Introduction

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.

Patients and Methods

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.

Results

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.

Conclusions

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.

中文翻译：

---

瘤内注射维杜莫德、放射外科、纳武单抗和伊匹单抗联合治疗微卫星稳定型结直肠癌伴肝转移

介绍

微卫星稳定转移性结直肠癌 (MSS mCRC) 在很大程度上难以抵抗免疫检查点抑制。我们假设肿瘤内TLR9激动剂、放射外科手术以及 PD-1 和 CTLA-4 双重阻断相结合会诱导局部免疫刺激焦点，从而引发全身免疫反应。

患者和方法

在这项 I 期单机构研究中，MSS mCRC 患者接受初始剂量的皮下维妥莫德、3 次瘤内注射维妥莫德和放射外科治疗，并联合纳武单抗和伊匹单抗。在基线和 7 (± 2) 周时测量细胞因子水平。患者被分为 4 个连续队列：(1) 不进行放射外科手术的安全磨合，(2) 肿瘤内治疗前的放射外科治疗，(3) 肿瘤内治疗前的放射外科治疗，时间线紧凑，(4) 完成后对肝外病变进行放射外科治疗瘤内治疗。

结果

共有 19 名患者入院。中位年龄为 59 岁（范围 40-71），68% 为男性，既往全身治疗次数中位为 3 次（范围 2-5）。除 1 名患者外，所有患者均未做出反应，原因是肿瘤突变负荷较高。队列 1 至队列 4 中报告的3 级肝毒性分别为 0%、0%、75% 和 17%。CXCL10 和 IL-10 的全身水平增加，中位值分别为 407 pg/mL 与 78 pg/mL ( P  = .01)，以及 66 pg/mL 与 40 pg/mL ( P  = .03)。

结论

瘤内注射维度莫德、放射外科、纳武单抗和易普利姆玛联合治疗 MSS mCRC 伴肝转移未发现有效。肝脏照射和瘤内注射维多莫德的并用与高肝毒性相关。