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 antibodies in cancer patients, 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, vascular endothelial growth factor (VEGF). The 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 prior to their engagement of the MHC/peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to non-internalizing 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, post-surgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared to non-targeted administration of an agonistic 4-1BB antibody or 4-1BB aptamer.

Reducing Toxicity of Immune Therapy Using Aptamer-Targeted Drug Delivery

“…Suggestive of the potency of aptamer-targeted immune modulation, the antitumor effects seen with the VEGF-targeted 4-1BB conjugates were substantially more pronounced than what has been reported in the literature. Consistent with the underlying premise of tumor targeting, the VEGF-targeted 4-1BB aptamer conjugates exhibited a significantly higher therapeutic index than an agonistic 4-1BB antibody; on a molar basis, one tenth the dose of aptamer conjugate elicited comparable antitumor effects without evidence of toxicity, whereas treatment with a therapeutic dose of antibody was associated with immune anomalies and liver toxicity (18). Ongoing studies using second-generation aptamers, nanoparticle-encapsulated formulations, and multivalent aptamer scaffolds, promise to further enhance their bioactivity and therapeutic value.…”

“…Another advantage of targeting immune modulation to the tumor stroma is that, unlike tumor-specific products like PSMA or Her-2, many stromasecreted products, like VEGF, osteopontin, tenascin-C, metalloproteases, and others, are expressed by virtually all tumor lesions. Underscoring both the potency and broad applicability of stromatargeted 4-1BB costimulation in preclinical murine tumor models, systemic administration of VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple tumors of distinct origin in subcutaneous, postsurgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models (18). Suggestive of the potency of aptamer-targeted immune modulation, the antitumor effects seen with the VEGF-targeted 4-1BB conjugates were substantially more pronounced than what has been reported in the literature.…”

Immunotherapy in glioblastoma: emerging options in precision medicine

“…How multiple immunotherapies can be safely combined and also be combined with other therapeutic modalities, such as small molecule inhibitors, tyrosine kinase inhibitors, viralbased strategies, antiangiogenic therapies and more, has yet to be determined. Additionally several preclinical studies are examining the best ways to combine therapeutic treatments for GBM [8,118,119]. Certainly there are ongoing and planned immunotherapy combinatorial clinical trials underway in GBM (NCT02423343, N C T 0 2 3 119 2 0 , N C T 0 2 5 2 9 0 7 2 , NCT02337491, NCT02017717, NCT02526017, N C T 0 2 4 2 3 3 4 3 , N C T 0 2 3 2 7 0 7 8 , NCT02327078, NCT02017717).…”

Selection of Aptamers to Glioblastoma

“…Выживаемость онкобольных с таким диагнозом редко превышает 12-15 месяцев [3]. Неблагоприятным является также прогноз выжи-ваемости пациентов с метастазами солидных опу-холей в головной мозг [2].…”