PD-1/PD-L1-dependent immune response in colorectal cancer.

Colorectal cancer (CRC) is still considered as the third most frequent cancer in the world. Microsatellite instability (MSI), inflammation, and microRNAs have been demonstrated as the main contributing factors in CRC. Subtype 1 CRC is defined by NK cells infiltration, induction of Th1 lymphocyte and cytotoxic T cell responses as well as upregulation of immune checkpoint proteins including programmed cell death-1 (PD-1). Based on the diverse features of CRC, such as the stage and localization of the tumor, several treatment approaches are available. However, the efficiency of these treatments may be decreased due to the development of diverse resistance mechanisms. It has been proven that monoclonal antibodies (mAbs) can increase the effectiveness of CRC treatments. Nowadays, several mAbs including nivolumab and pembrolizumab have been approved for the treatment of CRC. Immune checkpoint receptors including PD-1 can be inhibited by these antibodies. Combination therapy gives an opportunity for advanced treatment for CRC patients. In this review, an update has been provided on the molecular mechanisms involved in MSI colorectal cancer immune microenvironment by focusing on PD-ligand 1 (PD-L1) and treatment of patients with advanced immunotherapy, which were examined in the different clinical trial phases. Considering induced expression of PD-L1 by conventional chemotherapeutics, we have summarized the role of PD-L1 in CRC, the chemotherapy effects on the PD-1/PD-L1 axis and novel combined approaches to enhance immunotherapy of CRC by focusing on PD-L1.

Payandeh Z ，Khalili S ，Somi MH ，Mard-Soltani M ，Baghbanzadeh A ，Hajiasgharzadeh K ，Samadi N ，Baradaran B ... -  《-》

Is There a Role for Programmed Death Ligand-1 Testing and Immunotherapy in Colorectal Cancer With Microsatellite Instability? Part II-The Challenge of Programmed Death Ligand-1 Testing and Its Role in Microsatellite Instability-High Colorectal Cancer.

Marginean EC ，Melosky B 《-》

A new strategy for immunotherapy of microsatellite-stable (MSS)-type advanced colorectal cancer: Multi-pathway combination therapy with PD-1/PD-L1 inhibitors.

Colorectal cancer (CRC) is a frequent gastrointestinal malignancy with high rates of morbidity and mortality; 85% of these tumours are proficient mismatch repair (pMMR)-microsatellite instability-low (MSI-L)/microsatellite stable (MSS) CRC known as 'cold' tumours that are resistant to immunosuppressive drugs. Monotherapy with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors is ineffective for treating MSS CRC, making immunotherapy for MSS CRC a bottleneck. Recent studies have found that the multi-pathway regimens combined with PD-1/PD-L1 inhibitors can enhance the efficacy of anti-PD-1/PD-L1 in MSS CRC by increasing the number of CD8+ T cells, upregulating PD-L1 expression and improving the tumour microenvironment. This paper reviews the research progress of PD-1/PD-L1 inhibitors in combination with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, oncolytic virus, intestinal flora, antiangiogenic agents, chemotherapy, radiotherapy and epigenetic drugs for the treatment of pMMR-MSI-L/MSS CRC.

Cai L ，Chen A ，Tang D 《-》

PD-1/PD-L1 inhibitors for early and middle stage microsatellite high-instability and stable colorectal cancer: a review.

Programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are important immune checkpoint molecules that contribute to tumor immune evasion. However, the main treatment modalities for patients with early and intermediate stage colorectal cancer (CRC) are surgery, and the role of PD-1/PD-L1 inhibitors in these patients is not yet clear. Therefore, this study aims to review the treatment progress of PD-1/PD-L1 inhibitors for early- and intermediate-stage microsatellite high-instability (MSI-H) and stable (MSS) colorectal cancer, in order to provide more options for patients with early- and intermediate-stage colorectal cancer. A scoping review of clinical trial registries ( Clinicaltrials.gov and EU clinical trial registers) and PubMed/Medline database of trials on PD-1/PD-L1 Inhibitors for early and middle-stage MSI-H and MSS CRC was done up to March 2024. A total of 19 trials related to early to mid-stage MSH-I or MSS CRC were included. Among them, 6 trials are in recruiting status, 3 trials are in active, not recruiting status, 3 trials are completed, 1 trial is terminated, and 1 trial is unknown. Of these, 9 trials involve MSI-H type CRC, and 10 trials involve MSS type CRC. Preclinical phase I/II trials are predominant, with only 3 clinical phase III trials. In trials related to MSI-H type CRC, 4 studies involve PD-1/PD-L1 inhibitors combined with neoadjuvant therapy, and 5 studies involve combination therapy. In trials related to MSS type CRC, 3 studies involve PD-1/PD-L1 inhibitors combined with targeted therapy, 2 studies involve PD-1/PD-L1 inhibitors combined with chemotherapy, 1 study involves PD-1/PD-L1 inhibitor combined immunotherapy, 1 study involves PD-1/PD-L1 inhibitors combined with bacterial therapy, and 3 studies involve PD-1/PD-L1 inhibitors combined with comprehensive therapy. As for primary outcome measures, 4 trials select pathological complete response rates, 3 trials select progression-free survival rate, 3 trials select objective response rate, 3 trials select overall survival rate, 4 trials select disease-free survival rate, 1 trial selects clinical complete response rate, and 1 trial selects percentage of participants with a dose-limiting toxicity. For early- and middle-stage MSI-H and MSS CRC, PD-1/PD-L1 inhibitors have shown some therapeutic efficacy, as evidenced by phase I/II studies. However, contemporary trial designs exhibit heterogeneity, with relatively few inclusion criteria, the use of various drug combinations and regimens, and significant variations in reported endpoints. Nevertheless, more double-arm, multicenter, randomized controlled trials are still needed to confirm the efficacy of immunotherapy.

Wu H ，Deng M ，Xue D ，Guo R ，Zhang C ，Gao J ，Li H ... -  《-》

Clinical Development of Immunotherapy for Deficient Mismatch Repair Colorectal Cancer.

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States. Despite excellent prognosis for early stage disease, 5-year survival rates in metastatic disease remain low. A small subset of CRC is defined by a deficiency in mismatch repair (dMMR) resulting in high levels of microsatellite instability and are responsive to immunotherapy. Immune checkpoint inhibitors (ICIs) targeting the programmed death 1 (PD-1)/programmed death ligand 1 axis and cytotoxic T-lymphocyte antigen 4 have been explored and show robust clinical outcomes with prolonged progression-free survivals in nonrandomized single-arm clinical trials. On the basis of these data, single-agent therapy with pembrolizumab and nivolumab and combination therapy with nivolumab/ipilimumab have been approved by the US Food and Drug Administration for metastatic CRC that has progressed after treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Ongoing clinical trials are exploring the use of these agents in earlier lines of therapy such as first-line metastatic therapy and adjuvant therapy for stage III CRC. However, resistance to ICIs does occur in a subset of patients and ongoing clinical trials are exploring novel approaches in these PD-1-refractory patients. The aim of this review is to outline the development and decision-making of ICIs in the treatment of dMMR CRC and to discuss ongoing clinical trials in this therapeutic space.

Thomas J ，Leal A ，Overman MJ 《-》