Immune checkpoint inhibitors in colorectal cancer: limitation and challenges

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide with 5-FU still the primary chemotherapeutic of choice. With the increasing use of immunotherapies, much research is focused on the ability to make tumours more immunogenic, thereby rationalising combination with immunotherapy. Here we investigate whether NUC-3373, a phosphoramidate transformation of FUDR, enhances immunogenicity in CRC cell lines and facilitates lymphocyte mediated cell death in vitro. At sub IC50 doses NUC-3373 upregulates damage associate molecular patterns (DAMPs) in both HCT116 and SW480 cells and increases surface expression of MHCII and PD-L1. Pre-treatment with NUC-3373 and subsequent coculture with NK-92 MI natural killer cells caused an increase in LAMP1 expression (degranulation), production of gamma-IFN, and NK-mediated cytotoxicity compared to vehicle controls. Cocultures with patient-derived PBMCs with heterologous CRC cells pre-treated with NUC-3373 demonstrated increased cell death compared to both vehicle controls and monocultures of CRC cells exposed to NUC-3373. Lastly, the PD-1 immune checkpoint inhibitor nivolumab showed synergistic activity when HCT116 cells were pre-treated with NUC-3373. To conclude, we show that NUC-3373 can modulate immune signaling and may therefore facilitate immune mediated tumour cell death.

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Efficacy and challenges of anti-PD1 in MSI-H mCRC: a case report on concurrent infections and ir-AIHA

Pei,

Zhao,

Luo

et al. 2024

Front. Oncol.

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Anti-programmed cell death protein 1 (PD-1) therapy has demonstrated notable efficacy in treating patients with deficient mismatch repair/high microsatellite instability (dMMR/MSI-H) metastatic colorectal cancer (mCRC). However, its clinical application is fraught with challenges and can lead to significant immune-related adverse events (ir-AEs). In this report, we present a complicated case of an mCRC patient with MSI-H and mutations in β2M and LRP1B proteins, complicated by concurrent bacteremia and liver fluke infection, who received first-line anti-PD1 therapy. The patient exhibited a positive response to anti-PD1 treatment, even in the presence of concomitant antibiotic and anti-parasitic interventions. Additionally, the patient experienced immunotherapy-related autoimmune hemolytic anemia (ir-AIHA), a rare hematological ir-AE, which was effectively treated later on. Immunotherapy represents a pivotal and highly effective approach to tumor treatment. Baseline assessment of the MMR and MSI status is a crucial step before initiating immunotherapy, and regular ongoing assessments during the treatment course can facilitate early recognition of any secondary complications, enabling prompt intervention and ensuring optimal therapeutic outcomes. Overall, a multidisciplinary diagnostic and therapeutic algorithm can help maximize the therapeutic benefits of immunotherapy.

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Immune checkpoint inhibitors in colorectal cancer: limitation and challenges

Cited by 4 publications

References 154 publications

The emerging role of TIM-3 in colorectal cancer: a promising target for immunotherapy

The emerging role of TIM-3 in colorectal cancer: a promising target for immunotherapy

A phosphoramidate modification of FUDR, NUC-3373, causes DNA damage and DAMPs release from colorectal cancer cells, potentiating lymphocyte-induced cell death

Efficacy and challenges of anti-PD1 in MSI-H mCRC: a case report on concurrent infections and ir-AIHA

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