Effective cancer immunotherapy induces the killing of tumor cells by cytotoxic T lymphocytes (CTLs), resulting in tumor regression and a survival benefit for patients. Malignant tumors are often characterized by an intense proliferative capacity, and local to systemic invasiveness, and these lethal characteristics have rendered surgical resection, radiation treatment, and chemotherapy ineffective for many cancer patients. Tumors are also replete with antigens, resulting in immune recognition and significant immune-cell infiltrates, but tumor cells create microenvironments (e.g., production of immunosuppressive cytokines) that suppress anticancer activity. The potential for the innate immune system to react specifically and systemically against local and metastatic lesions, and to obtain memory that may prevent tumor recurrence has inspired the development of immunotherapies that seek to reprogram anticancer responses. A key challenge is to formulate treatment modalities that provide specific and persistent immunostimulation to sustain immune attack against tumor cells (predominantly by CTLs) until patients’ tumors are completely cleared
Current immunotherapeutic approaches are of two main types: cancer vaccines and adoptive T cell transfer. Cancer vaccines introduce tumor-associated antigens at the vaccine site and seek to cause tumor regression by relying on a cascade of events that are orchestrated by dendritic cells (DCs). Innate antigen recognition and processing is the responsibility of DCs, which, upon activation, have a potent ability to present tumor-antigens processed onto major histocompatibility complexes (MHC), and to translate pathogenic danger signals (e.g., lipopolysaccharides and bacterial DNA) into the expression of specific stimulatory molecules and cytokines. Activated DCs then migrate to lymphoid tissues to interact with nave T cells by presenting MHC-antigen peptides and immunostimulatory cytokines, which signal and propagate antigen-specific T cell differentiation and expansion The type and potency of the T cell response elicited by activated DCs, and, by extrapolation, cancer vaccines, depends on several factors: the type of antigen (endogenous versus exogenous), the microenvironment of the DC-antigen encounter, the extent of DC activation and the number of DCs that stimulate CTL differentiation and expansion. In contrast to vaccines, adoptive T cell transfer bypasses antigen delivery and mediators of T cell activation, by transfusing autologous or allogenic T cells that have been modified in ex vivo cultures and selected to target specific cancer antigens.
Although cancer vaccines and adoptive T cell transfers have induced CTL responses to specific tumor-associated antigens, and tumor regression in a subset of cancer patients, these treatments have failed to confer reproducible survival benefit. Clinical tests of cancer vaccines have utilized a variety of methods to deliver antigen, including delivery of bulk antigen in the form of tumor lysates and irradiated tumor cells or patient-derived DCs pulsated with tumor antigen in ex vivo cultures. Adjuvants and toll-like receptor (TLR) agonists are often mixed into vaccines to provide danger signals (factors associated with infectious microenvironments) in order to enhance DC maturation and amplify effector responses. However, the limitations of current approaches include short term antigen presentation and immunostimulation due to short, in vivo half-lives (within tissues and immune cells), and in the case of DC or T cell transplantation therapies, there is a rapid loss in cell viability and no control over cell function upon transplantation. The indiscriminate targeting and rapid loss of bioavailability and bioactivity in relation to current therapies likely reduces their efficiency, which limits DC and CTL activation resulting in transient to ineffective tumor attack. Intuitively, persistent induction of antitumor CTL activity is required to mediate tumor regression, and to clear large tumor burdens.
The development and application of immunologically active biomaterials that specifically target DCs and T cells, and regulate their responses to antigens and tumors are interest of study in present day Immunotechnology, which involves two biomaterial approaches that enable specific and sustained regulation of immune activity, and controlled immunostimulation: drug delivery and three-dimensional cell niches. Biopolymers of many different types have been formulated into particulate systems that control the bioavailability, the pharmacokinetics and the localization of proteins and nucleic acids, and we will discuss work to develop material vectors Immunologically for antigen and adjuvants with DC targeting ability. Moreover, as an alternative to approaches that utilize ex vivo cell manipulation (e.g., DC-based vaccines and Adoptive T cell transfer), biomaterials have been fashioned into biofunctional, three-dimensional matrices that create distinct, immunostimulatory microenvironments and regulate DC and T cell trafficking and activation in situ.
We also highlight the use of these delivery systems and niches to prime DC and T cell responses to tumors in animal models, and the prospects for their clinical impact in cancer immunotherapy. Sources and Inspiration for Biomaterials Biomaterials are derived from various combinations of natural or synthetic components, and, by definition, are intended to interact with biological systems. Biomaterials have historically been designed to augment cellular behavior that promotes tissue regeneration e.g., skin grafts or to replace tissue function [e.g., stents and prosthetics]; traditionally, these materials were fabricated to minimize host inflammatory and immune responses, due to their potentially destructive affects. However, our understanding of immunological regulation has progressed tremendously alongside the development of materials science, and at their intersection emerges the possibility to employ immunologically active biomaterials for cancer immunotherapy. In this section we discuss the sources and raw materials for the fabrication of biomaterial systems and the inspiration underlying their design as drug delivery agents and synthetic extracellular matrices to control cell processes.
