Anticancer immunotherapy in combination with proapoptotic therapy

Induction of immune responses against cancer-associated antigens is possible, but the optimal use of this strategy remains to be established and especially the combination of T cell therapy and the use of new targeted therapeutic agents should be investigated. The design of future clinical studies then has to consider several issues. Firstly, induction of anticancer T cell reactivity seems most effective in patients with low disease burden. Initial disease-reducing therapy including surgery, irradiation and conventional or new targeted chemotherapy should therefore be used, preferably through induction of immunogenic cancer cell death. Secondly, after the induction phase effector T cells will induce cancer cell apoptosis mainly through the intrinsic apoptosis-regulating pathway. The effect of this anticancer immune reactivity should be strengthened by the administration of chemotherapy that mediates additional proapoptotic signalling through the external apoptosis-initiating pathway, blocking of anti-apoptotic signalling or inhibition of survival signalling. Thirdly, conventional chemotherapy and new targeted therapy have direct immunosuppressive effects on the T cell system, but even patients with severe chemotherapy-induced lymphopenia have an operative T cell system and immunotherapy may therefore be initiated immediately or early after disease-reducing therapy when the cancer cell burden is expected to be lowest. Finally, chemotherapy toxicity on human T cells is not a random process, and one should especially focus on the possibility to strengthen anticancer immune reactivity through chemotherapy-induced elimination or inhibition of immunosuppressive regulatory T cells. All these issues need to be considered in the design of future clinical studies combining chemotherapy and immunotherapy.