Goswami Sangeeta, Gao Jianjun, Basu Sreyashi, Shapiro Daniel D, Karam Jose A, Tidwell Rebecca Slack, Ahrar Kamran, Campbell Matthew T, Shen Yu, Trevino Alexandro E, Mayer Aaron T, Espejo Alexsandra B, Seua Christian, Macaluso Marc D, Chen Yulong, Liu Wenbin, He Zhong, Yadav Shalini S, Wang Ying, Rao Priya, Zhao Li, Zhang Jianhua, Jindal Sonali, Futreal Andrew, Wang Linghua, Tannir Nizar M, Sharma Padmanee
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX.
Res Sq. 2024 Nov 12:rs.3.rs-4331053. doi: 10.21203/rs.3.rs-4331053/v1.
Surgical removal of primary tumors was shown to reverse tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT)-containing treatments is not understood. Here, we report the first prospective, non-comparative clinical trial to evaluate the feasibility, clinical benefits, and immunologic changes of combining three different ICT-containing strategies with cytoreductive surgery or biopsy for patients with metastatic clear cell renal cell carcinoma (mccRCC). Based upon baseline evaluation and surgical eligibility after 6 weeks of ICT treatment, 43 patients on this trial proceeded with cytoreductive surgery, while 36 patients who had medical comorbidities preventing surgery or did not have a lesion amenable for surgical resection underwent post-ICT biopsy as specified in the clinical trial protocol, and 25 patients who discontinued study participation due to progressive disease or toxicities or withdrawal of consent did not receive either procedure (total N=104). Our data demonstrated that, in the subgroup of patients receiving the combination of ICT with cytoreductive surgery or biopsy, no additional ICT- or procedure-related toxicities were observed as compared to historical data. The median OS (overall survival) was 54.7 months for patients who received ICT-containing regimens plus cytoreductive surgery (n=43). Immune-monitoring studies with co-detection by indexing (CODEX) identified distinct tumor spatial conformation of cellular subsets as a novel and improved predictor of response to ICT. Importantly, single-cell RNA-sequencing (sc-RNA-seq) data demonstrated that surgical removal of the tumor increased antigen-presenting dendritic cell population with a concurrent reduction in KDM6B-expressing immune-suppressive myeloid cells in the peripheral blood. Together, this study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated the potential enhancement of immune responses following ICT plus cytoreductive surgery in patients with metastatic disease.
在临床前转移性疾病模型中，手术切除原发性肿瘤可逆转肿瘤介导的免疫抑制。然而，在转移性情况下进行的减瘤手术如何调节患者的免疫反应，尤其是在含免疫检查点疗法（ICT）的治疗背景下，目前尚不清楚。在此，我们报告了第一项前瞻性、非对照临床试验，旨在评估将三种不同的含ICT策略与减瘤手术或活检相结合，用于转移性透明细胞肾细胞癌（mccRCC）患者的可行性、临床益处和免疫变化。根据基线评估和ICT治疗6周后的手术 eligibility，本试验中的43例患者进行了减瘤手术，而36例因内科合并症无法手术或没有适合手术切除的病变的患者，按照临床试验方案进行了ICT后活检，25例因疾病进展、毒性反应或撤回同意而停止研究参与的患者未接受任何一种手术（总计N = 104）。我们的数据表明，在接受ICT与减瘤手术或活检联合治疗的患者亚组中，与历史数据相比，未观察到额外的ICT或手术相关毒性。接受含ICT方案加减瘤手术的患者（n = 43）的中位总生存期（OS）为54.7个月。采用索引共检测（CODEX）的免疫监测研究确定，细胞亚群的独特肿瘤空间构象是对ICT反应的一种新的且改进的预测指标。重要的是，单细胞RNA测序（sc-RNA-seq）数据表明，手术切除肿瘤可增加抗原呈递树突状细胞群体，同时外周血中表达KDM6B的免疫抑制性髓样细胞减少。总之，本研究强调了在转移性情况下将ICT与减瘤手术相结合的可行性，并证明了ICT加减瘤手术后转移性疾病患者免疫反应的潜在增强。
