Dougan Michael, Nguyen Long H, Buchbinder Elizabeth I, Lazarus Hillard M
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Cancers (Basel). 2024 Jan 24;16(3):501. doi: 10.3390/cancers16030501.
Immune checkpoint inhibitor (ICI) therapy improves outcomes in several cancers. Unfortunately, many patients experience grade 3-4 treatment-related adverse events, including gastrointestinal (GI) toxicities which are common. These GI immune-related adverse events (irAEs) induced by ICIs present significant clinical challenges, require prompt intervention, and result in treatment delays or discontinuations. The treatment for these potentially severe and even fatal GI irAEs which include enterocolitis, severe diarrhea, and hepatitis may interfere with the anti-cancer approach. Sargramostim (glycosylated, yeast-derived, recombinant human GM-CSF) is an agent that has been used in clinical practice for more than 30 years with a well-recognized safety profile and has been studied in many therapeutic areas. The mechanism of action of sargramostim may treat moderate-to-severe GI irAEs without impairing the anti-cancer therapy. Some early data also suggest a potential survival benefit. Through the differentiation/maturation of monocytes, macrophages, and neutrophils and induction of anti-inflammatory T cell responses, GM-CSF aids in GI homeostasis, mucosal healing, and mucosal immunity. GM-CSF knockout mice are susceptible to severe colitis which was prevented with murine GM-CSF administration. For some patients with GI mucosa and immune cell function impairment, e.g., Crohn's disease, sargramostim reduces disease severity. In a prospective, randomized study (ECOG 1608), advanced melanoma patients had a reduction in grade 3-5 GI irAEs and less frequent colonic perforation in the sargramostim plus ipilimumab arm compared to ipilimumab alone. Sargramostim continues to be studied with ICIs for the prophylactic management of irAEs while also potentially providing a survival benefit.
免疫检查点抑制剂（ICI）疗法可改善多种癌症的治疗效果。不幸的是，许多患者会出现3-4级与治疗相关的不良事件，包括常见的胃肠道（GI）毒性。这些由ICI诱导的胃肠道免疫相关不良事件（irAEs）带来了重大的临床挑战，需要及时干预，并导致治疗延迟或中断。这些潜在的严重甚至致命的胃肠道irAEs的治疗，包括小肠结肠炎、严重腹泻和肝炎，可能会干扰抗癌治疗方法。沙格司亭（糖基化、酵母衍生的重组人粒细胞-巨噬细胞集落刺激因子）是一种已在临床实践中使用超过30年的药物，具有公认的安全性，并且已在许多治疗领域进行了研究。沙格司亭的作用机制可能在不损害抗癌治疗的情况下治疗中度至重度胃肠道irAEs。一些早期数据还表明可能有生存获益。通过单核细胞、巨噬细胞和中性粒细胞的分化/成熟以及诱导抗炎性T细胞反应，GM-CSF有助于胃肠道稳态、黏膜愈合和黏膜免疫。GM-CSF基因敲除小鼠易患严重结肠炎，给予鼠GM-CSF可预防。对于一些胃肠道黏膜和免疫细胞功能受损的患者，如克罗恩病患者，沙格司亭可降低疾病严重程度。在一项前瞻性随机研究（ECOG 1608）中，与单独使用伊匹单抗相比，晚期黑色素瘤患者在沙格司亭加伊匹单抗组中3-5级胃肠道irAEs减少，结肠穿孔的发生率更低。沙格司亭继续与ICI联合用于irAEs的预防性管理，同时也可能带来生存获益。
