微卫星稳定性转移性结直肠癌（MSS mCRC）很大程度上对免疫检查点抑制疗法具有耐药性。我们假设，在肿瘤内用TLR9激动剂进行联合治疗，包括放射外科手术和PD-1与CTLA-4的双重抑制，将会引起免疫刺激的局部集中，激发全身性免疫反应.在这个单机构I期研究中，我们采用s.c vidutolimod预先剂量，结合nivolumab和ipilimumab，对MSS mCRC患者进行肿瘤内注射vidutolimod和放射外科手术的治疗。基线和7（±2）周时测定了细胞因子水平。患者分为4个连续队列：（1）没有放射外科手术的安全预研究，（2）放射外科手术在肿瘤内治疗之前，（3）放射外科手术在肿瘤内治疗之前及治疗时间压缩，（4）在肿瘤内治疗完成后对肝外病灶进行放射外科手术。共有19例患者入组。中位年龄为59岁（范围40-71岁），68%为男性，先前系统治疗的中位次数为3次（范围2-5次）。除了一个与高肿瘤突变负荷相关的患者外，患者中没有出现有效反应。1到4组的级别3肝毒性分别报告为0％，0％，75％和17％。CXCL10和IL-10的全身水平增加，中位数分别为407与78 pg/mL（P = 0.01），以及66与40 pg/mL（P = 0.03）。肿瘤内注射vidutolimod、放射外科手术、nivolumab和ipilimumab的联合治疗并未发现对MSS mCRC伴肝转移具有疗效。肝脏照射和肿瘤内vidutolimod注射的并置与高肝毒性相关。© 2023 Elsevier Inc. 保留所有权利。

Microsatellite stable metastatic colorectal cancer (MSS mCRC) is largely refractory to immune checkpoint inhibition. We hypothesized that a combination of intratumoral TLR9 agonist, radiosurgery and dual PD-1 and CTLA-4 blockade would induce a local focus of immune stimulation, evoking a systemic immune response.In this phase I single-institution study, patients with MSS mCRC were treated with a priming dose of s.c vidutolimod, 3 intratumoral injections of vidutolimod and radiosurgery, combined with nivolumab and ipilimumab. Cytokine levels were measured at baseline and at 7 (± 2) weeks. Patients were accrued to 4 consecutive cohorts: (1) Safety run-in without radiosurgery, (2) Radiosurgery prior to intratumoral therapy, (3) Radiosurgery prior to intratumoral therapy with a condensed timeline, and (4) Radiosurgery to extrahepatic lesion following completion of intratumoral therapy.A total of 19 patients were accrued. Median age was 59 years (range 40-71), 68% were male, median number of previous systemic treatments was 3 (range 2-5). None of the patients responded, aside from 1 patient, attributed to high tumor mutational burden. Grade 3 liver toxicity was reported in 0%, 0%, 75%, and 17% in cohorts 1 to 4, respectively. Systemic levels of CXCL10 and IL-10 increased, with a median of 407 versus 78 pg/mL (P = .01), and 66 versus 40 pg/mL (P = .03), respectively.The combination of intratumoral vidutolimod, radiosurgery, nivolumab and ipilimumab was not found to be efficacious in MSS mCRC with liver metastases. The juxtaposition of liver irradiation and intratumoral vidutolimod injection was associated with high hepatic toxicity.Copyright © 2023 Elsevier Inc. All rights reserved.