ACTIVATION OF T-LYMPHOCYTES FOR THE ADOPTIVE IMMUNOTHERAPY OF CANCER

Background: Adoptive immunotherapy of malignancy involves the passive transfer of antitumor-reactive cells into a host in order to mediate t umor regression. Based on animal models, the transfer of immune lympho id cells can eradicate widely disseminated tumors and establish long-t erm systemic immunity. Critical for successful adoptive immunotherapy is the ability to isolate large numbers of immune cells. For clinical therapy, it will require the development of in vitro methods to promot e the sensitization and propagation of tumor-reactive cells. However, this is a formidable task since human cancers are postulated to be poo rly immunogenic because of their spontaneous origins. Results: Human l ymphoid cells for ex vivo activation and subsequent adoptive transfer have been derived from different sources, including peripheral blood, tumor and lymph nodes. Peripheral blood lymphocytes can be incubated w ith interleukin 2 to generate lymphokine-activated killer (LAK) cells. which nonspecifically lyse autologous and allogeneic tumor cells in v itro. LAK cell therapy represented the earliest attempt to treat advan ced human cancers, with encouraging results documented in patients wit h renal cell cancer and melanoma. From that experience, the use of mor e immunologically specific cellular agents with potentially greater th erapeutic efficacy has been investigated. One approach uses tumor-infi ltrating lymphocytes, which have been characterized experimentally to be more specific in tumor reactivity compared with LAK cells. Other te chniques have involved the use of lymphoid cells derived from lymph no des draining tumors or primed by tumor vaccines. In vitro activation o f these cells with tumor antigen or anti-CD3 monoclonal antibody resul ts in the generation of T cells that mediate the rejection of poorly i mmunogenic tumors in animal studies. These alternate methods are curre ntly being evaluated in clinical studies. Conclusions: Experimentally, cellular therapy is a potent method to eradicate progressive tumors. Initial clinical studies have demonstrated that this form of therapy i s technically feasible and can result in meaningful antitumor response s. Advances in this area will require improved methods to sensitize, i solate and ex and tumor-reactive T cells for adoptive transfer.