Immunotherapy in colorectal cancer: rationale, challenges and potential
By K. Ganesh, Z. Stadler, A. Cercek, R. Mendelsohn, J. Shia, N. Segal, L. Diaz. Nature reviews: Gastroenterology & hepatology, 2019
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Following initial successes in melanoma treatment, immunotherapy has rapidly become established as a major treatment modality for multiple types of solid cancers, including a subset of colorectal cancers (CRCs). Two programmed cell death 1 (PD1)-blocking antibodies, pembrolizumab and nivolumab, have shown efficacy in patients with metastatic CRC that is mismatch-repair-deficient and microsatellite instability-high (dMMR–MSI-H), and have been granted accelerated FDA approval. In contrast to most other treatments for metastatic cancer, immunotherapy achieves long-term durable remission in a subset of patients, highlighting the tremendous promise of immunotherapy in treating dMMR–MSI-H metastatic CRC. Here, we review the clinical development of immune checkpoint inhibition in CRC leading to regulatory approvals for the treatment of dMMR–MSI-H CRC. We focus on new advances in expanding the efficacy of immunotherapy to early-stage CRC and CRC that is mismatch-repair-proficient and has low microsatellite instability (pMMR–MSI-L) and discuss emerging approaches for targeting the immune microenvironment, which might complement immune checkpoint inhibition.Ganesh et al. describe the rationale for using immunotherapy in select patients with colorectal cancer, discuss clinical findings supporting its use and highlight current strategies and future directions for expanding the scope of immunotherapy in this disease.Key pointsColorectal cancer (CRC) can be categorized into tumours that are mismatch-repair-deficient or have high levels of microsatellite instability (dMMR–MSI-H; ~15%) and mismatch-repair-proficient or microsatellite instability-low tumours (pMMR–MSI-L; ~85%).dMMR–MSI-H CRC is associated with a high tumour mutation burden and immune cell infiltration.Immune checkpoint inhibitor (ICI) treatment, specifically with monoclonal antibodies targeting programmed cell death 1 (PD1) and cytotoxic T lymphocyte antigen 4 (CTLA4), results in improved survival in metastatic dMMR–MSI-H CRC, but pMMR–MSI-L CRC is largely unresponsive to current ICIs.The FDA has granted accelerated approval to the anti-PD1 antibodies pembrolizumab and nivolumab and to the combination of nivolumab with the anti-CTLA4 antibody ipilimumab for treatment of refractory dMMR–MSI-H CRC.Clinical evaluation of ICIs in first-line metastatic, adjuvant and neoadjuvant settings and in combination with other therapies and research into improved prognostic and predictive biomarkers of ICI response and improved activity in pMMR–MSI-L CRC are ongoing.Beyond PD1 blockade, monospecific and bispecific antibodies, cellular therapies, vaccines and cytokines targeting other immune checkpoint molecules, macrophages and other components of innate immunity are under active investigation.
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Citations in the corpus
- Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy (2020, background): “, 2018)3 As a detailed discussion of the different immunotherapeutic approaches, the regulatory pathways, and various T-lymphocyte populations involved in cancer immune surveillance is beyond the scope of this article, we want to refer the reader to the many excellent review articles that focus on t”
- Machine learning-based integration develops an immune-derived lncRNA signature for improving outcomes in colorectal cancer (2022, background): “Meanwhile, patients with dMMR/MSI-H were prone to have a higher distribution of IRLS, which was consistent with previously reported dMMR/MSI-H tumours having better prognosis and more tumour-in fi ltrating lymphocytes 37 .”