Experimental radioimmunotherapy

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Abstract
Radiolabeled monoclonal antibodies have been used for radioimmunotherapy studies with human tumor spheroids and murine and human tumor xenografts in experimental animals. This paper reviews the work that has been performed in these models with different types of cancer, and highlights those papers that have presented dosimetry estimates and attempts to correlate the findings. Radioimmunotherapy studies in multicell spheroids, as a model for micrometastases, have been performed in human neuroblastoma, colon cancer, and melanoma cell lines using 131I‐, 125I‐, 186Re‐, and 212Bi‐labeled antibodies. The uniform geometry of the spheroid has allowed radiation dose estimates to be made. Up to three logs of cell kill have been achieved with 131I‐ and 186Re‐specific antibody with minimal toxicity from labeled nonspecific antibody, but 212Bi‐antibody had little effect because of its short half‐life as shown by Langmuir. It appears that the two most important factors for therapeutic efficacy in this model are good penetration of the radiolabeled antibody and an adequate radionuclide half‐life to allow penetration of the immunoconjugate prior to significant radionuclide decay. Radioimmunotherapy studies in animals bearing transplants of colon cancer, leukemia, lymphoma, hepatoma, renal cell carcinoma, neuroblastoma, glioma, mammary carcinoma, small cell lung carcinoma, cervical carcinoma, ovarian carcinoma, and bladder cancer have been performed with 131I, 90Y, 186Re, 153Sm, and 177Lu beta emitting, and 212Bi alpha emitting radionuclides conjugated to monoclonal antibodies. A few studies compared different radionuclides in the same model system. The approaches that have been used in these studies to estimate tumor dosimetry include the MIRD approach, thermoluminescent dosimetry, autoradiography, and comparison to external irradiation. The majority of investigators have estimated the dose to tumor and normal organs using MIRD‐based calculations (time‐activity curve and equilibrium dose constant method). The range of tumor doses has been between 17 and 11 171 mGy/MBq of administered radioactivity. The effectiveness of radiolabeled monoclonal antibody therapy depends on a number of factors relating to the antibody such as specificity, affinity, and immunoreactivity. The density, location, and heterogeneity of expression of tumor‐associated antigen within tumors will affect the localization and therapeutic efficacy of radiolabeled antibodies, as will physiological factors such as the tumor vascularity, blood flow, and permeability. These factors are discussed and examples are presented. In the future, it is recommended that investigators make comparisons of different radionuclides in the same system, which should include an analysis of the relative toxicity. It is also recommended that comparisons to external beam radiation be made for both tumor and normal tissue damage. It is also recommended that investigators look at radiation dose heterogeneity using thermoluminescent dosimeters and autoradiography, so that the range of tumor radiation dose and dose‐rate is reported. It is hoped that an answer to how heterogeneity in radiolabeled antibody deposition in experimental tumors and spheroids affects absorbed dose distribution and the radiobiological consequences will be understood. It is also hoped that a definitive answer will be obtained for what radionuclides and forms of antibody are optimum for radioimmunotherapy of leukemias, micrometastases, and solid tumors, and most importantly how best to apply these techniques and information to the treatment of cancer clinically.

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