Phase 1 evaluation of intralesionally injected TLR9-agonist PF-3512676 in patients with basal cell carcinoma or metastatic melanoma
Phase 1 evaluation of intralesionally injected TLR9-agonist PF-3512676 in patients with basal cell carcinoma or metastatic melanoma
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DOI：
10.1097/cji.0b013e318174a4df
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发表时间：
2008-06-01
影响因子：
3.9
通讯作者：
Trefzer, Uwe
中科院分区：
文献类型：
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作者：
Hofmann, Maja A.;Kors, Christian;Trefzer, Uwe
合成的寡脱氧核苷酸（ODN），如PF-3512676，含有未甲基化的胞嘧啶-鸟嘌呤基序（CpG ODN），已被体外和小鼠模型鉴定为高效的免疫激活剂。CpG ODNs通过触发人B细胞和浆细胞样树突状细胞表达的toll样受体9来诱导先天和适应性免疫反应。一项I期研究启动，旨在研究PF-3512676在基底细胞癌（BCC）或皮肤或皮下黑色素瘤转移患者病灶内治疗的安全性、耐受性、血清细胞因子水平、细胞免疫反应和临床活性。在5例BCC患者和5例黑色素瘤患者的皮肤或皮下转移中，每14天注射一次患者内递增剂量的PF-3512676（高达10mg）。PF-3512676耐受性良好。9/10患者在注射部位出现局部肿胀和红斑。III级血液学不良事件（淋巴细胞减少症）发生率仅有1例。BCC患者局部肿瘤消退（1例完全消退，4例部分消退），转移性黑色素瘤患者（1例完全消退）。使用PF-3512676治疗后，所有患者的白细胞介素-6升高，8/10例患者的干扰素- γ诱导蛋白-10升高，7/10例患者的白细胞介素-12p40升高，6/10例患者的肿瘤坏死因子- α升高。所有患者均行活组织检查；两种组织学类型的大多数病变治疗后均可见中度至丰富的淋巴细胞浸润。PF-3512676用于皮肤肿瘤的病灶内治疗是安全且耐受性良好的。尽管剂量相对较低，但在BCC和皮肤或皮下转移性黑色素瘤病变患者中均显示出临床活性。
Synthetic oligodeoxynucleotides (ODNs), such as PF-3512676, that contain unmethylated cytosine-guanine motifs (CpG ODN) have been identified as highly potent immune activators by in vitro examinations and in murine models. CpG ODNs induce innate and adaptive immune responses by triggering Toll-like receptor 9 expressed by human B cells and plasmacytoid dendritic cells. A phase I study was initiated to investigate safety, tolerability, serum cytokine levels, cellular immune responses, and clinical activity of intralesional treatment with PF-3512676 in patients with basal cell carcinoma (BCC) or cutaneous or subcutaneous melanoma metastases. Intrapatient escalating doses of PF-3512676 (up to 10mg) were injected intralesionally every 14 days in 5 patients with BCC and in cutaneous or subcutaneous metastases of 5 patients with melanoma. PF-3512676 was well tolerated. Local swelling and erythema occurred at the injection site in 9/10 patients. There was only I incidence of a grade III hematologic adverse event (lymphocytopenia). Local tumor regressions were observed in patients with BCC (I complete regression, 4 partial regressions) and metastatic melanoma (I complete regression). After treatment with PF-3512676, interleukin-6 was increased in all patients, interferon-gamma induced protein-10 in 8/10 patients, interleukin-12p40 in 7/10 patients, and tumor necrosis factor-alpha levels in 6/10 patients. All patients had biopsies; moderate to abundant cellular infiltrates of lymphocytes were found post-treatment in most lesions of both histologic types. Intralesional treatment of skin tumors with PF-3512676 was safe and well tolerated. Despite the relatively low dosage, clinical activity was demonstrated both in patients with BCC and with cutaneous or subcutaneous metastatic melanoma lesions.