title: Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy.
abstract: Despite the recent successes of using immune modulatory Abs in patients with cancer, autoimmune pathologies resulting from the activation of self-reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. To reduce the observed and expected toxicities associated with immune modulation, here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient, whereby an agonistic 4-1BB oligonucleotide aptamer is targeted to the tumor stroma by conjugation to an aptamer that binds to a broadly expressed stromal product, VEGF. This approach was predicated on the premise that by targeting the costimulatory ligands to products secreted into the tumor stroma, the T cells will be costimulated before their engagement of the MHC-peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to noninternalizing cell surface products expressed on the tumor cells. Underscoring the potency of stroma-targeted costimulation and the broad spectrum of tumors secreting VEGF, in preclinical murine tumor models, systemic administration of the VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, postsurgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared with nontargeted administration of an agonistic 4-1BB Ab or 4-1BB aptamer.
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
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: Randall
authors.initials: R
authors.lastname: Brenneman
authors.affiliation: Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Anthony
authors.initials: A
authors.lastname: Williams
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: Agata
authors.initials: A
authors.lastname: Levay
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ling-Yuan
authors.initials: LY
authors.lastname: Kong
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rao
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shouhao
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Heimberger
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
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015197:Carcinogenicity Tests; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D052157:Aptamers, Nucleotide; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse