and delivery of a mix of molecules that interact with multiple immune-provoking pathways, intended to induce the immune system into a greater, more sustained response to a cancer-targeted antigen.
While vaccination has emerged in recent years as a powerful frontier in the development of effective cancer therapies by training adaptive immune cells to recognize and eliminate tumor cells, effective adjuvanticity has remained a hurdle. Vaccines have two essential components: an antigen, which is uniquely expressed on the pathogen (or cancer cell), and an adjuvant, which activates the innate costimulatory signaling critical for priming an adaptive immune response. Historically, infectious disease vaccine design has transitioned from whole-pathogen vaccines to modern-day subunit vaccines to mitigate the risk of infection upon inoculation, but this shift has introduced notable trade-offs in efficacy. Chief among these limitations is that subunit vaccines largely include only single-adjuvant formulations, unlike their whole-pathogen counterparts, which include multiple innate immune agonists (or adjuvants) that together provide robust adjuvanticity.
Here, we use a versatile nanomaterials engineering approach to address this critical gap and report on the development and testing of a dual-adjuvant lipid-based nanoparticle system, termed “super-adjuvant” nanoparticles, that promotes powerful vaccine-specific immune responses when co-delivered with tumor antigen or lysate and directed to lymph nodes as a prophylactic approach. We focus here on the specific attributes of lipid-based nanomaterials, which enable co-encapsulation of hydrophilic and hydrophobic agonists on the same nanoparticle, synthesis within a small ∼30-60-nm-size window for rapid draining to lymph nodes and ready uptake by target dendritic cells, and “stealth” poly ethylene glycol (PEG) surface functionalization for physiological solubility.
We use a neutral lipid matrix to co-encapsulate hydrophilic cyclic-di guanosine monophosphate (cdGMP), an agonist of the STING pathway, and hydrophobic monophosphoryl lipid A (MPLA), an agonist of the Toll-like receptor 4 (TLR4) pathway together on the same nanoparticle for co-delivery to the same target dendritic cell. Previously delivered as a systemic formulation and directed to tumors, we demonstrated that dual-adjuvant nanoparticles promoted interferon (IFN)-β-mediated expansion of tumor antigen-presenting cells, such as dendritic cells, macrophages, and natural killer cells, and harnessed CD8+ T cell-mediated anti-tumor control for clearance.
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