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Efficacy and side effects of immune checkpoint inhibitors in the treatment of colorectal cancer.

ABSTRACT: Colorectal cancers (CRCs) remain one of the most common and challenging neoplasia in the Western world. The response rate of immunotherapeutic treatment approaches in a subset of advanced CRCs is remarkable and has sustainably changed treatment regimens. Unfortunately, currently available immunotherapeutics only displayed significant antitumoral activity - in terms of progression free survival (PFS) and objective response rate (ORR) - in microsatellite instability-high (MSI-H)/DNA mismatch repair deficient (dMMR) CRCs. Subsequently, these remarkable results had led to the US Food and Drug Administration's approval of both immune checkpoint inhibitors (ICIs) pembrolizumab and nivolumab in the treatment of advanced MSI-H/dMMR CRCs. However, in microsatellite stable (MSS)/DNA mismatch repair proficient (pMMR) CRCs, ICIs have clearly failed to meet their expectations and are therefore not considered effective. As the vast majority of CRCs display a molecular MSS/pMMR profile, current treatment approaches endeavor to improve tumor immunogenicity that consecutively leads to increased proinflammatory cytokine levels as well as tumor infiltrating T-cells, which in turn may be targeted by various immunotherapeutic agents. Therefore, ongoing studies are investigating novel synergistic therapy modalities and approaches to overcome a "cold" to "hot" tumor conversion in MSS/pMMR CRCs. In this review, we summarize the efficacy and possible immune-related adverse events as well as novel therapeutic approaches of ICIs in the treatment of MSI-H/dMMR and MSS/pMMR CRCs.

SUBMITTER: Manz SM

PROVIDER: S-EPMC8053828 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors.

Project description:PurposeMicrosatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10% to 40% of patients with MSI mCRC will experience a primary resistance to ICI.Experimental designIn two cohorts of patients with MSI mCRC treated with ICI (exploratory, N = 103; validation, N = 35), 3' RNA sequencing was performed from primary tumors. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed.ResultsIn the exploratory cohort, the unsupervised clustering allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A ("stromalHIGH-proliferationLOW"), cluster B ("stromalHIGH-proliferationMED"), and cluster C ("stromalLOW-proliferationHIGH"), with an enrichment of patients progressing at first disease assessment under ICI in cluster A (30% vs. 12% in cluster B and 8.1% in cluster C; P = 0.074). Progression-free survival (PFS) was also significantly shorter in patients belonging to cluster A, compared with clusters B or C (P < 0.001) with 2-year PFS rates of 33.5%, 80.5%, and 78.3%, respectively. In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B [HR, 0.19; 95% confidence interval (CI), 0.08-0.45; P < 0.001] and cluster C (HR, 0.25; 95% CI, 0.10-0.59; P = 0.02), compared with patients belonging to cluster A. The association of this clustering with PFS under ICI was confirmed in the validation cohort. PFS related to non-ICI-based regimens was not significantly different according to cluster.ConclusionsThis unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The "stromalHIGH-proliferationLOW" cluster is associated with a poorer prognosis with ICI treatment.

| S-EPMC10502457 | biostudies-literature

Predictive molecular markers for the treatment with immune checkpoint inhibitors in colorectal cancer.

Project description:Colorectal cancer is one of the most common malignant tumors and, hence, has become one of the most important public health issues in the world. Treatment with immune checkpoint inhibitors (ICIs) successfully improves the survival rate of patients with melanoma, non-small-cell lung cancer, and other malignancies, and its application in metastatic colorectal cancer is being actively explored. However, a few patients develop drug resistance. Predictive molecular markers are important tools to precisely screen patient groups that can benefit from treatment with ICIs. The current article focused on certain important predictive molecular markers for ICI treatment in colorectal cancer, including not only some of the mature molecular markers, such as deficient mismatch repair (d-MMR), microsatellite instability-high (MSI-H), tumor mutational burden (TMB), programmed death-ligand-1 (PD-L1), tumor immune microenvironment (TiME), and tumor-infiltrating lymphocytes (TILs), but also some of the novel molecular markers, such as DNA polymerase epsilon (POLE), polymerase delta 1 (POLD1), circulating tumor DNA (ctDNA), and consensus molecular subtypes (CMS). We have reviewed these markers in-depth and presented the results from certain important studies, which suggest their applicability in CRC and indicate their advantages and disadvantages. We hope this article is helpful for clinicians and researchers to systematically understand these markers and can guide the treatment of colorectal cancer.

| S-EPMC8761449 | biostudies-literature

Treatment Efficacy of Immune Checkpoint Inhibitors for Patients with Advanced or Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis.

