Clinical Response to Immunotherapy Targeting Programmed Cell Death Receptor 1/Programmed Cell Death Ligand 1 in Patients With Treatment-Resistant Microsatellite Stable Colorectal Cancer With and Without Liver Metastases

Wang, Chongkai; Sandhu, Jaideep; Ouyang, Ching; Ye, Jian; Lee, Peter P.; Fakih, Marwan

doi:10.1001/jamanetworkopen.2021.18416

Cited by 70 publications

(65 citation statements)

References 41 publications

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“…Thus, liver metastases may be one of the reasons for the ineffectiveness of ICI therapy in patients with MSS mCRC, which was supported by a recent study by Want et al. ( 48 ). Therefore, an in-depth investigation into the mechanisms of drug resistance development in CRC liver metastasis models may focus on future research.…”

Section: Introductionmentioning

confidence: 68%

Visual Analysis of Colorectal Cancer Immunotherapy: A Bibliometric Analysis From 2012 to 2021

Teng

et al. 2022

Front. Immunol.

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An increasing number of studies have shown that immunotherapy serves a significant role in treating colorectal cancer (CRC) and has become a hotspot. However, few studies used the bibliometric method to analyze this field comprehensively. This study collected 1,899 records of CRC immunotherapy from 2012 to October 31, 2021, and used CiteSpace to analyze regions, institutions, journals, authors, and keywords to predict the latest trends in CRC immunotherapy research. The United States and China, contributing more than 60% of publications, were the main drivers in this field. Sun Yat-sen University was the most active institution, while the National Cancer Institute had the highest frequency of citations. Most publications were published in the Journal for Immunotherapy of Cancer. Adam E Snook was the most prolific writer, while Dung T. Le was the most commonly co-cited author. “T cell”, “MMI” and “PD-1blocked” were the most widely studied aspects of CRC immunotherapy. “Immune checkpoint inhibitor”, “combination therapy”, “drug therapy” and “liver metastases” were current research hotspots. “Tumor microenvironment”, “neutrophils”, “tumor-associated macrophages”, and “suppressor cell” have emerged as research hotspots in recent years. “Gut microbiota”, “nanoparticle” and “tumor mutational burden” as recently emerged frontiers of research that should be closely monitored.

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Section: Introductionmentioning

confidence: 68%

Visual Analysis of Colorectal Cancer Immunotherapy: A Bibliometric Analysis From 2012 to 2021

Teng

et al. 2022

Front. Immunol.

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“…Other strategies involve identifying specific groups of patients within MSS CRC that are more likely to respond to treatment. One recent investigation revealed that patients with liver metastases had a lower response rate compared to patients without metastases (objective response rate 0% versus 19.5%, respectively), suggesting that IT should be more seriously considered for early-stage patients [ 236 ].…”

Section: Sensitizing Crc To Itmentioning

confidence: 99%

Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers

Carlsen

Huntington

El‐Deiry

2022

Cancers

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Though early-stage colorectal cancer has a high 5 year survival rate of 65–92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair-proficient patients to immunotherapy.

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“…A recent study by Want et al supports this possibility. Among 95 patients with MSS mCRC treated with PD-1/PD-L1 targeted therapy, the overall ORR was 8.4%, where patients without liver metastasis achieved an ORR of 19.5% and those with liver metastases showed no response [ 75 ]. Moreover, patients without liver metastasis had superior progression-free survival compared with those with liver metastasis (4.0 vs. 1.5 months, p < 0.001).…”

Section: Mechanisms Of Intrinsic Resistance To Immune Checkpoint Blockade In Mss/pmmr Mcrcmentioning

confidence: 99%

“…Moreover, patients without liver metastasis had superior progression-free survival compared with those with liver metastasis (4.0 vs. 1.5 months, p < 0.001). Moreover, multivariate analysis indicated that liver metastasis was one of the most important predictors of faster progression after PD-1/PD-L1 blockade, even after adjusting for other variables such as the primary tumor size, RAS status, BRAF status, and TMB [ 75 ]. As some patients with MSS mCRC who do not have liver metastases favorably respond to ICIs, it is necessary to thoroughly investigate the possibility of immune checkpoint blockade in this subset of patients.…”

Section: Mechanisms Of Intrinsic Resistance To Immune Checkpoint Blockade In Mss/pmmr Mcrcmentioning

confidence: 99%

Combination Immunotherapies to Overcome Intrinsic Resistance to Checkpoint Blockade in Microsatellite Stable Colorectal Cancer

Kim

Chon

Kim

2021

Cancers

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Although immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of treating various malignancies, progress has been severely limited in metastatic colorectal cancer (mCRC). ICIs are effective in a fraction of patients with microsatellite instability-high mCRC but have little clinical efficacy in patients with microsatellite stable (MSS) mCRC, which accounts for 95% of mCRC cases. MSS mCRCs are considered to have intrinsic resistance to ICI monotherapy through multiple mechanisms. 1) They are poorly immunogenic because of their low tumor mutation burden; 2) frequent activation of the WNT/β-catenin signaling pathway excludes intratumoral CD8+ T cell immunity; 3) the tumor microenvironment is immunosuppressive because of the presence of various immunosuppressive cells, including tumor-associated macrophages and regulatory T cells; and 4) frequent liver metastasis in MSS mCRC may reduce the efficacy of ICIs. To overcome these resistance mechanisms, combination approaches using various agents, including STING agonists, MEK inhibitors, VEGF/R inhibitors, WNT/β-catenin inhibitors, oncolytic viruses, and chemo/radiotherapy, are actively ongoing. Preliminary evidence of the efficacy of some has been shown in early clinical trials. This review summarizes novel combination immunotherapy strategies described in recent preclinical and clinical studies to overcome the limitations of ICI monotherapy in MSS mCRC.

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Clinical Response to Immunotherapy Targeting Programmed Cell Death Receptor 1/Programmed Cell Death Ligand 1 in Patients With Treatment-Resistant Microsatellite Stable Colorectal Cancer With and Without Liver Metastases

Cited by 70 publications

References 41 publications

Visual Analysis of Colorectal Cancer Immunotherapy: A Bibliometric Analysis From 2012 to 2021

Visual Analysis of Colorectal Cancer Immunotherapy: A Bibliometric Analysis From 2012 to 2021

Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers

Combination Immunotherapies to Overcome Intrinsic Resistance to Checkpoint Blockade in Microsatellite Stable Colorectal Cancer

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