Polypeptide and protein immunomodulators are subject to absorption, biodistribution, metabolism and degradation at sites and rates which may not permit effective interactions with components of the immune system. Drug carrier technology can overcome some of these obstacles. Because of the lipid and particulate nature of liposomes, increased delivery of immunomodulators to lymphatics, lymph nodes, lymphatic organs and concentrations of macrophages is possible when an immunomodulator is associated with a liposome. Interleukin-2 (IL-2) liposomes have been shown to have less toxicity and increased immunotherapeutic effects in a number of model systems and are currently in human clinical trials. Local routes such as aerosol delivery to the lung are particularly well suited to use with liposomes containing immunomodulators. Polypeptides can also enhance the interaction of an immunomodulator with the immune system via increased immunostimulation; this can provide a means to enhance oral delivery and to achieve depot effects. Polysaccharide microspheres have been shown to be effective biodegradable carriers of immunomodulators. Finally, genetically engineered bacteria, viruses and mammalian cells may function as delivery systems for immunomodulatory peptides and proteins. Attenuated Salmonella strains can deliver immunomodulators to the gut-associated lymphoid tissue, liver and spleen. In mouse experiments using tumour cells producing granulocyte-macrophage colony-stimulating factor (GM-CSF), irradiated tumour preparations produced GM-CSF and were capable of eliciting effective cell-mediated immune responses, including destruction and elimination of tumour as well as resistance to tumour challenge (i.e. memory response). A wide variety of immunomodulators have been tested using this strategy; IL-2 and GM-CSF are among the most potent inducers of both cell-mediated effector and memory responses. In summary, use of delivery systems can significantly enhance the immunomodulatory potential of polypeptides and proteins.
