Intraperitoneal Pretargeted Radioimmunotherapy for Colorectal Peritoneal Carcinomatosis.
Intraperitoneal Pretargeted Radioimmunotherapy for Colorectal Peritoneal Carcinomatosis.
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DOI：
10.1158/1535-7163.mct-21-0353
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发表时间：
2022-01
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
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腹膜癌（PC）被认为是无法治愈的，需要更有效的治疗。本研究验证了gpa33导向的腔室内预靶向放射免疫治疗（PRIT）可以治愈结肠直肠癌的假设。裸鼠腹腔内植入荧光素酶转导的表达gpa33的SW1222细胞，用于侵袭性PC（例如，切除肿瘤0.369±0.246 g；第29天n = 17）。对于GPA33-PRIT，我们首先给予高亲和力抗gpa33 /抗dota双特异性抗体（BsAb），然后分别给予清除剂（i.v）和放射性标记的dota -放射性半抗原（i.p.），用于β / γ -发射体治疗和PET成像。以S-2-（4-氨基苄）-1,4,7,10-四氮杂环十二烷四乙酸螯合物（DOTA-Bn）为原料制备了dota放射性半抗原。在小鼠肿瘤植入后26-27 d对单周期和三周期治疗的疗效和毒性进行了评价。与对照组相比，单周期治疗（[177Lu]LuDOTA-Bn 111 MBq；肿瘤剂量：4992 cGy）显著延长中位生存期（MS）约2倍至84.5 d （P = 0.007）。采用三周期治疗（每周一次，总剂量为333 MBq，肿瘤剂量为14975 cGy）， 6/8（75%）患者长期存活（MS bb0 183 d）。此外，在这些接受治疗的长期幸存者中，有一只小鼠在尸检时完全无病（显微镜下“治愈”）；其余患者病情稳定，可通过PET-CT [86Y]DOTA-Bn检测到。治疗对照组的MS时间为42-52.5天（P < 0.001）， 19/20的小鼠在69天内死于进行性i.p.疾病。多周期GPA33 DOTA-PRIT显著延长了生存期，具有可复性骨髓抑制，无慢性骨髓（血液929 cGy）或肾脏（982 cGy）放射毒性，血液ti为12，肾脏ti为12。没有达到预定时间。
Peritoneal carcinomatosis (PC) is considered incurable, and more effective therapies are needed. Herein we test the hypothesis that GPA33-directed intracompartmental pretargeted radioimmunotherapy (PRIT) can cure colorectal PC. Nude mice were implanted intraperitoneally (i.p.) with luciferase-transduced GPA33-expressing SW1222 cells for aggressive PC (e.g., resected tumor mass 0.369 ± 0.246 g; n = 17 on day (d) 29). For GPA33-PRIT, we administered i.p. a high-affinity anti-GPA33/anti-DOTA bispecific antibody (BsAb), followed by clearing agent (i.v.), and lutetium-177 (Lu-177) or yttrium-86 (Y-86) radiolabeled DOTA-radiohapten (i.p.) for beta/gamma-emitter therapy and PET imaging, respectively. The DOTA-radiohaptens were prepared from S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid chelate (DOTA-Bn). Efficacy and toxicity of single- vs. three-cycle therapy were evaluated in mice 26–27 d post-tumor implantation. Single-cycle treatment ([177Lu]LuDOTA-Bn 111 MBq; tumor dose: 4992 cGy) significantly prolonged median survival (MS) approximately two-fold to 84.5 d in comparison with controls (P = 0.007). With three-cycle therapy (once weekly, total 333 MBq; tumor dose: 14975 cGy), 6/8 (75%) survived long-term (MS > 183 d). Furthermore, for these treated long-term survivors, one mouse was completely disease-free (microscopic “cure”) at necropsy; the others showed stabilized disease, which was detectable during PET-CT using [86Y]DOTA-Bn. Treatment controls had MS ranging from 42–52.5 d (P < 0.001) and 19/20 mice succumbed to progressive i.p. disease by 69 d. Multi-cycle GPA33 DOTA-PRIT significantly prolongs survival with reversible myelosuppression and no chronic marrow (929 cGy to blood) or kidney (982 cGy) radiotoxicity, with TIs of 12 for blood and 12 for kidneys. MTD was not reached.
影响因子：
3.1
作者：
Orcutt, Kelly Davis;Nasr, Khaled A.;Whitehead, David G.;Frangioni, John V.;Wittrup, K. Dane
通讯作者：
Wittrup, K. Dane