Clinical and in vitro responses to immune modulators in cancer patients.

A review of the literature is presented and includes the history of Immunotherapy for cancer; current concepts of the role of cells and cytokines in Immunotherapy for cancer and the mechanisms of cellular cytotoxicity. Twenty-one patients with advanced cancer or minimal residual cancer after potentially curative surgery were treated with the cytokine Interleukin-2 or Interleukin-2 plus chemotherapy. The treatment was well tolerated but was associated with a variety of side-effects. The most commonly seen toxicities were pyrexia, mild confusion, derangement of hepatic function and a skin rash. The severity of the side-effects was variable and were more pronounced in the hypernephroma patients. All toxicities were reversible except for mild renal dysfunction in the hypernephroma patients. Objective tumour responses were observed only in the hypernephroma patients and despite intensive monitoring, no test was found to correlate or predict tumour responses. Changes in the lymphocyte subsets of peripheral blood and skin in response to Interleukin-2 treatment were monitored and no consistent pattern was seen with the exception that patients who went on to develop tumour responses had a heavier pre-treatment lymphocytic infiltrate in their skin. Cellular cytotoxicity was measured during Interleukin-2 treatment and no consistent pattern was seen. Monoclonal antibodies to a range of cell surface antigens were found to modify cellular cytotoxicity in normal healthy controls. Monoclonal antibodies to the CD3 antigen were found to consistently enhance cellular cytotoxicity in vitro in normal healthy controls and the mechanism by which this occurs was evaluated. The only cancer patients who responded to anti-CD3 monoclonal antibody in a similar manner to the controls were those patients who subsequently developed tumour responses. This suggests that normally functioning CD3+ve cells are required for the development of a tumour response with Interleukin-2. Further experiments demonstrated a synergistic effect between anti-CD3 and Interleuldn-2 on enhancement of cellular cytotoxicity in vitro. This work suggests that anti-CD3 monoclonal antibodies, either alone or in combination with Interleukin-2 may have an important therapeutic role in cancer treatment.