Ritchie D, Mileshkin L, Wall D, Bartholeyns J, Thompson M, Coverdale J, Lau E, Wong J, Eu P, Hicks R J, Prince H M
Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Locked Bag, 1 A'Beckett St, 8006 East Melbourne, Australia.
Cancer Immunol Immunother. 2007 Feb;56(2):155-63. doi: 10.1007/s00262-006-0181-3. Epub 2006 May 30.
Radio-labelling of blood cells is an established technique for evaluating in vivo migration of normal cells to sites of pathology such as infection and haemorrhage. A limitation of cellular immunotherapies to induce anti-tumour responses is in part due to the uncertain ability of cellular effectors to reach their intended target. We extended the approach of cell radiolabelling to accurately examine the in vivo distribution of cellular immunotherapy with ex-vivo macrophage activated killer (MAK) cells. We describe the use of two methods of cell labelling for tracking the destination of autologous-derived macrophage activated killer (MAK) cells linked to the bi-specific antibody MDX-H210 delivered either by intravenous (i.v.) or intraperitoneal (i.p.) injection in ten patients with peritoneal relapse of epithelial ovarian carcinoma. Our results demonstrate the feasibility of generating high numbers and purity of GMP quality MAK cells, which can be radiolabelled with (18)F-FDG or (111)In-oxime. MAK cell administration produced minimal infusional toxicity and demonstrated a reproducible pattern of in vivo distribution and active in vivo tracking to sites of known tumour following 8 of 16 i.v. infusions or 4 of 6 i.p. infusions. However, the leakage of (18)F-FDG limited the ability to confidently confirm the tracking of MAK cells to tumour in all cases and improved PET labels are required. The addition of MDX-H210 bispecific antibody did not alter the distribution of cells to tumour sites, but did accelerate the clearance of i.v. administered MAK cells from the pulmonary circulation. This data demonstrates that cellular cancer immunotherapies may be successfully delivered to the sites of active tumour following either i.v. or i.p. injection in a proportion of patients with metastatic cancer. Incorporation of tracking studies in early cycles of cellular immunotherapy may allow selection of patients who demonstrate successful targeting of the immunotherapy for ongoing treatment.
血细胞的放射性标记是一种用于评估正常细胞在体内向感染和出血等病理部位迁移的成熟技术。细胞免疫疗法诱导抗肿瘤反应的一个局限性部分归因于细胞效应器到达其预期靶点的能力不确定。我们扩展了细胞放射性标记方法，以准确检测体外巨噬细胞激活的杀伤细胞（MAK）进行细胞免疫治疗后的体内分布。我们描述了使用两种细胞标记方法来追踪与双特异性抗体MDX-H210相连的自体来源巨噬细胞激活的杀伤细胞（MAK）的去向，该抗体通过静脉注射（i.v.）或腹腔注射（i.p.）给予10例上皮性卵巢癌腹膜复发患者。我们的结果表明，生成大量且纯度符合GMP质量的MAK细胞是可行的，这些细胞可用（18）F-FDG或（111）In-肟进行放射性标记。MAK细胞给药产生的输注毒性极小，并显示出可重复的体内分布模式，在16次静脉输注中的8次或6次腹腔输注中的4次后，能在体内积极追踪到已知肿瘤部位。然而，（18）F-FDG的渗漏限制了在所有情况下可靠确认MAK细胞向肿瘤追踪的能力，因此需要改进PET标记。添加MDX-H210双特异性抗体并未改变细胞向肿瘤部位的分布，但确实加速了静脉注射的MAK细胞从肺循环中的清除。该数据表明，在一部分转移性癌症患者中，细胞癌症免疫疗法通过静脉注射或腹腔注射均可成功递送至活跃肿瘤部位。在细胞免疫治疗的早期周期纳入追踪研究，可能有助于选择那些显示免疫治疗成功靶向的患者进行持续治疗。
