Radioimmunotherapy with Tenarad, a 131I-labelled antibody fragment targeting the extra-domain A1 of tenascin-C, in patients with refractory Hodgkin's lymphoma
Radioimmunotherapy with Tenarad, a 131I-labelled antibody fragment targeting the extra-domain A1 of tenascin-C, in patients with refractory Hodgkin's lymphoma
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DOI：
10.1007/s00259-013-2658-6
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发表时间：
2014-05-01
影响因子：
9.1
通讯作者：
Lastoria, Secondo
中科院分区：
文献类型：
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作者：
Aloj, Luigi;D'Ambrosio, Laura;Lastoria, Secondo
Tenascin-C的外区A1(TC-A1)在肿瘤的细胞外基质和新形成的血管中高表达，因此是放射性核素治疗的有价值的靶点。Tenarad是一种全人小抗体或小免疫蛋白(SIP，分子量80 kDa)，标记有I-131，来自TC-A1结合抗体。以前的I/II期研究表明，用于放射免疫治疗(RIT)的类似化合物(I-131-L19SIP)对各种癌症类型都有初步疗效。在这项正在进行的I/II期试验中，Tenarad用于常规治疗无效的复发霍奇金淋巴瘤(HL)患者。8名患者(4名男性，4名女性，年龄19-41岁)在2010年4月至2011年3月期间入选。所有患者都接受了之前三种化疗方案的中位数(范围从三到六)，七名患者还接受了自体干细胞移植(ASCT)或骨髓移植。此外，7名患者接受了外照射。所有患者均有结节病、体质B症状，部分患者表现为骨骼(4例)、肺(3例)、肝(2例)和脾(1例)的结外病变。基线评估包括全身FDG PET增强CT和诊断性Tenarad平面和SPECT研究。如果肿瘤摄取率高于肌肉摄取率的4倍以上，患者被认为有资格接受治疗剂量的替那得(2.05 GBq/m(2))。所有患者都符合资格并接受治疗剂量的替那得。只有一名患者出现了4级血小板减少和白细胞减少，需要住院和治疗干预。所有其他患者都有3级或更低的血液学毒性，这些毒性自动消失。首次疗效评估(治疗后4-6周)，1例完全缓解，1例部分缓解，5例病情稳定。五名患者接受了三次重复的Tenarad治疗。1例患者表现为SD，随后改善为PR，3例在维持SD的同时显示临床益处，1例显示病情进展。Tenarad RIT对化疗难治性HL有效，并在大多数患者中产生客观缓解或临床益处。尽管以前的治疗、以前的ASCT和多次Tenarad给药的负荷很高，但毒性是可以接受的。进一步的研究计划确定HL患者这种类型的RIT的最有效的治疗方案。
The extra-domain A1 of tenascin-C (TC-A1) is highly expressed in the extracellular matrix of tumours and on newly formed blood vessels and is thus a valuable target for radionuclide therapy. Tenarad is a fully human miniantibody or small immunoprotein (SIP, molecular weight 80 kDa) labelled with I-131 that is derived from a TC-A1-binding antibody. Previous phase I/II studies with a similar compound (I-131-L19SIP) used for radioimmunotherapy (RIT) have shown preliminary efficacy in a variety of cancer types. In this ongoing phase I/II trial, Tenarad was administered to patients with recurrent Hodgkin's lymphoma (HL) refractory to conventional treatments.Eight patients (four men, four women; age range 19 - 41) were enrolled between April 2010 and March 2011. All patients had received a median of three previous lines of chemotherapy (range three to six) and seven had also undergone autologous stem cell transplantation (ASCT) or bone marrow transplantation. In addition, seven patients received external beam radiation. All patients had nodal disease, constitutional B symptoms and some showed extranodal disease in skeletal bone (four patients), lung (three), liver (two) and spleen (one). Baseline assessments included whole-body FDG PET with contrast-enhanced CT and diagnostic Tenarad planar and SPECT studies. Patients were considered eligible to receive a therapeutic dose of Tenarad (2.05 GBq/m(2)) if tumour uptake was more than four times higher than that of muscle.All patients were eligible and received the therapeutic dose of Tenarad. Only one patient developed grade 4 thrombocytopenia and leucocytopenia, requiring hospitalization and therapeutic intervention. All other patients had haematological toxicity of grade 3 or lower, which resolved spontaneously. At the first response assessment (4 - 6 weeks after therapy), one patient showed a complete response, one showed a partial response (PR) and five had disease stabilization (SD). Five patients were given up to three repeated Tenarad treatments. One patient showed SD which then improved to a PR, three showed clinical benefit while maintaining SD and one patient showed disease progression.Tenarad RIT is effective in chemorefractory HL and resulted in objective responses or clinical benefit in the majority of patients. Toxicity was acceptable despite the high load of prior treatments, previous ASCT and multiple Tenarad administrations. Further studies are planned to define the most effective schedule for this type of RIT in HL patients.