Division of Nephrology, Department of Internal Medicine, University of California, Davis, California.
Comprehensive Cancer Center, University of California, Davis, California.
Kidney360. 2020 May 28;1(5):376-388. doi: 10.34067/kid.0000282019.
Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and is increasing in incidence. Despite new therapies, including targeted therapies and immunotherapies, most RCCs are resistant to treatment. Thus, several laboratories have been evaluating new approaches to therapy, both with single agents as well as combinations. Although we have previously shown efficacy of the dual PAK4/nicotinamide phosphoribosyltransferase (NAMPT) inhibitor KPT-9274, and the immune checkpoint inhibitors (CPI) have shown utility in the clinic, there has been no evaluation of this combination either clinically or in an immunocompetent animal model of kidney cancer.
In this study, we use the renal cell adenocarcinoma (RENCA) model of spontaneous murine kidney cancer. Male BALB/cJ mice were injected subcutaneously with RENCA cells and, after tumors were palpable, they were treated with KPT-9274 and/or anti-programmed cell death 1 (PDCD1; PD1) antibody for 21 days. Tumors were measured and then removed at animal euthanasia for subsequent studies.
We demonstrate a significant decrease in allograft growth with the combination treatment of KPT-9274 and anti-PD1 antibody without significant weight loss by the animals. This is associated with decreased (MOUSE) expression, indicating dependence of these tumors on NAMPT in parallel to what we have observed in human RCC. Histology of the tumors showed substantial necrosis regardless of treatment condition, and flow cytometry of antibody-stained tumor cells revealed that the enhanced therapeutic effect of KPT-9274 and anti-PD1 antibody was not driven by infiltration of T cells into tumors.
This study highlights the potential of the RENCA model for evaluating immunologic responses to KPT-9274 and checkpoint inhibitor (CPI) and suggests that therapy with this combination could improve efficacy in RCC beyond what is achievable with CPI alone.
肾癌（或肾细胞癌，RCC）是美国第六大常见恶性肿瘤，其发病率正在上升。尽管有新的治疗方法，包括靶向治疗和免疫治疗，但大多数 RCC 对治疗有耐药性。因此，一些实验室一直在评估新的治疗方法，包括单一药物和联合用药。虽然我们之前已经证明了双重 PAK4/烟酰胺磷酸核糖基转移酶（NAMPT）抑制剂 KPT-9274 的疗效，以及免疫检查点抑制剂（CPI）在临床上的应用，但无论是在临床上还是在免疫功能正常的肾癌动物模型中，都没有对这种联合用药进行评估。
在这项研究中，我们使用了自发性鼠肾癌细胞腺癌细胞（RENCA）模型。雄性 BALB/cJ 小鼠皮下注射 RENCA 细胞，当肿瘤可触及后，用 KPT-9274 和/或抗程序性细胞死亡 1（PDCD1；PD1）抗体治疗 21 天。在动物安乐死时测量肿瘤大小，并取出肿瘤进行后续研究。
我们发现，KPT-9274 和抗 PD1 抗体联合治疗可显著抑制移植物生长，而动物体重无明显下降。这与（MOUSE）表达的降低有关，表明这些肿瘤对 NAMPT 的依赖性与我们在人肾细胞癌中观察到的一致。肿瘤组织学显示，无论治疗条件如何，肿瘤都有大量坏死，而经抗体染色的肿瘤细胞流式细胞术显示，KPT-9274 和抗 PD1 抗体联合治疗的增强疗效不是由 T 细胞浸润肿瘤引起的。
本研究强调了 RENCA 模型在评估 KPT-9274 和检查点抑制剂（CPI）免疫反应方面的潜力，并表明这种联合治疗可能会提高 RCC 的疗效，超过单独使用 CPI 所能达到的疗效。
