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疗效受到肿瘤内抗体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、稳定地与肿瘤局部抗体受体结合；(2)快速清除全身放射性。我们用一种胰腺癌反应性单抗(NR-LU-10)和链霉亲和素的结合物作为预定位的、肿瘤特异性的高亲和力受体来预先靶向上皮性肿瘤。48小时后，用生物素化的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90Y-DOTA-生物素配体进行放射治疗。在初步的第一阶段研究以优化这种PRIT方案的成分的剂量和时机后，40名难治性上皮性肿瘤患者(卵巢11例，结肠10例，卧床9例，乳房6例，杂项4例)注射剂量递增的90Y。获得了正常组织和肿瘤的剂量估算。在目前可评估疗效的33例患者中，有2例部分反应(前列腺和卵巢)，4例轻微反应(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分；III/IV级，2分)；血小板减少(I/II级，9分；III/IV级，7分)；中性粒细胞减少(I/II级，8分；III/IV级，4分)；和腹泻(I/II级，6分；III/IV级，4分)。PRIT的剂量限制毒性为腹泻，剂量水平为140mCI/m~2，90Y。90Y PRIT的第二阶段试验计划在前列腺癌、结肠癌或小细胞肺癌患者中进行，剂量为120mCI/m2。

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.