PO.CL05.05 · 临床研究
粒子治疗、ATM和PD-1抑制用于pMMR直肠癌
Particle therapy, ATM and PD-1 inhibition for pMMR rectal cancer
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摘要 Abstract
中文摘要
背景与目的：结直肠癌是癌症死亡的主要原因，大多数直肠癌为错配修复功能完整型（pMMR），使其对PD-1抑制剂（PD1i）在很大程度上耐药。虽然PD1i在错配修复缺陷型肿瘤中可实现出色的完全缓解率，但这类肿瘤仅占直肠癌的<5%。对于其余95%的患者，迫切需要有效的免疫治疗策略。我们评估了两种高LET辐射方法，以使pMMR直肠癌对PD1i产生启动效应并增强局部控制：1）弥散性α发射体放射治疗（DaRT）植入物，以及2）LET优化（布拉格峰）质子+ATM抑制剂。鉴于临床治疗计划中可达到的LETd相对较低，我们评估了将ATM抑制剂与质子联合，以判断其能否产生更接近α/碳离子的效应。
方法：对HCT116、HT29、SW480和CT26进行体外质子照射，方法同前，剂量平均LET（LETd）值为：入口段（ENT）2.2 keV/um，布拉格峰（BP）质子7.0 keV/um。雌性Balb/C小鼠在一侧胁部皮下接种1×10^6个CT26细胞、在对侧胁部接种1×10^5个细胞，分别建立原发和继发（远隔效应）肿瘤。PD1i单克隆抗体（RMP1-14，Bio X Cell）经腹腔注射，每72小时100ug，共4剂。ATM抑制剂AZD1390经口灌胃给药，剂量20 mg/kg，于照射前1小时口服。对于体内研究，使用PXI SmART小动物照射器以对侧侧向束（225 kVp、20 mA、0.3mm铜滤片）递送辐射。质子照射计划按前述方法制定。我们采用飞行时间质谱流式（CyTOF），基于多种细胞标志物对肿瘤微环境（TME）中的CD45淋巴细胞亚群进行分析。
结果：在初步数据中，我们证明DaRT和BP质子+ATMi均与PD1i协同，通过增加DNA损伤、激活固有免疫通路并减轻肿瘤微环境内的免疫抑制，显著提高原发和远隔肿瘤的完全缓解率。至关重要的是，这一效应在对PD1i或常规X射线+PD1i均无应答的pMMR模型中得以观察到，凸显了本工作的创新性和潜在影响。
结论：DaRT和BP质子+ATMi可使pMMR结直肠癌对PD1i产生启动效应，且所有要素均可临床转化。
查看英文原文 English abstract
Background and Aims: Colorectal cancer is a leading cause of cancer mortality and most rectal cancers are mismatch repair proficient (pMMR), making them largely resistant to PD-1 inhibitors (PD1i). While PD1i achieves excellent complete response rates in MMR-deficient tumors, these represent <5% of rectal cancers. For the remaining 95% of patients, effective immunotherapy strategies are urgently needed. We evaluated two high-LET radiation approaches to prime pMMR rectal cancers to PD1i and enhance local control: 1) Diffusing alpha emitter Radiation Therapy (DaRT) implants, and 2) LET-optimized (Bragg Peak) protons + ATM inhibitor. An ATM inhibitor was evaluated with protons to evaluate whether it could produce a more alpha/carbon-like effect given the lower comparative LETd achievable in clinical treatment plans.
Methods: In vitro proton irradiation of HCT116, HT29, SW480, and CT26 was performed as previously with dose averaged LET (LETd) values of 2.2 keV/um for ENT and 7.0 keV/um for BP protons. Female Balb/C mice were subcutaneously inoculated with 1×10^6 CT26 cells on one flank and 1×10^5 cells on the contralateral flank to establish primary and secondary (abscopal) tumors, respectively. PD1i monoclonal antibody (RMP1-14 Bio X Cell) was administered i.p. 100ug every 72 hours for 4 total doses. The ATM inhibitor AZD1390 was delivered via oral gavage at 20 mg/kg, PO 1 hour prior to radiation. For in vivo studies, radiation was delivered using a PXI SmART small animal irradiator with opposing lateral beams (225 kVp, 20 mA, 0.3mm Cu filter). Proton irradiation plans were produced as previously described. We used mass cytometry by time of flight (CyTOF) using the TME CD45 lymphocyte subpopulations based on multiple cell markers.
Result: In our preliminary data we demonstrate that both DaRT and BP protons+ATMi synergize with PD1i to dramatically increase complete response rates at both primary and abscopal tumors by increasing DNA damage, activating innate immune pathways, and reducing immunosuppression within the tumor microenvironment. Critically, this effect was observed in a pMMR model which did not respond to PD1i or conventional X-rays+PD1i, highlighting the innovation and potential impact of this work.
Conclusion: DaRT and BP protons ATMi prime pMMR colorectal cancer to PD1i, and all elements are clinically translatable.
利益披露 Disclosure
C. M. Callaghan,
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