Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy.
Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy.
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DOI：
10.1158/2326-6066.cir-14-0007
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发表时间：
2014-09
影响因子：
10.1
通讯作者：
Gilboa E
中科院分区：
文献类型：
--
作者：
Schrand B;Berezhnoy A;Brenneman R;Williams A;Levay A;Kong LY;Rao G;Zhou S;Heimberger AB;Gilboa E
尽管最近在癌症患者中使用免疫调节抗体取得了成功，但由自身反应性T细胞活化引起的自身免疫病理学排除了充分利用其治疗潜力所必需的剂量递增。为了减少与免疫调节相关的观察到的和预期的毒性，在这里，我们描述了一种临床上可行的和广泛适用的方法，以限制免疫共刺激患者的播散性肿瘤病变，其中激动性4-1BB寡核苷酸适体通过与适体结合而靶向肿瘤基质，所述适体结合广泛表达的基质产物血管内皮生长因子（VEGF）。该方法的前提是，通过将共刺激配体靶向分泌到肿瘤基质中的产物，T细胞将在它们与肿瘤细胞上的MHC/肽复合物接合之前被共刺激，从而避免了将共刺激配体靶向肿瘤细胞上表达的非内化细胞表面产物的需要。强调了基质靶向共刺激的效力和分泌VEGF的广谱肿瘤，在临床前鼠肿瘤模型中，VEGF靶向4-1BB适体缀合物的全身施用在皮下、手术后肺转移、甲基胆甾烷诱导的纤维肉瘤和癌基因诱导的自体神经胶质瘤模型中产生针对多种不相关肿瘤的有效抗肿瘤免疫，并且与激动性4-1BB抗体或4-1BB适体的非靶向给药相比显示出上级治疗指数。
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.