Immune-checkpoint inhibitors for metastatic colorectal cancer : a systematic review of clinical outcomes

Background. Colorectal cancer (CRC) is the fourth most deadly cancer worldwide. Unfortunately, a quarter of the patients are diagnosed at late stages, when surgical options are limited. Targeted therapies, particularly immune-checkpoint inhibitors (ICIs), are the latest addition and have been studied herein regarding their efficacy outcomes. Methods. Clinical studies were identified through the PubMed, Scopus and Cochrane databases. Any trial that evaluated ICIs in patients with metastatic CRC (mCRC) and reported the objective response rate was deemed eligible. Data analysis was performed by employing the random-effects model in STATA v.17. Results. A total of 461 articles were identified; 13 clinical trials were included, encompassing a total cohort of 1209 patients. Our study determined that a single PD-1/PD-L1 checkpoint blockade provides durable clinical response in mCRC patients with high microsatellite instability (MSI-H). The combinatorial therapy of CTLA-4 + PD-1 inhibitors also showed high response rates in pre-treated MSI-H patients. The single-arm REGONIVO trial reported durable clinical response in patients with microsatellite stable (MSS) status. Conclusions. Our study surmises that PD-1/PD-L1 inhibitors as well as combination therapy with CTLA-4 and PD-1 inhibitors show encouraging response rates in mCRC patients, albeit exclusively in patients with cancer that are of MSI-H status. A single study suggests that nivolumab + regorafenib can reach a durable response rate in MSS patients; however, further studies in larger randomized settings are required

Major hurdles of immune-checkpoint inhibitors in pancreatic ductal adenocarcinoma

In 2030, pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of cancer-related mortality in the world. Unfortunately, neither conventional chemotherapy nor novel immunotherapeutic strategies can provide durable responses and the survival prognosis remains very low. PDAC is notorious for its immuneresistant features and unique genomic landscape facilitating tumor escape from immunosurveillance. Novel immune-checkpoint inhibitors (ICI) failed to show promising efficacy and other multi-modal approaches are currently being validated in multiple clinical trials. In this paper, we provide our opinion on the major mechanisms responsible for PDAC resistance to ICI therapy and provide our view on future strategies which may overcome those barriers

Examining the gut-liver axis in liver cancer using organoid models

The World Health Organization predicts that by 2030 liver cancer will cause 1 million deaths annually, thus becoming the third most lethal cancer worldwide. Hepatocellular carcinoma and cholangiocarcinoma are the two major primary cancer subtypes involving the liver. Both are often diagnosed late, and hence response to treatment and survival are poor. It is therefore of utmost importance to understand the mechanisms by which liver cancers initiate and progress. The causes of primary liver cancer are diverse, resulting primarily from obesity, chronic alcohol abuse or viral hepatitis. Importantly, both alcohol and high fat diet can promote intestinal permeability, enabling microbial translocation from the gut into the liver. As a result, these microbial antigens and metabolites exacerbate hepatic inflammation and fibrosis, increasing the risk of primary liver cancer. Organoids are primary, three-dimensional, stem cell derived liver models that can recapitulate many of the disease phenotypes observed in vivo. This review aims to summarize the advantages of organoid culture to examine the gut-liver axis with respect to cancer initiation and progression. In particular, the use of gut and liver organoid mono- and co-cultures together and with immune cell populations to best recapitulate disease mechanisms and develop therapeutic interventions

Pharmacogenetics of anticancer monoclonal antibodies

Pharmacogenetics is the study of therapeutic and adverse responses to drugs based on an individual’s genetic background. Monoclonal antibodies (mAbs) are a rapidly evolving field in cancer therapy, however a number of newly developed and highly effective mAbs (e.g., anti-CTLA-4 and anti-PD-1) possess pharmacogenomic profiles that remain largely undefined. Since the first chemotherapeutic mAb Rituximab was approved in 1997 by the US Food and Drug Administration for cancer treatment, a broad number of other mAbs have been successfully developed and implemented into oncological practice. Nowadays, mAbs are considered as one of the most promising new approaches for cancer treatment. The efficacy of mAb treatment can however be significantly affected by genetic background, where genes responsible for antibody presentation and metabolism, for example, can seriously affect patient outcome. This review will focus on current anticancer mAb treatments, patient genetics that shape their efficacy, and the molecular pathways that bridge the two.

Immune-checkpoint inhibitors for advanced hepatocellular carcinoma : a synopsis of response rates

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer‐related death worldwide. A first‐line standard of care (SoC), sorafenib results in median overall survival (OS) of 12 months in Child‐Pugh class A patients, and 6 months in Child‐Pugh class B patients with objective response rates (ORR) not exceeding 19%. These low efficacy rates have driven research on alternative therapeutic options, particularly immune‐checkpoint inhibitors (ICIs). We reviewed the response rates (estimated by RECIST 1.1 criteria) across patients with advanced HCC treated with ICIs in phase I‐IV clinical trials published between December 2012 to December 2020; 17 reports were identified as eligible and included in the quantitative analysis. Within the selected studies pembrolizumab + lenvatinib reached the highest absolute ORR (36%), with first line atezolizumab + bevacizumab showing the second highest ORR (27.3%). With regards to second line therapy nivolumab + ipilimumab reached an ORR of 32% and pembrolizumab alone resulted in an ORR of 17% among sorafenib‐experienced patients with advanced HCC. In summary, current studies show high response rates of ICIs in patients with advanced HCC. Nonetheless, further studies are required in the second‐line setting to further evaluate ICI therapeutic superiority. Finally, it is of particular interest to examine the therapeutic potential of ICIs for patients with decompensated liver disease (Child‐Pugh class C), currently not eligible for any systemic therapy

Non-coding RNA and immune-checkpoint inhibitors : friends or foes?

Non-coding RNAs (ncRNAs) are an abundant component of the human transcriptome. Their biological role, however, remains incompletely understood. Nevertheless, ncRNAs are highly associated with cancer development and progression due to their ability to modulate gene expression, protein translation and growth pathways. Immune-checkpoint inhibitors (ICIs) are considered one of the most promising and highly effective therapeutic approaches for cancer treatment. ICIs are monoclonal antibodies targeting immune checkpoints such as CTLA-4, PD-1 and PD-L1 signalling pathways that stimulate T cell cytotoxicity and can result in tumor growth suppression. This Review will summarize existing knowledge regarding ncRNAs and their role in cancer and ICI therapy. In addition, we will discuss potential mechanisms by which ncRNAs may inuence ICI treatment outcomes