Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

Development ofκ-carrageenan hydrogels with mechanically stronger structures via a solvent-replacement method

Strongκ-carrageenan(KC)hydrogels were fabricated via solvent replacement with sorbitol,and the effects of KC mass fraction and solvent replacement on the structural characteristics encapsulation capability of the hydrogels were evaluated.Microstructural observation showed that the 3D network structures of hydrogels exhibited a complete and continuous skeleton.FTIR spectra of KC hydrogels revealed the formation of intermolecular hydrogen bonds after sorbitol replacement.The stability against heating and freeze-thawing of hydrogels was enhanced due to the addition of sorbitol and the rise in KC mass fraction.The hydrogel with 1.5 wt%KC after sorbitol replacement presented the best stability.Frequency sweep tests suggested that storage modulus of the samples were influenced by sorbitol replacement and KC concentration.Swelling tests revealed that the hydrogels after replacement with a higher KC content(1.25,1.50 wt%)presented higher swelling capacity,and they were more stable in alkaline and acidic solutions.When epigallocatechin gallate(EGCG)was incorporated within the hydrogels,the hydrogels after sorbitol replacement offered higher protection capability.The information obtained in this study indicated that sorbitol replacement strengthened KC hydrogels,and they could act more appropriately as accountable carriers for bioactives.