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

传统的放射免疫疗法治疗人类癌症的效果受到抗体在肿瘤中的定位不足和循环放射性对骨髓的毒性的限制。PRIT具有以下优点：(1)快速、高效、特异、稳定地结合肿瘤定位抗体受体；(2)快速消除全身放射性。我们用一种胰腺癌反应性单克隆抗体（NR-LU-10）和链霉亲和素的偶联物预先靶向上皮肿瘤，作为一种预先定位的、肿瘤特异性的高亲和力受体。48小时后，剩余的循环偶联物用生物素化的人血清白蛋白清除。最后，24小时后使用小分子90y - dota生物素配体传递放射性。在初步的I期研究中，优化了PRIT方案各成分的剂量和时间，40例难治性上皮肿瘤患者（11例卵巢，10例结肠，9例前列腺，6例乳腺，4例其他）注射了90Y的增加剂量。获得了正常组织和肿瘤的剂量估计。在目前可评估应答的33例患者中，有2例部分应答（前列腺和卵巢），4例轻微应答（2例卵巢，1例结肠，1例前列腺），9例病情稳定。毒性包括恶心和呕吐（I/II级，20分；III/IV级，3分）；肝功能升高（I/II级，16例；III/IV级，2例）；血小板减少症（I/II级，9例；III/IV级，7例）；中性粒细胞减少症（I/II级，8例；III/IV级，4例）；腹泻（I/II级，6分；III/IV级，4分）。在140 mCi/m2 90Y剂量水平下，PRIT的剂量限制毒性为腹泻。计划在前列腺癌、结肠癌或小细胞肺癌患者中进行120mci /m2剂量90Y PRIT的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.