title: Reducing Toxicity of Immune Therapy Using Aptamer-Targeted Drug Delivery.
abstract: Modulating the function of immune receptors with antibodies is ushering in a new era in cancer immunotherapy. With the notable exception of PD-1 blockade used as monotherapy, immune modulation can be associated with significant toxicities that are expected to escalate with the development of increasingly potent immune therapies. A general way to reduce toxicity is to target immune potentiating drugs to the tumor or immune cells of the patient. This Crossroads article discusses a new class of nucleic acid-based immune-modulatory drugs that are targeted to the tumor or to the immune system by conjugation to oligonucleotide aptamer ligands. Cell-free chemically synthesized short oligonucleotide aptamers represent a novel and emerging platform technology for generating ligands with desired specificity that offer exceptional versatility and feasibility in terms of development, manufacture, and conjugation to an oligonucleotide cargo. In proof-of-concept studies, aptamer ligands were used to target immune-modulatory siRNAs or aptamers to induce neoantigens in the tumor cells, limit costimulation to the tumor lesion, or enhance the persistence of vaccine-induced immunity. Using increasingly relevant murine models, the aptamer-targeted immune-modulatory drugs engendered protective antitumor immunity that was superior to that of current "gold-standard" therapies in terms of efficacy and lack of toxicity or reduced toxicity. To overcome immune exhaustion aptamer-targeted siRNA conjugates could be used to downregulate intracellular mediators of exhaustion that integrate signals from multiple inhibitory receptors. Recent advances in aptamer development and second-generation aptamer-drug conjugates suggest that we have only scratched the surface.
authors.affiliation: Department of Microbiology and Immunology, Dodson Interdisciplinary Immunotherapy Institute, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida. egilboa@med.miami.edu.
authors.forename: Eli
authors.initials: E
authors.lastname: Gilboa
authors.affiliation: Department of Microbiology and Immunology, Dodson Interdisciplinary Immunotherapy Institute, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Alexey
authors.initials: A
authors.lastname: Berezhnoy
authors.affiliation: Department of Microbiology and Immunology, Dodson Interdisciplinary Immunotherapy Institute, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Brett
authors.initials: B
authors.lastname: Schrand
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D052157:Aptamers, Nucleotide / Q000008:administration & dosage* / Q000276:immunology; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects* / Q000379:methods*; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; D061026:Programmed Cell Death 1 Receptor; D034741:RNA, Small Interfering