Targeting the PD-1 pathway: a new hope for gastrointestinal cancers

Bi̇lgi̇n, Burak; Şendur, Mehmet Ali Nahit; Akıncı, Muhammed Bülent; Dede, Didem Şener; Yalçın, Bülent

doi:10.1080/03007995.2017.1279132

Cited by 64 publications

(51 citation statements)

References 49 publications

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“…Together, our results emphasize the challenges and major obstacles in making immunotherapy a cornerstone in CRC treatment. Currently, many clinical trials of gastrointestinal and CRC immunotherapies are ongoing (listed in Refs which could offer new successful combination strategies with more curative potential for CRC patients.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of PD‐1 follows tumour development in the AOM/DSS model of inflammation‐induced colorectal cancer in mice

et al. 2019

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Summary Chronic inflammation may drive development of cancer as observed in inflammation‐induced colorectal cancer (CRC). Though immune cells can infiltrate the tumour microenvironment, cancer cells seem to evade anti‐tumour responses, which is one of the established hallmarks of cancer. Targeting the programmed cell death protein‐1 (PD‐1)/PD‐L1 signalling pathway is currently at the forefront in the development of anti‐tumour immunity‐based therapies for multiple malignancies. By blocking the immune‐checkpoint of activated T‐cells, it is possible to rewire the adaptive resistance induced by the PD‐1 ligands expressed in the tumour microenvironment. However, adverse immunotherapy‐modulated events could complicate the treatment of individuals with preexisting chronic inflammatory conditions. In this study, we investigated the expression of different systemic and mucosal T‐cell subsets during the course of azoxymethane (AOM)/dextran sulphate sodium (DSS)‐induced colitis and colitis‐associated CRC. In addition, we examined the expression of PD‐1 and its ligands PD‐L1 and PD‐L2 as well as other molecular targets related to T‐cell exhaustion. We found a significant increase in PD‐1 expression on all examined mucosal T‐cell subsets of the colon and the ileum, which correlated with disease progression. We also observed an upregulation of PD‐L1 and PD‐L2 mRNA expression throughout the AOM/DSS regime. Blocking PD‐1 signalling with an anti‐PD1 antibody did not affect the tumour burden in the AOM/DSS‐treated mice, but did potentiate the weight loss in the third DSS cycle, indicating possible immune‐mediated toxicity. This raises a concern for patients with colitis‐associated CRCs and should be further investigated.

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Section: Discussionmentioning

confidence: 99%

Upregulation of PD‐1 follows tumour development in the AOM/DSS model of inflammation‐induced colorectal cancer in mice

et al. 2019

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“…Overman et al presented their preliminary results of a phase II trial of nivolumab therapy with or without ipilimumab on 120 metastatic and recurrent CRC patients. A partial response was seen in 25.5–33% of MMR-D and 10% (1 of 10) of MMR-P CRC 13. Given these clinical data reporting responses in a high percentage of patients, we tested a second algorithm to consider lower cut-offs.…”

Section: Discussionmentioning

confidence: 99%

“…While several ongoing phase II and III clinical trials evaluating ICPIs such as nivolumab, pembrolizumab, atezolizumab and durvalumab enrolled patients with CRC, currently there is no FDA approved ICPI for the treatment of CRC 13. Also the data on PD-L1 expression in CRC are conflicting,14–16 which may be due to variations in IHC protocols, antibody clones, scoring and interpretation criteria, case composite and sampling.…”

Section: Introductionmentioning

confidence: 99%

PD-L1 protein expression in tumour cells and immune cells in mismatch repair protein-deficient and -proficient colorectal cancer: the foundation study using the SP142 antibody and whole section immunohistochemistry

et al. 2017

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AimsRoutine application of PD-L1 immunohistochemistry (IHC) in colorectal cancer (CRC) is limited due to lack of standardized scoring criteria, antibody clones, and intratumoral staining heterogeneity. We assessed PD-L1 protein expression on full face CRC tissue sections and applied two algorithms based on the published clinical trials that support the recent FDA approval for immune checkpoint inhibitors (ICPI) therapy in non-small cell lung cancer (NSCLC).MethodsPD-L1/CD274 IHC (Roche/Ventana, clone SP142) was performed on representative tumour blocks from 52 mismatch repair-deficient (MMR-D) and 52 MMR-proficient (MMR-P) CRCs. Membranous PD-L1 expression was scored for the tumour cell (TC) and tumour-infiltrating immune cell (IC) components. PD-L1 positivity status was determined based on the published NSCLC clinical trials that utilized the Ventana SP142 assay. Hybrid capture-based comprehensive genomic profiling (CGP) was performed on a separate set of 2268 clinically advanced CRCs and the frequency of PD-L1/PD-L2 amplification was determined.ResultsPD-L1 expression in the TC and IC correlated with MMR-D (p=0.013, p<0.0001), T stage (p=0.036, p=0.0036) and clinical stage (p=0.022, p=0.0037). PD-L1 positivity status correlated with MMR-D by two algorithms. Five of 2268 (<1%) advansced CRCs demonstrated amplification of either the PD-L1 or PD-L2 genes by CGP.ConclusionsPD-L1 expression in TC and IC is associated with advanced stage and MMR-D. PD-L1 positivity status by the published algorithm is associated with MMR-D. PD-L1 amplification is extremely uncommon in CRC. Evaluation of whole tissue section and incorporation of IC staining enhance the sensitivity to screen patients who may benefit from ICPI therapy.

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“…Recent therapeutic approaches that add epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) targeted agents to standard chemotherapy have produced a prolonged overall survival (OS) of up to 30 months in patients with metastatic disease [1]. However, research is ongoing to further improve the outcome of metastatic CRC (mCRC) patients.…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoints as a Target for Colorectal Cancer Treatment

Passardi

Canale

Valgiusti

et al. 2017

IJMS

126

103

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Anti-tumor immunity is a new line of research for the treatment of patients with solid tumors. In this field, negative regulators of the immune system called immune checkpoints play a key role in limiting antitumor immunologic responses. For this reason, immune checkpoint-inhibiting agents, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 receptor (PD1) and its ligand PD-L1, have been developed as antitumor drugs, producing interesting results in preclinical and clinical studies. We present an updated review of the biological background and clinical development of immune checkpoint inhibitors in colorectal cancer (CRC). Early trial results on PD1 and PD-L1 blockade appear promising, especially in CRC patients with microsatellite instability (MSI). Clinical trials are ongoing to confirm these preliminary results, evaluate combination strategies and identify biomarkers to predict which patients are most likely to benefit from, or show resistance to, the effects of checkpoint inhibition.

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Targeting the PD-1 pathway: a new hope for gastrointestinal cancers

Abstract: Both pembrolizumab and nivolumab show promising efficacy with acceptable safety data in published trials in GI cancers, especially in refractory MSI positive metastatic colorectal cancer.

Cited by 64 publications

References 49 publications

Upregulation of PD‐1 follows tumour development in the AOM/DSS model of inflammation‐induced colorectal cancer in mice

Upregulation of PD‐1 follows tumour development in the AOM/DSS model of inflammation‐induced colorectal cancer in mice

PD-L1 protein expression in tumour cells and immune cells in mismatch repair protein-deficient and -proficient colorectal cancer: the foundation study using the SP142 antibody and whole section immunohistochemistry

Immune Checkpoints as a Target for Colorectal Cancer Treatment

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