Combined cytotoxic chemotherapy and immunotherapy of cancer: modern times.

Monoclonal antibodies targeting programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoints have improved the treatments of cancers. However, not all patients equally benefit from immunotherapy. The use of cytotoxic drugs is practically inevitable to treat advanced cancers and metastases. The repertoire of cytotoxics includes 80 products that principally target nucleic acids or the microtubule network in rapidly proliferating tumor cells. Paradoxically, many of these compounds tend to become essential to promote the activity of immunotherapy and to offer a sustained therapeutic effect. We have analyzed each cytotoxic drug with respect to effect on expression and function of PD-(L)1. The major cytotoxic drugs-carboplatin, cisplatin, cytarabine, dacarbazine, docetaxel, doxorubicin, ecteinascidin, etoposide, fluorouracil, gemcitabine, irinotecan, oxaliplatin, paclitaxel and pemetrexed-all have the capacity to upregulate PD-L1 expression on cancer cells (via the generation of danger signals) and to promote antitumor immunogenicity, via activation of cytotoxic T lymphocytes, maturation of antigen-presenting cells, depletion of immunosuppressive regulatory T cells and/or expansion of myeloid-derived suppressor cells. The use of 'immunocompatible' cytotoxic drugs combined with anti-PD-(L)1 antibodies is a modern approach, not only for increasing the direct killing of cancer cells, but also as a strategy to minimize the activation of immunosuppressive and cancer cell prosurvival program responses.