Percutaneous Intratumoral Immunoadjuvant Gel Increases the Abscopal Effect of Cryoablation for Checkpoint Inhibitor Resistant Cancer.
Percutaneous Intratumoral Immunoadjuvant Gel Increases the Abscopal Effect of Cryoablation for Checkpoint Inhibitor Resistant Cancer.
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经皮瘤内免疫辅助凝胶可增加冷冻消融对检查点抑制剂耐药癌症的远隔效应。
DOI：
10.1002/adhm.202301848
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发表时间：
2024
影响因子：
10
通讯作者：
Travers
中科院分区：
文献类型：
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作者：
Som,Avik;Rosenboom,Jan-Georg;Wehrenberg-Klee,Eric;Chandler,Alana;Ndakwah,Gabrielle;Chen,Eric;Suggs,Jack;Morimoto,Joshua;Kim,Jonathan;Mustafa,AbdulRehman;Marcos-Vidal,Asier;Fintelmann,FlorianJ;Basu,Arijit;Langer,Robert;Travers
经皮冷冻消融术是转移性和原发性癌症的常用临床治疗方法。有罕见的临床报告冷冻消融术诱导远处转移的消退，称为“远位”效应。瘤内免疫佐剂可能能够增加冷冻消融的远位率，但现有的瘤内治疗需要频繁注射，并且无法确认靶向递送，导致临床试验结果不佳。为了解决这些缺点，开发了用于FDA批准的Toll样受体7（TLR 7）激动剂咪喹莫特（“Imigel”）的可注射的基于温度响应性凝胶的控释制剂，其在注射时形成肿瘤驻留储库并且含有用于在计算机断层扫描（CT）下可视化的造影剂。基于聚乳酸-共-乙醇酸-聚乙二醇-聚乳酸-共-乙醇酸（PLGA-PEG-PLGA）的两亲性共聚物凝胶的潜在胶束性质能够实现高药物浓度和对数释放曲线，该对数释放曲线与来自冷冻消融的新抗原释放相加，仅需要单次注射。流变学测试证明了体温下粘度的热响应性增加和通过microCT的射线不透性。在两种侵袭性结直肠癌和乳腺癌双重肿瘤模型中，在其他免疫治疗耐药的转移性肿瘤中证明了其显著增加冷冻消融远位率的能力，其中全缓解或无缓解，缓解者通常在90天生存研究中显示双侧肿瘤完全消退。
Percutaneous cryoablation is a common clinical therapy for metastatic and primary cancer. There are rare clinical reports of cryoablation inducing regression of distant metastases, known as the “abscopal” effect. Intratumoral immunoadjuvants may be able to augment the abscopal rate of cryoablation, but existing intratumoral therapies suffer from the need for frequent injections and inability to confirm target delivery, leading to poor clinical trial outcomes. To address these shortcomings, an injectable thermoresponsive gel‐based controlled release formulation is developed for the FDA‐approved Toll‐like‐receptor 7 (TLR7) agonist imiquimod (“Imigel”) that forms a tumor‐resident depot upon injection and contains a contrast agent for visualization under computed tomography (CT). The poly‐lactic‐co‐glycolic acid‐polyethylene glycol‐poly‐lactic‐co‐glycolic acid (PLGA‐PEG‐PLGA)‐based amphiphilic copolymer gel's underlying micellar nature enables high drug concentration and a logarithmic release profile that is additive with the neo‐antigen release from cryoablation, requiring only a single injection. Rheological testing demonstrated the thermoresponsive increase in viscosity at body temperature and radio‐opacity via microCT. Its ability to significantly augment the abscopal rate of cryoablation is demonstrated in otherwise immunotherapy resistant metastatic tumors in two aggressive colorectal and breast cancer dual tumor models with an all or nothing response, responders generally demonstrating complete regression of bilateral tumors in 90‐day survival studies.