Project description:The treatment efficacy of immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC) has been reported heterogeneously across clinical trials. We conducted a systematic review and meta-analysis to evaluate the efficacy of ICIs in patients with advanced/metastatic CRC. Ovid-Medline was searched to identify clinical trials providing the efficacy outcomes of overall response rate (ORR) or disease control rate (DCR). The pooled ORR and DCR were estimated across all studies and subgroups. Meta-regression was performed to find the influencing factors for treatment efficacy. A total of thirty studies (1870 patients) were eligible. The overall ORR and DCR were 20.1% and 58.5%, respectively, but these results were heterogeneous across studies. Multivariate meta-regression revealed that microsatellite phenotype (odds ratio of MSI-H/dMMR versus MSS/pMMR: 1.67, p < 0.001) and drug regimen (odds ratio of monotherapy versus combination therapy: 1.07, p = 0.019) were the source of heterogeneity and also significantly influenced factors for the efficacy of the treatment. Although the efficacy of ICIs as a first-line therapy was higher than that of ICIs as the second- or more-line therapy (ORR: 51.5% vs. 13.4%, DCR: 85% vs. 49.5%), multivariate regression showed that the line of therapy was not a significant factor for the treatment efficacy. Our study suggests that the microsatellite phenotype and drug regimen, rather than the line of treatment, are the primary factors influencing the treatment response among advanced/metastatic CRC patients treated with an ICI-based regimen.

| S-EPMC8397178 | biostudies-literature

Standard therapies: solutions for improving therapeutic effects of immune checkpoint inhibitors on colorectal cancer.

Project description:Immunotherapy using immune checkpoint inhibitors has opened a new era for cancer management. In colorectal cancer, patients with a phenotype of deficient mismatch repair or high microsatellite instability benefit from immunotherapy. However, the response of rest cases to immunotherapy alone is still poor. Nevertheless, preclinical data have revealed that either ionizing irradiation or chemotherapy can improve the tumoral immune milieu, because these approaches can induce immunogenic cell death among cancer cells. In this regard, combination use of standard therapy plus immunotherapy should be feasible. In this review, we will introduce the specific roles of standard therapies, including radiotherapy, chemotherapy, antiangiogenic and anti-EGFR therapy, in improving therapeutic effect of immune checkpoint inhibitors on colorectal cancer.

| S-EPMC7466849 | biostudies-literature

Alpha-fetoprotein predicts the treatment efficacy of immune checkpoint inhibitors for gastric cancer patients.

Project description:BackgroundImmune checkpoint inhibitors (ICIs) are commonly used in conjunction with chemotherapy to improve treatment outcomes for patients with gastric cancer. Since AFP could influence immunity by both inhibiting natural killer (NK) cells and regulating negatively the function of dendritic cells, we evaluated the influence of baseline serum alpha-fetoprotein (AFP) levels on the curative effect of ICIs in advanced gastric cancer (AGC) patients.MethodsA retrospective analysis was conducted on 158 AGC patients who underwent ICI treatment. The patients were divided into high and low groups based on the AFP threshold of 20 ng/ml. The efficacy of ICI treatment was assessed using objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).ResultsThe higher levels of baseline AFP were found to be associated with a decrease in the effectiveness of ICIs, as evidenced by a DCR of 50.0% in the group with high AFP levels compared to 87.7% in the group with low AFP levels (P < 0.001). Further analysis using Kaplan-Meier survival techniques indicated that a high AFP level was linked to shorter progression-free survival (PFS) (P < 0.001) and overall survival (OS) (P = 0.001) in AGC individuals receiving ICIs. After propensity score matching, a log rank test revealed that the high AFP group had a decrease in median PFS (P = 0.011) and median OS (P = 0.036) compared to the low AFP group. The high AFP levels also showed its association with shorter PFS and OS in the subgroup analysis of ICI plus chemotherapy patients.ConclusionsBaseline AFP levels may predict immune checkpoint inhibitor treatment efficacy in AGC patients.

| S-EPMC10895833 | biostudies-literature

Growth hormone associated with treatment efficacy of immune checkpoint inhibitors in gastric cancer patients.

Project description:BackgroundImmune checkpoint inhibitors (ICIs) combined with chemotherapy have been widely employed to improve the outcome of gastric cancer patients. In the present study, the impact of posttreatment growth hormone (GH) levels on the treatment efficacy of ICIs for advanced gastric cancer (AGC) patients was assessed.MethodsSeventy-five AGC patients treated with anti-PD-1 antibodies at The Fourth Hospital of Hebei Medical University were involved. We divided AGC patients into two groups as high-GH group and low-GH group based on the GH level. Immunotherapy efficacy was assessed in terms of objective response rate, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) based on the National Comprehensive Cancer Network Guidelines. The enumeration data were compared by χ 2 test or Fisher's exact test. Survival curves were drawn by the Kaplan-Meier method, and comparisons between the curves were made using the log-rank test. Multivariate survival analysis was performed using a Cox proportional hazards model.ResultsThe higher GH levels were associated with a lower DCR of ICIs with a DCR of 30.0% in the high-GH group and 53.3% in the low-GH group (P = 0.046). The subsequent univariate analysis showed that a high GH level was associated with both shorter PFS (P = 0.016) and shorter OS at the borderline statistical level (P = 0.052) in AGC patients treated with ICIs. Cox model analysis also proved that the GH level was an independent risk factor for the outcome of AGC patients (PFS: P = 0.013, HR, 2.424, 95% CI, 1.202-4.890; OS: P = 0.014, HR, 3.301, 95% CI, 1.279-8.519).ConclusionsThe post-treatment GH level might be a predictor for ICIs treatment in AGC patients.

