Combined cytotoxic chemotherapy and immunotherapy of cancer: modern times

Abstract

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.

Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities

“…PD-1 inhibitors along with anti-CTLA-4 antibodies have received FDA approvals for a range of cancers and trials involving other inhibitory checkpoints, such as LAG-3 and TIM-3 are ongoing ( 23 – 25 ). Conventional cytotoxic chemotherapies promote anticancer immunity through the release of tumor-associated antigens and/or depletion of immunosuppressive cells ( 26 , 27 ). Chemotherapy regimens in tandem with ICIs have been extensively studied and have become treatment options for NSCLC, triple-negative breast cancer and urothelial carcinoma ( 28 – 31 ).…”

<p>Refractory Metastatic Colorectal Cancer: Current Challenges and Future Prospects</p>

“…Standard cytotoxic chemotherapy has been shown to increase antigen presentation and the ratio of cytotoxic to regulatory T-cells, with resulting increased PD-1 expression. 82 In mouse CRC models, both 5-FU and oxaliplatin increased PDL-1 expression, and when followed by an anti-PD1 agent improved OS. 82,83 Irinotecan and anti-PD1 demonstrated an additive effect on tumor regression in mice.…”

“…82 In mouse CRC models, both 5-FU and oxaliplatin increased PDL-1 expression, and when followed by an anti-PD1 agent improved OS. 82,83 Irinotecan and anti-PD1 demonstrated an additive effect on tumor regression in mice. 84 Multiple clinical trials, mainly in the refractory setting, are now examining combinations with ICI (Table 3).…”

Estimation of US Patients with Cancer who may Respond to Cytotoxic Chemotherapy

“…Also, there is a dose-dependent association of cytotoxic agents and tumor response, but at the expense of increased toxicity [ 11 ]. Interestingly, there have been increased interest in utilization of cytotoxic agents with some novel targeted agents or even immunotherapeutics, with some thought about certain cytotoxic agents possibly having an effect on sensitizing cancer cells to these therapies, as has been demonstrated with PD-L1 inhibitors [ 12 ].…”