Objectives: Keyhole limpet haemocyanin (KLH) is a high-molecular-weight protein antigen collected from the haemolymph of the sea mollusk Megathura crenulata. It is a powerful non-specific immune response modifier that induces both a cell-mediated and a humoral response in animals and man. Thus, it is commonly used clinically as a measure of immune competence. In 1974, Olson studied the immune competence of bladder cancer patients by intradermal application of KLH. He later observed a significant reduction of recurrent disease in this patient group compared to another not immunized with KLH. This prompted a variety of experimental and clinical studies using KLH as an immunotherapy for recurrent bladder cancer. Methods: Three different bladder cancer models have been used for experimental studies: intravesical transplantation of tumour cells in syngeneic mouse bladders; subcutaneous transplantation of tumour cells in syngeneic mice; direct chemical induction of bladder tumours by feeding rats with the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine. Results: The efficacy of KLH as an immunotherapeutic agent has been compared with different immune response modifiers alone or in combination with these in 11 experimental studies. Most of the studies used different concentration and application schedules for KLH. In addition a pre-immunisation prior to inoculation of the tumour was not performed in all studies. Therefore it is not useful to compare the results of these studies. However, most of the experiments demonstrated a significant effect on tumour appearance and extension after treatment with KLH. Intralesional or systemic application of KLH seemed to be superior to intravesical treatment. Pre-immunisation with KLH several days or weeks before tumour inoculation also seems to be a key point of success. No study reported severe side-effects after application of KLH; additionally performed toxicity studies underlined the good tolerability of KLH. Conclusion: Based on all the experimental studies, KLH has to be judged as an effective and safe immunotherapeutic drug for the treatment of experimental bladder cancer. Prospective randomised clinical trials should evaluate the role of KLH as an immunotherapeutic alternative in the prophylaxis of recurrent bladder cancer and should determine whether the efficacy of KLH in man may be improved by systemic application.

Keywords:
Immunotherapy, Bladder cancer, Animal experiment, Haemocyanin
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2000
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