STUDY OF 90 YTTRIUM/DOTA/BIOTIN LOCALIZATION IN ADVANCED CANCER

传统的放射免疫疗法在治疗人类癌症中的疗效受到抗体在肿瘤中定位不足和循环放射性对骨髓毒性的限制。PRIT具有以下优点：（1）快速、高效、特异性和稳定地结合肿瘤局部抗体受体，（2）快速消除全身的放射性。我们用泛癌反应性单克隆抗体（NR-LU-10）和链霉亲和素的结合物作为一种预先定位的肿瘤特异性高亲和力受体，预先靶向上皮肿瘤。48小时后，用生物素化人血清白蛋白清除剩余的循环结合物。最后，24小时后，使用小分子90 Y-DOTA-生物素配体递送放射性。 在初步I期研究以优化该PRIT方案组分的剂量和时间后，40名患有难治性上皮肿瘤的患者（11名卵巢，10名结肠，9名前列腺，6名乳腺，4名其他）注射剂量递增的90 Y。获得正常组织和肿瘤的剂量学估计。在目前可评价缓解的33例患者中，有2例部分缓解（前列腺和卵巢），4例轻微缓解（2例卵巢，1例结肠，1例前列腺），9例患者病情稳定。毒性包括恶心和呕吐（I/II级，20例患者; III/IV级，3例患者）;肝功能检查升高（I/II级，16例患者; III/IV级，2例患者）;血小板减少症（I/II级，9例患者; III/IV级，7例患者）;中性粒细胞增多症（I/II级，8例患者; III/IV级，4例患者）;和腹泻（I/II级，6例患者; III/IV级，4例患者）。PRIT的剂量限制性毒性为140 mCi/m2 90 Y剂量水平下的腹泻。计划在前列腺癌、结肠癌或小细胞肺癌患者中进行120 mCi/m2的90 Y PRIT II期试验。

The efficacy of conventional radioimmunotherapy in the treatment of human cancer is limited by inadequate localization of antibody in tumor and toxicity to marrow from circulating radioactivity. PRIT offers the advantages of (1) rapid, efficient, specific, and stable binding of tumor localized antibody receptor, and (2) rapid elimination of radioactivity from the whole body. We pretargeted epithelial tumors with a conjugate of a pancarcinoma-reactive monoclonal antibody (NR-LU-10) and streptavidin to act as a prelocalized, tumor-specific high affinity receptor. Forty-eight hours later the remaining circulating conjugate was cleared with biotinylated human serum albumin. Finally, 24 hours later radioactivity was delivered using a small molecule 90Y-DOTA-biotin ligand. After preliminary Phase I studies to optimize the doses and timing of the components of this PRIT regimen, 40 patients with refractory epithelial neoplasms (11 ovary, 10 colon, 9 prostrate, 6 breast, 4 misc.) were injected with increasing doses of 90Y. Dosimetry estimates for normal tissues and tumor were obtained. Of 33 patients currently evaluable for response, there were two partial responses (prostate and ovary), four minor responses (2 ovary, 1 colon, 1 prostate), and nine patients with stable disease. Toxicity has consisted of nausea and vomiting (Grade I/II, 20 pts.; Grade III/IV, 3 pts.); elevated liver function tests (Grade I/II, 16 pts.; Grade III/IV, 2 pts.); thrombocytopenia (Grade I/II, 9 pts.; Grade III/IV, 7pts.); Neutropenia (Grade I/II, 8 pts.; Grade III/IV, 4 pts.); and diarrhea (Grade I/II, 6 pts.; Grade III/IV, 4 pts.). The dose limiting toxicity of the PRIT was diarrhea at a dose level of 140 mCi/m2 90Y. Phase II trials of 90Y PRIT at 120 mCi/m2 are planned in patients with prostate, colon or small cell lung cancer.