Current Treatments of Metastatic Colorectal Cancer with Immune Checkpoint Inhibitors—2020 Update

Abstract

During the last 20 years, chemotherapy has improved survival rates of colorectal cancer (CRC). However, the majority of metastatic cases do not respond to or progress after first line conventional chemotherapy and contribute to the fatalities of patients with CRC. Insights into the immune contexture of the tumor microenvironment (TME) have enabled the development of new systemic treatments that boost the host immune system against the tumor—the immune checkpoint inhibitors (ICI). These promising drugs have already shown astonishing efficacies in other cancer types and have raised new hope for the treatment of metastatic CRC (mCRC). In this review, we will summarize the results of the clinical trials that led to their accelerated approval by the U.S. Food and Drug Administration (FDA) in 2017, as well as all relevant recent studies conducted since then—some of which are not published yet. We will focus on therapeutic efficacy, but also discuss the available data for drug safety and security, changes in quality of life indicators and predictive biomarkers for treatment response. The burgeoning evidence for a potential use of ICIs in other settings than mCRC will also be mentioned. For each trial, we have made a preliminary assessment of the quality of clinical trial design and of the “European Society of Medical Oncology (ESMO) magnitude of clinical benefit” (ESMO-MCBS) in order to provide the first evidence-based recommendation to the reader.

Single-cell RNA sequencing reveals distinct cellular factors for response to immunotherapy targeting CD73 and PD-1 in colorectal cancer

“… 2 Recent clinical trials examining the use of immune checkpoint inhibitors (ICIs) are anticipated to improve survival rates in CRC. 3 4 Nevertheless, no clinically approved ICI for the treatment of CRC exists currently. Ongoing clinical trials examining cancer immunotherapies are focused on programmed cell death protein 1 (PD-1) signaling inhibitors such as pembrolizumab, nivolumab, and atezolizumab.…”

“…Ongoing clinical trials examining cancer immunotherapies are focused on programmed cell death protein 1 (PD-1) signaling inhibitors such as pembrolizumab, nivolumab, and atezolizumab. 3 5–7 To extend the beneficial effects of cancer immunotherapy to more patients, ongoing efforts are aimed at developing new target-based cancer immunotherapeutic drugs. Adenosine signaling has emerged as a key metabolic pathway that regulates tumor immunity.…”

Three-Dimensional Culture Models to Study Innate Anti-Tumor Immune Response: Advantages and Disadvantages

“…The immune system can deeply interact with tumor cells in a hostile TME. While the reactivation of the adaptive immunity by ICB is an additional therapeutic tool against cancer, several solid tumors do not show relevant responses to ICB therapy [ 7 , 8 , 9 , 13 , 77 , 98 , 143 , 160 , 177 ]. NK cells can successfully eliminate tumor cells, but are regulated by a complex balance of positive and negative signals, delivered from the receptor ligands expressed on tumor cells.…”

“…In this case, using appropriate tools such as humanized monoclonal antibodies (hmAb) to programmed cell death receptor 1 (PD1), programmed cell death receptor ligand 1 (PDL1) or cytotoxic activated T lymphocyte 4 receptor (CTLA4), it is possible to reactivate the adaptive anti-tumor-specific immune response [ 7 , 8 , 9 , 10 , 11 ]. This strategy is effective when IC-inhibited tumor-specific T cells are already present in the host, thus targeted hmAb can relieve the tumor microenvironment (TME)-mediated immunosuppression [ 11 , 12 , 13 , 14 , 15 , 16 ].…”

Molecular Targeted Agent and Immune Checkpoint Inhibitor Co-Loaded Thermosensitive Hydrogel for Synergistic Therapy of Rectal Cancer

“…These adjuvant therapies reduce local recurrence around the tumor bed and suppress distant metastasis after surgical resection. In recent years, preoperative chemoradiotherapy for patients with locally advanced rectal cancer is also an alternative to improve surgical resection rate and sphincter preservation rate (Weiser et al, 2009;Sauer et al, 2012); however, when a rectal tumor deteriorates after conventional treatment, molecular targeted therapy and checkpoint blockade immunotherapy are preeminent candidates for interdicting tumor advancement (Tokumaru et al, 2019;Jung et al, 2020).…”