Monday article #27: Delivering immunotherapy with implantable and injectable biomaterials
Though current immunotherapy showed promising results in treating cancer, there simply exist limitations such as serious off-site effects due to the required high dose injections or infusions. The scope and efficacy of traditional immunotherapies are therefore limited, highlighting the need for alternative treatment strategies. The emerging interest in biomaterials brought about a new advancement in immunotherapy, that is the synergic effects of biomaterials with various adjuvants and immunotherapies could be the solution to these existing limitations.
What is a biomaterial?
Macroscale biomaterial is known to be any biocompatible carrier material with a bulk size of 1mm3 and more, which offers spatial and temporal control over loaded agents. This regulates the release of such agents and their presentation to the surrounding biological environment. Biomaterials can be produced from a wide range of natural or synthetic components, each with its special chemical functionalities. Materials including alginate, hyaluronic acid, collagen, nucleic acids and more, can then be developed into a bulk implantable or injectable system.
Poly (lactide-co-glycolide) acid, also known as PLG or PLGA, is the widely used FDA-approved polymer for biomaterial scaffolds, owing to its biodegradability and biocompatibility. This means PLGA can be degraded into the biocompatible lactic and glycolytic acid simply by hydrolysis. Nonetheless, it allows flexibility in designing devices as PLGA can be easily customised and tuned. Materials composed of PLGA are typically strong and stiff, relatively to others. They also form large pores that are useful for bulk loading of payloads including drugs, proteins and cells. PLGA is also commonly used to encapsulate payloads into nanoparticles for better delivery properties.
Alginate, which is the salt when alginic acid is mixed with metals such as calcium or sodium, is another widely used, FDA-approved biomaterial for hydrogels. It is known for its low cost for large-scale manufacture, its low immunogenicity, and its inherently ionic chemical functionality and hydrophilicity. Alginate discards the need for additional crosslinking as its carboxylic acid moieties in the sugar subunits easily allow in-solution electrostatic crosslinking with multiple cations, forming useful macroscale biomaterial. It is found in numerous biomedical applications such as wound healing, drug delivery and tissue engineering, as its hydrogel form retains high structural similarity to our extracellular matrix.
Implantable and Injectable Biomaterial
Implantable porous scaffolds are biomaterials that can be functionalised or preloaded with various chemical agents, biological factors, or cells prior to physical insertion into a living host. A minor surgical procedure is carried out to insert the implant that normally has a consistent size of a small tablet or pill, into a subcutaneous or resected tissue space. From this implanted porous scaffold, the preloaded payload can then be released in a controlled manner, very often to recruit immune cells to the site for further cell programming. For instance, in a 2017 study by Stephan lab, alginate scaffolds are used to highlight their capability to co-deliver programmed CAR T cells and cyclic-dinucleotide (CDN) STING agonist danger signals to treat fully established solid tumours, instead of tumour resection beds with approximately 1% residual tumour tissue. The effectiveness of the implant was further reinforced for the combined release of CAR T cells and STING agonist from the implant successfully eradicated tumours in 4 out of 10 of the treated mice. This is accompanied by an extension of survival days by 37 days, which is 4.6 fold higher than the intratumoral co-injections of CAR T cells and STING agonists. This study concluded that alginate scaffold significantly enhanced the efficacy of CAR T cell treatment when intravenous injections failed to demonstrate so. It also showed the significance of STING agonists to complete tumour eradication as the T-cell-loaded implant without CDN failed to do so despite the doubled survival rate. However, the downside of an implantable system is that it requires invasive surgical procedures to place the implant in a tumour resection bed or near a solid tumour, meaning that the areas that can be accessed by the implant are limited. Further, the implant must remain in its position for a significant amount of time, which is very likely to compromise our normal organ function.
Image from: https://www.sciencedirect.com/science/article/abs/pii/S1742706119301205
This is where injectable system, such as hydrogels become more favourable for it possesses several strengths when compared to implantable system. Firstly, the preload can be localised anywhere a needle can reach, which is simpler and less invasive. This allows us to avoid tissue damage and any complications associated with the inflammatory responses after surgery. Secondly, its viscoelastic property allows them to flow and interface with various living systems. This also allows them to conform to any available spaces before transforming into a persistent implant, thus preventing the compromisation of our organ functionality. Despite overcoming the limitations of an implantable system, an injectable system is restricted to liquid or gel form for it to be injectable. This heavily limits the types of materials or agents that can be used. To note, many useful and desirable materials simply failed to possess the mechanical properties necessary for injectability. This means that the design space is definite and that more complex three-dimensional structures will be prohibited, which implantable scaffolds can achieve. An injectable system can be composed of various natural and/or synthetic components. For example, in one of the pioneering works in this field, an injectable Michael addition polymer hydrogel vaccine is developed to act as an immune priming centre. This being said, the hydrogel is loaded with chemo-attractants and immunomodulatory agents to promote dendritic cell infiltration and immune programming. In this particular study, it is found that such injectable therapies improved survival up to 2 fold in a weakly immunogenic A20 B cell lymphoma model.
Overall, implantable and injectable systems are shown to improve the efficacy of traditional immunotherapies significantly. Both systems consist of their own advantages and disadvantages. The fundamental of which system is to be used will depend entirely on the goal of the project, for they each have their own unique strengths when used for proper applications. Still, more studies are required to further enhance our understanding of the design criterias needed for the ‘ideal’ immunotherapeutic biomaterial and whether such material can be developed.
Article by: Lim Tze Yee