Landry M R, DuRoss A N, Neufeld M J, Hahn L, Sahay G, Luxenhofer R, Sun C
Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, 97201, OR, USA.
Department of Chemistry and Pharmacy, University Würzburg, Röntgenring 11, Würzburg, 97070, Germany.
Mater Today Bio. 2020 Oct 22;8:100082. doi: 10.1016/j.mtbio.2020.100082. eCollection 2020 Sep.
Multimodal therapy is often used in oncology to overcome dosing limitations and chemoresistance. Recently, combination immunoradiotherapy has shown great promise in a select subset of patients with colorectal cancer (CRC). Furthermore, molecularly targeted agents delivered in tandem with immunotherapy regimens have been suggested to improve treatment outcomes and expand the population of responding patients. In this study, radiation-sensitizing small molecules niraparib (PARP inhibitor) and HS-173 (PI3K inhibitor) are identified as a novel combination that synergistically enhance toxicity and induce immunogenic cell death both and in a CRC model. These inhibitors were co-encapsulated in a polymer micelle to overcome solubility limitations while minimizing off-target toxicity. Mice bearing syngeneic colorectal tumors (CT26) were administered these therapeutic micelles in combination with X-ray irradiation and anti-CTLA-4 immunotherapy. This combination led to enhanced efficacy demonstrated by improved tumor control and increased tumor infiltrating lymphocytes. This report represents the first investigation of DNA damage repair inhibition combined with radiation to potentiate anti-CTLA-4 immunotherapy in a CRC model.
多模态疗法常用于肿瘤学领域，以克服剂量限制和化疗耐药性。最近，联合免疫放射疗法在一部分特定的结直肠癌（CRC）患者中显示出巨大的前景。此外，有人提出与免疫治疗方案串联使用分子靶向药物可改善治疗效果并扩大有反应患者的群体。在本研究中，辐射增敏小分子尼拉帕利（PARP抑制剂）和HS-173（PI3K抑制剂）被确定为一种新型组合，在CRC模型中能协同增强毒性并诱导免疫原性细胞死亡。这些抑制剂被共包封在聚合物胶束中，以克服溶解度限制，同时将脱靶毒性降至最低。给携带同基因结肠肿瘤（CT26）的小鼠施用这些治疗性胶束，并结合X射线照射和抗CTLA-4免疫疗法。这种联合疗法通过改善肿瘤控制和增加肿瘤浸润淋巴细胞显示出增强的疗效。本报告是在CRC模型中首次研究DNA损伤修复抑制与放疗相结合以增强抗CTLA-4免疫疗法的研究。
