Abstract

Background

A scavenger receptor CLEVER-1 is highly expressed on tumor associated macrophages (TAMs) and mediates the clearance of “unwanted” self-components. Pre-clinical studies demonstrate that CLEVER-1 inhibition increases TAM pro-inflammatory cytokine secretion and antigen presentation reactivating CD8+ T cell responses with robust anti-tumor activity (Viitala et al., 2019). Targeting CLEVER-1 could overcome the immunosuppressive tumor microenvironment and has led to the development of FP-1305, a humanized anti-CLEVER-1 IgG4-antibody.

Methods

MATINS (Macrophage Antibody To INhibit immune Suppression) trial is a multicenter first-in-human phase I/II study (NCT03733990) to assess the tolerability, safety and preliminary efficacy of FP-1305 in patients with advanced, IO-refractory melanoma, cholangiocarcinoma, hepatocellular, colorectal, and pancreatic ductal adenocarcinoma. Biomarker analysis included CLEVER-1 determination, immune cell profiling by mass cytometry and analysis of cytokine production.

Results

11 patients (median age 57) were enrolled in four cohorts (0.3, 1.0, 3.0 or 10 mg/kg) and received 1-8 cycles (median 3) of FP-1305 every three weeks. FP-1305 has been well tolerated without dose-limiting toxicities and maximum tolerated dose (MTD) has not been reached. Promising early efficacy results have recently been reported (ESMO 2019, LBA19). FP-1305 dosing led to increased Th1 skewing (CXCR3⁺CCR6^-) of CD4 and CD8 T cell populations with downregulation of several inhibitory immune checkpoint molecules. Increase in circulating IFN gamma was detected but it was most prominent in the patient showing durable partial response.

Conclusion

FP-1305 is the first macrophage checkpoint inhibitor candidate promoting immune switch with promising tolerability and clinical anti-tumor activity. FP-1305 represents a novel treatment option to provoke immune response against cold tumors.

Clinical trial identification

NCT03733990.

Legal entity responsible for the study

Faron Pharmaceuticals.

Funding

Finnish Academy, Finnish Cancer Foundations, Sigrid Juselius Foundation, Faron Pharmaceuticals.

Disclosure

M. Hollmén: Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Faron Pharmaceuticals. P. Jaakkola: Advisory / Consultancy: Faron Pharmaceuticals. A. Minchom: Advisory / Consultancy: Faron Pharmaceuticals. S. Jalkanen: Shareholder / Stockholder / Stock options: Faron Pharmaceuticals. M. Karvonen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Faron Pharmaceuticals. J. Mandelin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Faron Pharmaceuticals. J. Koivunen: Advisory / Consultancy: Faron Pharmaceuticals; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: KaikuHealth. P. Bono: Advisory / Consultancy, Travel / Accommodation / Expenses, Spouse / Financial dependant: Faron Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: OrionPharma. All other authors have declared no conflicts of interest.

中文翻译：

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新型抗巨噬细胞抗体（抗Clever-1 mAb； FP-1305）在患有晚期实体瘤的MATINS试验患者中诱导的2O免疫转换生物标志物

抽象的

背景

清道夫受体CLEVER-1在肿瘤相关的巨噬细胞（TAM）上高表达，并介导“不需要的”自身成分的清除。临床前研究表明，CLEVER-1抑制作用可增加TAM促炎性细胞因子的分泌，并通过抗原呈递重新激活具有强大抗肿瘤活性的CD8 + T细胞应答（Viitala等，2019）。靶向CLEVER-1可以克服免疫抑制性肿瘤微环境，并导致了人源化抗CLEVER-1 IgG4抗体FP-1305的开发。

方法

MATINS（抑制免疫抑制的巨噬细胞抗体）试验是一项多中心的人体首次I / II期研究（NCT03733990），旨在评估FP-1305在IO难治性黑色素瘤，胆管癌患者中的耐受性，安全性和初步疗效。 ，肝细胞癌，结肠直肠癌和胰腺导管腺癌。生物标志物分析包括CLEVER-1测定，通过大规模细胞术进行免疫细胞谱分析以及细胞因子产生分析。

结果

11名患者（中位年龄57岁）参加了四个队列（0.3、1.0、3.0或10 mg / kg），每三周接受1-8个周期（中位数3）的FP-1305。FP-1305具有良好的耐受性，没有剂量限制的毒性，并且尚未达到最大耐受剂量（MTD）。最近报道了有希望的早期疗效结果（ESMO 2019，LBA19）。FP-1305加药导致向Th1偏斜增加（CXCR3 ⁺ CCR6 ^-）CD4和CD8 T细胞群的具有若干抑制性免疫检查点的分子的下调。检测到循环中的IFNγ升高，但在患者中表现出持久的部分反应最为明显。

结论

FP-1305是第一个以有希望的耐受性和临床抗肿瘤活性促进免疫转换的巨噬细胞检查点抑制剂候选物。FP-1305代表了一种新的治疗选择，可激发针对寒冷肿瘤的免疫反应。

临床试验鉴定

NCT03733990。

负责研究的法人实体

法伦制药。

资金

芬兰科学院，芬兰癌症基金会，Sigrid Juselius基金会，法伦制药。

揭露

M.Hollmén：研究补助金/资金（机构），差旅/住宿/费用，股东/股东/股票期权：Faron Pharmaceuticals。P. Jaakkola：咨询/顾问：Faron Pharmaceuticals。答：Minchom：咨询/顾问：Faron Pharmaceuticals。S. Jalkanen：股东/股东/股票期权：Faron Pharmaceuticals。M. Karvonen：股东/股东/股票期权，全职/兼职：Faron Pharmaceuticals。J. Mandelin：股东/股东/股票期权，全职/兼职：Faron Pharmaceuticals。J. Koivunen：咨询/顾问：Faron Pharmaceuticals；咨询/顾问：诺华；咨询/顾问：辉瑞；咨询/顾问：勃林格殷格翰公司；咨询/顾问：KaikuHealth。P. Bono：咨询/顾问，旅行/住宿/费用，配偶/财务受养人：Faron Pharmaceuticals；咨询/顾问，差旅/住宿/费用：MSD；咨询/顾问：辉瑞；咨询/顾问：诺华；咨询/顾问：百时美施贵宝；咨询/顾问：OrionPharma。所有其他作者都声明没有利益冲突。