Clinical and immune correlate results from a phase 1b study of the histone deacetylase inhibitor mocetinostat with ipilimumab and nivolumab in unresectable stage III/IV melanoma.
Clinical and immune correlate results from a phase 1b study of the histone deacetylase inhibitor mocetinostat with ipilimumab and nivolumab in unresectable stage III/IV melanoma.
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DOI：
10.1097/cmr.0000000000000818
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发表时间：
2022-10-01
影响因子：
2.2
通讯作者：
Woods, David M.
中科院分区：
文献类型：
--
作者：
Weber, Jeffrey S.;Levinson, Benjamin A.;Laino, Andressa S.;Pavlick, Anna C.;Woods, David M.
关键词：
检查点免疫疗法（CPI）改善了转移性黑色素瘤患者的结局，伊匹单抗和纳武单抗联合治疗的客观缓解率约为58%。临床前数据表明，组蛋白脱乙酰酶（HDAC）抑制增强抗肿瘤免疫活性，并可能增加CPI。在一项Ib期开放标签试点试验（NCT 03565406）中，未经治疗的转移性黑色素瘤患者接受I/IV类HDAC抑制剂mocetinostat口服治疗，每周三次，联合nivolumab和ipilimumab每三周一次，持续12周，随后是12周的维持周期，即nivolumab每两周一次，mocetinostat的剂量和时间表与诱导相同。试验终点为安全性、推荐II期剂量的定义、反应的初步评估和相关标志物测定。通过流式细胞术和Luminex测定法评估基线和治疗期间采集的患者PBMC和血清样本的免疫相关性。10例患者接受了治疗，9例使用70 mg，1例使用50 mg mocetinostat。在70 mg队列中，8例患者出现客观缓解。50 mg队列中的患者出现早期疾病进展。所有患者都有2级或更高的毒性，6例有3-4级毒性。患者PBMC显示髓源性抑制细胞显著减少，并有抗炎单核细胞表型减少的趋势。患者血清显示颗粒酶A和TNF显著上调，并有颗粒酶B和IFNγ增加的趋势。总的来说，CPI和mocetinostat的组合具有有利的响应率，但具有高水平的毒性。免疫相关性的评估支持从免疫抑制表型向增强免疫应答的转变。
Checkpoint immunotherapies (CPI) have improved outcomes for metastatic melanoma patients, with objective response rates with combination ipilimumab and nivolumab ~58%. Preclinical data suggest that histone deacetylase (HDAC) inhibition enhances antitumor immune activity and may augment CPI. In a phase Ib open-label, pilot trial (NCT03565406), patients with therapy-naive metastatic melanoma were treated with the class I/IV HDAC inhibitor mocetinostat orally three times a week in combination with nivolumab and ipilimumab every three weeks for 12 weeks followed by 12-week maintenance cycles of nivolumab every two weeks and mocetinostat at the same dose and schedule as induction. The endpoints of the trial were safety, definition of a recommended phase 2 dose, preliminary assessment of response, and correlative marker determination. Patient PBMC and serum samples collected at baseline and on-treatment were assessed by flow cytometry and Luminex assays for immune correlates. Ten patients were treated, nine with 70mg and one with 50mg mocetinostat. In the 70mg cohort, eight patients had objective responses. The patient in the 50mg cohort had an early progression of disease. All patients had grade 2 or higher toxicities, and six had grade 3–4 toxicities. Patient PBMC showed significant decreases in myeloid-derived suppressor cells and trends towards reduced anti-inflammatory monocyte phenotypes. Patient serum showed significant upregulation of Granzyme A and TNF and trends towards increased Granzyme B and IFNγ. Collectively, combination CPI and mocetinostat had favorable response rates but with high levels of toxicity. Assessment of immune correlates support a shift away from immunosuppressive phenotypes towards enhanced immune responses.