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Purpose: Recent studies from this laboratory with (212)Pb-trastuzumab have shown the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using (212)Pb as an in vivo generator of (212)Bi. The objective of the studies presented here was improvement of the efficacy of alpha-particle radioimmunotherapy using a chemotherapeutic agent., Experimental Design: In a series of experiments, a treatment regimen was systematically developed in which athymic mice bearing i.p. LS-174T xenografts were injected i.p. with gemcitabine at 50 mg/kg followed by (212)Pb radioimmunotherapy., Results: In a pilot study, tumor-bearing mice were treated with gemcitabine and, 24 to 30 h later, with 5 or 10 muCi (212)Pb-trastuzumab. Improvement in median survival was observed at 5 microCi (212)Pb-trastuzumab in the absence (31 days) or presence (51 days) of gemcitabine: 45 and 70 days with 10 microCi versus 16 days for untreated mice (P < 0.001). Multiple doses of gemcitabine combined with a single (212)Pb radioimmunotherapy (10 microCi) administration was then evaluated. Mice received three doses of gemcitabine: one before (212)Pb-trastuzumab and two afterwards. Median survival of mice was 63 versus 54 days for those receiving a single gemcitabine dose before radioimmunotherapy (P < 0.001), specifically attributable to (212)Pb-trastuzumab (P = 0.01). Extending these findings, one versus two treatment cycles was compared. A cycle consisted of sequential treatment with gemcitabine, 10 microCi (212)Pb radioimmunotherapy, then one or two additional gemcitabine doses. In the first cycle, three doses of gemcitabine resulted in a median survival of 90 versus 21 days for the untreated mice. The greatest benefit was noted after cycle 2 in the mice receiving 10 microCi (212)Pb-trastuzumab and two doses of gemcitabine with a median survival of 196.5 days (P = 0.005). Pretreatment of tumor-bearing mice with two doses of gemcitabine before (212)Pb radioimmunotherapy was also assessed with gemcitabine injected 72 and 24 h before (212)Pb-trastuzumab. The median survival was 56 and 76 days with one and two doses of gemcitabine versus 49 days without gemcitabine. The effect may not be wholly specific to trastuzumab because (212)Pb-HuIgG with two doses of gemcitabine resulted in a median survival of 66 days (34 days without gemcitabine)., Conclusions: Treatment regimens combining chemotherapeutics with high-LET targeted therapy may have tremendous potential in the management and care of cancer patients.

A simple and rapid procedure was developed for the purification of cyclotron-produced 203Pb via the 203Tl(d,2n) 203Pb reaction. A Pb(II) selective ion-exchange resin, with commercial name Pb Resin from Eichrom Technologies, Inc., was used to purify 203Pb from the cyclotron-irradiated Tl target with excellent recovery of the enriched Tl target material. The purified 203Pb was used to radiolabel the monoclonal antibody Herceptin. The in vitro and in vivo properties of the 203Pb radioimmunoconjugate were evaluated.

The studies reported herein demonstrate the efficacy of alpha-particle-targeted radiation therapy of peritoneal disease with Herceptin as the targeting vehicle. Using the CHX-A-DTPA linker, Herceptin was radiolabeled with indium-111 and bismuth-213 with high efficiency without compromising immunoreactivity. A pilot radioimmunotherapy study treating mice bearing 5-day LS-174T (i.p.) xenografts, a low but uniform HER2 expressing, human colon carcinoma, with a single dose of (213)Bi-CHX-A"-Herceptin, proved disappointing. This defined the effect of tumor burden/size on tumor response to radioimmunotherapy with alpha-radiation. A more successful experiment with a lower tumor burden (3 days) in mice followed. A specific dose-response (P = 0.009) was observed, and although a maximum-tolerated dose was not determined, a dose of 500 to 750 muCi was selected as the operating dose for future experiments based on changes in animal weight. Median survival was increased from 20.5 days for the mock-treated mice to 43 and 59 days with 500 and 750 muCi, respectively. The therapeutic effectiveness of (213)Bi-CHX-A"-Herceptin was also evaluated in a second animal model for peritoneal disease with a human pancreatic carcinoma (Shaw). The results of this study were not as dramatic as with the former model, and higher doses were required to obtain an increase in survival of the mice (P = 0.001).