| S-EPMC9395680 | biostudies-literature

Safety and Efficacy of Personalized Cancer Vaccines in Combination With Immune Checkpoint Inhibitors in Cancer Treatment.

Project description:Cancer immunotherapy can induce sustained responses in patients with cancers in a broad range of tissues, however, these treatments require the optimized combined therapeutic strategies. Despite immune checkpoint inhibitors (ICIs) have lasting clinical benefit, researchers are trying to combine them with other treatment modalities, and among them the combination with personalized cancer vaccines is attractive. Neoantigens, arising from mutations in cancer cells, can elicit strong immune response without central tolerance and out-target effects, which is a truly personalized method. Growing studies show that the combination can elevate the antitumor efficacy with acceptable safety and minimal additional toxicity compared with single agent vaccine or ICI. Herein, we have searched these preclinical and clinical trials and summarized safety and efficacy of personalized cancer vaccines combined with ICIs in several malignancies. Meanwhile, we discuss the rationale of the combination and future challenges.

| S-EPMC8193725 | biostudies-literature

Immune Checkpoint Inhibitors in Colorectal Cancer: Challenges and Future Prospects.

Project description:Immunotherapy is a new pillar of cancer therapy that provides novel opportunities to treat solid tumors. In this context, the development of new drugs targeting immune checkpoints is considered a promising approach in colorectal cancer (CRC) treatment because it can be induce specific and durable anti-cancer effects. Despite many advances in the immunotherapy of CRC, there are still limitations and obstacles to successful treatment. The immunosuppressive function of the tumor microenvironment (TME) is one of the causes of poor response to treatment in CRC patients. For this reason, checkpoint-blocking antibodies have shown promising outcomes in CRC patients by blocking inhibitory immune checkpoints and enhancing immune responses against tumors. This review summarizes recent advances in immune checkpoint inhibitors (ICIs), such as CTLA-4, PD-1, PD-L1, LAG-3, and TIM-3 in CRC, and it discusses various therapeutic strategies with ICIs, including the double blockade of ICIs, combination therapy of ICIs with other immunotherapies, and conventional treatments. This review also delineates a new hopeful path in the combination of anti-PD-1/anti-PD-L1 with other ICIs such as anti-CTLA-4, anti-LAG-3, and anti-TIM-3 for CRC treatment.

| S-EPMC8467932 | biostudies-literature

Efficacy and safety of immune checkpoint inhibitors in non-small cell lung cancer.

Project description:Immune checkpoint inhibitors (ICIs) are new therapeutic strategies for non-small cell lung cancer (NSCLC). We aimed to quantitatively evaluate the efficacy and safety of ICIs in NSCLC. Pubmed, Embase, Cochrane Library, and Web of Science were searched for randomized clinical trials comparing ICIs with control therapies in NSCLC. Data were pooled according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A total of 12 trails comprising 6,919 NSCLC patients were included in this meta-analysis. ICIs therapies significantly improved progression-free survival (PFS) (HR, 0.838; P < 0.001), overall survival (OS) (HR, 0.747; P < 0.001) and objective response rates (ORR) (RR, 1.311; P < 0.001) in NSCLC. Prognostic benefit was observed irrespective of age, sex, treatment line, performance status and histology. Survival improvement of ICIs was limited for NSCLC patients with non-smoker (PFS, P = 0.468; OS, P = 0.317) or central nervous system (CNS) metastasis (PFS, P = 0.209; OS, P = 0.090), or positive EGFR mutation (PFS, P = 0.083; OS, P = 0.522) or PD-L1 expression level less than 5% (PFS, P = 0.370; OS, P = 0.047). The relative risks of all-grade and high-grade (≥3) anemia, neutropenia, leukopenia, thrombocytopenia, stomatitis, nausea, pyrexia, asthenia and neuropathy were all decreased in patients received ICIs compared with control therapies. This meta-analysis provides clinical evidence that ICIs improve PFS, OS, and ORR in NSCLC with fewer adverse effects. Our data establish ICIs as a prefer treatment option for NSCLC patients with smoker, no CNS metastasis, wild type EGFR, and high PD-L1 expression.

| S-EPMC6136858 | biostudies-other

Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer.

Project description:A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.

| S-EPMC7795541 | biostudies-literature

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