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.
Bruserud
Øystein
Ø
Section for Hematology, Institute for Internal Medicine, University of Bergen, Bergen, Norway. oystein.bruserud@haukeland.no
Ersvaer
Elisabeth
E
Olsnes
Astrid
A
Gjertsen
Bjørn Tore
BT
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D019496:Cancer Vaccines / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*
D000970:Antineoplastic Agents; D019496:Cancer Vaccines