Raw Materials
Nature provides numerous sources of structural proteins and polysaccharides, derived from plants and animals, that may be modified into immuno-active biomaterials. Natural materials, including collagen protein derived from the connective tissue of animals, chitosan polysaccharides extracted from the exoskeleton of crustaceans and alginate polysaccharides isolated from seaweed, have been fashioned into gels and utilized as drug delivery devices or as depots for cell transplantation. These materials have been utilized in the clinic for cosmetic and wound care applications with established biocompatibility. Further, the concentrations, molecular weight and crosslinking density of collagen, chitosan and alginate macromolecules can be modified to develop gels with defined degradation rates, stiffness, and functional groups, which can influence the release kinetics or binding of immunostimulatory biomolecules for drug delivery, or the viability and activation state of cells interacting with the material matrix.
Biodegradable devices may also be fabricated from a variety of synthetic polymers, and are frequently used as drug delivery vehicles. Polyglycolide (PGA), polylactide (PLA), and their copolymers polylactide-co-glycolide (PLG) which degrade, by hydrolysis, into the natural metabolites, lactic and glycolic acid, have been widely used in the clinic setting as biodegradable sutures, and are commonly fabricated into particulate systems for the controlled delivery of biomolecules. Polyanhydrides are another class of biodegradable materials that have been utilized as drug delivery vehicles, such as wafers for the clinical delivery of chemotherapeutic agents at the site of glioblastoma resection and as investigative vaccine carriers. In addition, liposome particles (phospholipid bilayers) and block copolymers with hydrophobic and hydrophilic domains are assembled into vesicles or micelle carriers that encapsulate proteins and nucleic acids to protect them from in vivo degradation and for their controlled release.
Controlled Delivery and Cell Targeting
Engineering solutions are needed for delivering therapeutic biomolecules to specific sites of treatment with controlled kinetics, which has inspired the development of biomaterials as delivery vehicles. Molecular therapeutics form the basis for the prevention and treatment of many human diseases; however, their use is limited by short in vivo half-lives which limits their bioavailability to target cells and tissues. Therefore, in some cases, multiple, systemic administrations of therapeutic molecules are utilized to prolong therapeutic stimulation but this increases nonspecific cell/tissue exposure and may cause severe adverse reactions, which limits the time-course and benefit of treatment.
Biomaterials are now tailored with defined physical properties such as degradation mechanisms and rates, and specialized surface characteristics, that protect encapsulated bioactive molecules against degradation in vivo, control their release kinetics and allow for specific cellular targeting in vivo. To efficiently target therapeutic agents (e.g., immunostimulatory cytokines), researchers are developing sophisticated micro- and nano-particulate systems that carry particular surface molecules (e.g., antibodies) Immunologically to recognize and bind to specific cells. The size and surface properties of these particulate systems are also modified to control particle localization within specified tissues and body compartments (e.g., lymphoid tissues). Material carriers are not only designed to encapsulate and protect proteins and nucleic acids from degradation in vivo, but they may also be designed with specific degradation properties allowing the delivery of its bioactive load at specific tissue locations or, for intercellular delivery, at defined intervals within the cell-internalization pathway.
Synthetic ECMs
The natural extracellular matrix (ECM), in structure and function, has inspired the development and application of three-dimensional biomaterial systems that produce distinct microenvironments that transmit chemical and mechanical cues to cells in situ. The interstitial space of tissues contains fibrous ECM proteins (for example, collagens and laminins), and gels of polysaccharides like glycosaminoglycan and heparin sulfate.
The ECM presents a variety of cell adhesion ligands, provides support and anchorage for cells, regulates cellular communication/migration, and sequesters a wide range of cellular growth factors – to act as a local depot. The ECM components and the corresponding degradative enzymes are produced by resident cells in response to local stimuli (e.g., inflammation), which may cause ECM remodeling and a redistribution of cell signals until homeostasis is reachieved between cells and matrix. Thus, the ECM interacts dynamically with cells to regulate their processes, and this ability may be translated to biomaterial systems.
Three-dimensional biomaterial constructs are now engineered to provide the necessary structural support as synthetic ECMs for cell transplantation and delivery, as long-term depots for the controlled presentation of bioactive molecules, and as niches with controlled microenvironments that regulate cell function. The porosity and degradation rate of these materials may be optimized to provide a residence for cells, and to regulate host cell infiltration or cell deployment for therapy. Adhesion ligands may be patterned onto biomaterial surfaces to orient the spatial distribution of cells and cell-cell communication like immune synapes.
