Bates Amber M, Brown Ryan J, Pieper Alexander A, Zangl Luke M, Arthur Ian, Carlson Peter M, Le Trang, Sosa Gustavo A, Clark Paul A, Sriramaneni Raghava N, Kim KyungMann, Patel Ravi B, Morris Zachary S
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.
Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.
Front Oncol. 2021 Apr 15;11:645352. doi: 10.3389/fonc.2021.645352. eCollection 2021.
Surgical resection or hypo-fractionated radiation therapy (RT) in early-stage non-small cell lung cancer (NSCLC) achieves local tumor control, but metastatic relapse remains a challenge. We hypothesized that immunotherapy with anti-CTLA-4 and bempegaldesleukin (BEMPEG; NKTR-214), a CD122-preferential IL2 pathway agonist, after primary tumor RT or resection would reduce metastases in a syngeneic murine NSCLC model. Mice bearing Lewis Lung Carcinoma (LLC) tumors were treated with combinations of BEMPEG, anti-CTLA-4, and primary tumor treatment (surgical resection or RT). Primary tumor size, mouse survival, and metastatic disease at the time of death were assessed. Flow cytometry, qRT-PCR, and cytokine analyses were performed on tumor specimens. All mice treated with RT or surgical resection of primary tumor alone succumbed to metastatic disease, and all mice treated with BEMPEG and/or anti-CTLA-4 succumbed to primary tumor local progression. The combination of primary tumor RT or resection and BEMPEG and anti-CTLA-4 reduced spontaneous metastasis and improved survival without any noted toxicity. Flow cytometric immunoprofiling of primary tumors revealed increased CD8 T and NK cells and decreased T-regulatory cells with the combination of BEMPEG, anti-CTLA-4, and RT compared to RT alone. Increased expression of genes associated with tumor cell immune susceptibility, immune cell recruitment, and cytotoxic T lymphocyte activation were observed in tumors of mice treated with BEMPEG, anti-CTLA-4, and RT. The combination of BEMPEG and anti-CTLA-4 with primary tumor RT or resection enabled effective control of local and metastatic disease in a preclinical murine NSCLC model. This therapeutic combination has important translational potential for patients with early-stage NSCLC and other cancers.
早期非小细胞肺癌（NSCLC）的手术切除或大分割放疗（RT）可实现局部肿瘤控制，但转移性复发仍是一个挑战。我们假设，在原发性肿瘤放疗或切除后，使用抗CTLA-4和贝姆培加德西ukin（BEMPEG；NKTR-214，一种CD122优先的IL2通路激动剂）进行免疫治疗，将减少同基因小鼠NSCLC模型中的转移。携带Lewis肺癌（LLC）肿瘤的小鼠接受了BEMPEG、抗CTLA-4和原发性肿瘤治疗（手术切除或放疗）的联合治疗。评估了原发性肿瘤大小、小鼠存活率以及死亡时的转移性疾病。对肿瘤标本进行了流式细胞术、qRT-PCR和细胞因子分析。仅接受原发性肿瘤放疗或手术切除的所有小鼠均死于转移性疾病，而所有接受BEMPEG和/或抗CTLA-4治疗的小鼠均死于原发性肿瘤局部进展。原发性肿瘤放疗或切除与BEMPEG和抗CTLA-4的联合使用减少了自发转移并提高了存活率，且未发现任何毒性。与单独放疗相比，原发性肿瘤的流式细胞免疫分析显示，BEMPEG、抗CTLA-4和放疗联合使用时，CD8 T细胞和NK细胞增加，调节性T细胞减少。在用BEMPEG、抗CTLA-4和放疗治疗的小鼠肿瘤中，观察到与肿瘤细胞免疫易感性、免疫细胞募集和细胞毒性T淋巴细胞活化相关的基因表达增加。在临床前小鼠NSCLC模型中，BEMPEG和抗CTLA-4与原发性肿瘤放疗或切除的联合使用能够有效控制局部和转移性疾病。这种治疗组合对早期NSCLC和其他癌症患者具有重要的转化潜力。
