Repurposing of Commercially Existing Molecular Target Therapies to Boost the Clinical Efficacy of Immune Checkpoint Blockade.
Debottam SinhaPhilip MoseleyXuehan LuQuentin G WrightBrian G GabrielliIan Hector FrazerJazmina L G CruzPublished in: Cancers (2022)
Immune checkpoint blockade (ICB) is now standard of care for several metastatic epithelial cancers and prolongs life expectancy for a significant fraction of patients. A hostile tumor microenvironment (TME) induced by intrinsic oncogenic signaling induces an immunosuppressive niche that protects the tumor cells, limiting the durability and efficacy of ICB therapies. Addition of receptor tyrosine kinase inhibitors (RTKi) as potential modulators of an unfavorable local immune environment has resulted in moderate life expectancy improvement. Though the combination strategy of ICB and RTKi has shown significantly better results compared to individual treatment, the benefits and adverse events are additive whereas synergy of benefit would be preferable. There is therefore a need to investigate the potential of inhibitors other than RTKs to reduce malignant cell survival while enhancing anti-tumor immunity. In the last five years, preclinical studies have focused on using small molecule inhibitors targeting cell cycle and DNA damage regulators such as CDK4/6, CHK1 and poly ADP ribosyl polymerase (PARP) to selectively kill tumor cells and enhance cytotoxic immune responses. This review provides a comprehensive overview of the available drugs that attenuate immunosuppression and overcome hostile TME that could be used to boost FDA-approved ICB efficacy in the near future.
Keyphrases
- cell cycle
- small molecule
- dna damage
- end stage renal disease
- immune response
- cell proliferation
- dna repair
- ejection fraction
- healthcare
- chronic kidney disease
- squamous cell carcinoma
- small cell lung cancer
- newly diagnosed
- palliative care
- peritoneal dialysis
- oxidative stress
- protein protein
- quality improvement
- cell therapy
- toll like receptor
- drug delivery
- dna damage response
- human health
- patient reported outcomes
- cancer therapy
- pain management
- dendritic cells
- patient reported
- combination therapy
- replacement therapy
- chronic pain
- affordable care act
- drug induced
- binding protein