A Phase I dose-escalation study using 90Y-CYT-356 monoclonal antibody was performed in 12 patients with hormone-refractory prostate carcinoma. Biodistribution studies using 111In-CYT-356 were performed 1 week before 90Y-CYT-356 administration. Of the 12 patients, 58% had at least one site of disease imaged after administration of 111In-CYT-356. The dose of 90Y ranged from 1.83-12 mCi/m2. Both 111In and 90Y-CYT-356 were tolerated well, without significant nonhematological toxicity. Myelosuppression was the dose-limiting toxicity and occurred at dose levels of 4.5-12 mCi/m2. Of the patients receiving </=9 mCi/m2, 55% had grade 1 or 2 leukopenia and/or thrombocytopenia. Two of three patients treated with 12 mCi/m2 experienced grade 3 thrombocytopenia and leukopenia. One patient treated with 12 mCi/m2 had grade 4 neutropenia. The maximum tolerated dose of 90Y-CYT-356 was 9 mCi/m2. Only one patient developed a human anti-mouse antibody 4 weeks after treatment. No patient attained a complete or partial response based on prostate-specific antigen and/or radiological criteria. Three patients had transient subjective improvement in the symptomatology of their disease. In addition, patients treated with 12 mCi/m2 of 90Y-CYT-356 had a slightly longer freedom from disease progression than patients treated with doses of 90Y-CYT-356 </=9 mCi/m2.

/pdf/treatment-of-hormone-refractory-prostate-cancer-with-90y-cyt-4fbcw94jdm.pdf

Treatment of hormone-refractory prostate cancer with 90Y-CYT-356 monoclonal antibody.

Improved methods for treatment of cancer which involve the targeting of slow-growing, relatively mutationally-spared cancer stem line are provided. These methods are an improvement over previous cancer therapeutic methods because they provide for very early cancer treatment and reduce the likelihood of clinical relapse after treatment.

Novel methods of cancer diagnosis and therapy targeted against a cancer stem line

Monoclonal antibodies (MoAb) labeled with 90 Y are being used for radioimmunotherapy. Because 90 Y is a beta emitter, quantitative information from imaging is suboptimal. With the concept of a matched pair of isotopes, 111 In is used as a surrogate marker for 90 Y. We evaluated the differences in biodistribution between 111 In- and 90 Y-labeled murine antiTac MoAb directed against the IL-2Rα receptor. Methods: The antiTac was conjugated to the 2-(4-isothiocyanatobenzyl)-6-methyl-diethylenethamine pentaacetic acid (1B4M-DTPA, also known as MX-DTPA). Nine patients with adult T-cell leukemia were treated. Patients received approximately 185 MBq (5 mCi) 111 In-labeled antiTac for imaging and 185-555 MBq (5-15 mCi) 90 Y-labeled antiTac for therapy. The immunoreactivity of 111 In-labeled antiTac was 90% ± 6%, whereas for 90 Y-labeled antiTac, it was 74% ± 12%. Results: The differences in blood and plasma kinetics of the two isotopes were small. The area undemeath the blood radioactivity curve was 1.91 percentage ± 0.58 percentage injected dose (%ID) × h/mL for 111 In and 1.86% ± 0.64 %ID × h/mL for 90 Y. Urinary excretion of 90 Y was significantly greater than that of 111 In in the first 24 h (P = 0.001), but later, the excretion of 111 In was significantly greater (P = 0.001 to P = 0.04). Core biopsies of bone marrow showed a mean of 0.0029 ± 0.0012 %ID/g for 111 In, whereas the 90 Y concentration was 0.0049 ± 0.0021 %ID/g. Analyses of activity bound to circulating cells showed concentrations of 500-30,000 molecules of antiTac per cell. When cell-bound activity was corrected for immunoreactive fraction, the ratio of 111 In to 90 Y in circulating cells was 1.11 ± 0.17. Three biopsies of tumor-involved skin showed ratios of 111 In to 90 Y of 0.7, 0.9 and 1.1. Conclusion: This study shows that differences typically ranging from 10% to 15% exist in the biodistribution between 111 In- and 90 Y-labeled antiTac. Thus, it appears that 111 In can be used as a surrogate marker for 90 Y when labeling antiTac with the 1B4M chelate, although underestimates of the bone marrow radiation dose should be anticipated.

Similarities and differences in 111In- and 90Y-labeled 1B4M-DTPA antiTac monoclonal antibody distribution.

Clinical radioimmunotherapy†1

Targeted radionuclide therapy (TRT) seeks molecular and functional targets within patient tumor sites. A number of agents have been constructed and labeled with beta, alpha, and Auger emitters. Radionuclide carriers spanning a broad range of sizes; e.g., antibodies, liposomes, and constructs such as nanoparticles have been used in these studies. Uptake, in percent-injected dose per gram of malignant tissue, is used to evaluate the specificity of the targeting vehicle. Lymphoma (B-cell) has been the primary clinical application. Extension to solid tumors will require raising the macroscopic absorbed dose by several-fold over values found in present technology. Methods that may effect such changes include multistep targeting, simultaneous chemotherapy, and external sequestration of the agent. Toxicity has primarily involved red marrow so that marrow replacement can also be used to enhance future TRT treatments. Correlation of toxicities and treatment efficiency has been limited by relatively poor absorbed dose estimates partly because of using standard (phantom) organ sizes. These associations will be improved in the future by obtaining patient-specific organ size and activity data with hybrid SPECT/CT and PET/CT scanners.

Targeted radionuclide therapy

This Phase I trial explores the use of high-dose 90 Y conjugated to the antibreast cancer monoclonal antibody BrE-3 and autologous hematologic cell support in the treatment of women with stage four breast cancer. Nine women with heavily pretreated disease were enrolled. All of the patients had BrE-3-positive tumors by immunostaining and were treated with increasing doses of 90 Y (15 mCi/m 2 , 3 patients), 20 mCi/M 2 (six patients), and a fixed (50 mg) dose of BrE-3. 111 In-labeled BrE-3 (5 mCi) was given simultaneously for scanning purposes. The only toxicity noted was hematological. Grade 4 platelet toxicity requiring transfusion support occurred in four patients. Grade 4 WBC toxicity was seen in two patients that resolved in 3–9 days. All hematological nadirs occurred approximately 25 days after treatment. Objective partial responses were noted in 4 of 8 (50%) patients with measurable tumors. Dose escalation is ongoing.

https://cancerres.aacrjournals.org/content/canres/55/23_Supplement/5921s.full.pdf

High-Dose 90Y Mx-Diethylenetriaminepentaacetic Acid (DTPA)-BrE-3 and Autologous Hematopoietic Stem Cell Support (AHSCS) for the Treatment of Advanced Breast Cancer: A Phase I Trial

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High-Dose 90Y Mx-Diethylenetriaminepentaacetic Acid (DTPA)-BrE-3 and Autologous Hematopoietic Stem Cell Support (AHSCS) for the Treatment of Advanced Breast Cancer: A Phase I Trial