Abstract
BackgroundCD8-positive cells might play a crucial role in the therapeutic response to radiation, which has however not been investigated in radioimmunotherapy (RIT). The aim of this study was to evaluate whether cytotoxic T cells affect the response of established tumors and, above all, if they delay or prevent the development of distant metastases after RIT, using an immunocompetent syngeneic rat colon carcinoma model.MethodsThe cytotoxic T cells were depleted in 15 rats by anti-CD8 before the injection of the radioimmunoconjugate (400 MBq/kg body weight 177Lu-BR96, which binds to the tumor-associated antigen Lewis Y). Fifteen other rats were treated with RIT only. Both groups were followed for 99 days. Blood samples were collected at least once weekly, and tumors were monitored twice weekly.ResultsTwenty-nine of the 30 animals exhibited local complete response. The non-responder was treated with anti-CD8 and RIT but succumbed later due to metastases. Five animals in the group given anti-CD8 + RIT were sacrificed due to metastatic disease, and 4 additional animals were found to have metastases at autopsy. In the group given RIT, 4 animals developed metastatic disease, but no metastases were found in the remaining 11 animals at autopsy. Thus, at the end of the study, 6 animals in the anti-CD8 + RIT group were free from metastases, while 11 were free from metastases in the group receiving RIT.CD3+CD4−CD8+ lymphocytes were consistently depleted by the anti-CD8 treatment. The myelosuppression was otherwise similar in the two groups. The initial depletion of CD8-positive cells in our syngeneic rat colon carcinoma model resulted in a higher frequency of animals developing metastases.ConclusionsDepletion of CD8-positive cells during RIT in an immunocompetent rat tumor model might influence the number of animals developing metastases, indicating that the immune system may be important in the long-term outcome of RIT.
Highlights
CD8-positive cells might play a crucial role in the therapeutic response to radiation, which has not been investigated in radioimmunotherapy (RIT)
Using our immunocompetent syngeneic rat colon carcinoma model, we have previously shown that RIT consisting of the beta emitter 177Lu (400 MBq/kg body weight) conjugated to the monoclonal antibody BR96 resulted in complete response in 17 of 19 animals [2]
instant thinlayer chromatography (ITLC) showed the radiochemical purity to be 95% and 4% aggregates or fragments were observed with high-performance liquid chromatography (HPLC)
Summary
CD8-positive cells might play a crucial role in the therapeutic response to radiation, which has not been investigated in radioimmunotherapy (RIT). The aim of this study was to evaluate whether cytotoxic T cells affect the response of established tumors and, above all, if they delay or prevent the development of distant metastases after RIT, using an immunocompetent syngeneic rat colon carcinoma model. Using our immunocompetent syngeneic rat colon carcinoma model, we have previously shown that RIT consisting of the beta emitter 177Lu (400 MBq/kg body weight) conjugated to the monoclonal antibody BR96 resulted in complete response in 17 of 19 animals [2]. Cyclosporin A, a substance known to have its major effects on T cells [3,4,5,6,7,8], was given to prevent the development of immune response to the therapeutic mouse/human chimeric antibody. Treatment with cyclosporin A prolonged the time to complete response
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