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Journal of the National Cancer Institute Aug 2023Intratumoral microbes may have multifunctional roles in carcinogenesis. Microsatellite instability (MSI) is associated with higher tumor immunity and mutational burden....
Intratumoral microbes may have multifunctional roles in carcinogenesis. Microsatellite instability (MSI) is associated with higher tumor immunity and mutational burden. Using whole transcriptome and whole genome sequencing microbial abundance data, we investigated associations of intratumoral microbes with MSI, survival, and MSI-relevant tumor molecular characteristics across multiple cancer types including colorectal cancer (CRC), stomach adenocarcinoma, and endometrial carcinoma. Among 451 CRC patients, our key finding was strong associations of multiple CRC-associated genera, including Dialister and Casatella, with MSI. Dialister and Casatella abundance was associated with improved overall survival (hazard ratiomortality = 0.56, 95% confidence interval = 0.34 to 0.92, and hazard ratiomortality = 0.44, 95% confidence interval = 0.27 to 0.72), respectively, comparing higher relative to lower quantiles. Multiple intratumor microbes were associated with immune genes and tumor mutational burden. Diversity of oral cavity-originating microbes was also associated with MSI among CRC and stomach adenocarcinoma patients. Overall, our findings suggest the intratumor microbiota may differ by MSI status and play a role in influencing the tumor microenvironment.
Topics: Humans; Microsatellite Instability; Colorectal Neoplasms; Stomach Neoplasms; Adenocarcinoma; Tumor Microenvironment
PubMed: 37192013
DOI: 10.1093/jnci/djad083 -
Drugs Oct 2022Pucotenlimab (Puyouheng™) is a humanised immunoglobulin (Ig) G4 monoclonal antibody (mAb) being developed by Lepu Biopharma for the treatment of solid tumours,... (Review)
Review
Pucotenlimab (Puyouheng™) is a humanised immunoglobulin (Ig) G4 monoclonal antibody (mAb) being developed by Lepu Biopharma for the treatment of solid tumours, including gastrointestinal cancer, metastatic melanoma, liver cancer, bladder cancer, non-small cell lung cancer and breast cancer. Pucotenlimab binds to PD-1 and blocks its interaction with its ligands, PD-L1 and PD-L2, thereby restoring the ability of immune cells to target cancer cells. In July 2022, pucotenlimab received conditional first approval in China for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumours, including patients with advanced colorectal cancer who have experienced disease progression after previous therapy with fluorouracil, oxaliplatin and irinotecan, as well as patients with other advanced solid tumours who have experienced disease progression after previous first-line therapy and have no satisfactory treatment alternatives. In September 2022, pucotenlimab was approved in China for the treatment of unresectable or metastatic melanomas after the failure of previous systemic therapy. This article summarizes the milestones in the development of pucotenlimab leading to the first approval for the treatment of MSI-H/dMMR advanced solid tumours.
Topics: Humans; Antineoplastic Agents, Immunological; DNA Mismatch Repair; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Microsatellite Instability; Colorectal Neoplasms; Disease Progression
PubMed: 36308601
DOI: 10.1007/s40265-022-01787-z -
ESMO Open Feb 2022Microsatellite instability (MSI) testing and tumor mutational burden (TMB) are genomic biomarkers used to identify patients who are likely to benefit from immune...
INTRODUCTION
Microsatellite instability (MSI) testing and tumor mutational burden (TMB) are genomic biomarkers used to identify patients who are likely to benefit from immune checkpoint inhibitors. Pembrolizumab was recently approved by the Food and Drug Administration for use in TMB-high (TMB-H) tumors, regardless of histology, based on KEYNOTE-158. The primary objective of this retrospective study was real-world applicability and use of immunotherapy in TMB/MSI-high patients to lend credence to and refine this biomarker.
METHODS
Charts of patients with advanced solid tumors who had MSI/TMB status determined by next generation sequencing (NGS) (FoundationOne CDx) were reviewed. Demographics, diagnosis, treatment history, and overall response rate (ORR) were abstracted. Progression-free survival (PFS) was determined from Kaplan-Meier curves. PFS1 (chemotherapy PFS) and PFS2 (immunotherapy PFS) were determined for patients who received immunotherapy after progressing on chemotherapy. The median PFS2/PFS1 ratio was recorded.
RESULTS
MSI-high or TMB-H [≥20 mutations per megabase (mut/MB)] was detected in 157 adults with a total of 27 distinct tumor histologies. Median turnaround time for NGS was 73 days. ORR for most recent chemotherapy was 34.4%. ORR for immunotherapy was 55.9%. Median PFS for patients who received chemotherapy versus immunotherapy was 6.75 months (95% confidence interval, 3.9-10.9 months) and 24.2 months (95% confidence interval, 9.6 months to not reached), respectively (P = 0.042). Median PFS2/PFS1 ratio was 4.7 in favor of immunotherapy.
CONCLUSION
This real-world study reinforces the use of TMB as a predictive biomarker. Barriers exist to the timely implementation of NGS-based biomarkers and more data are needed to raise awareness about the clinical utility of TMB. Clinicians should consider treating TMB-H patients with immunotherapy regardless of their histology.
Topics: Adult; Biomarkers, Tumor; Humans; Immunotherapy; Microsatellite Instability; Neoplasms; Retrospective Studies
PubMed: 34953399
DOI: 10.1016/j.esmoop.2021.100336 -
Drugs Jul 2022Serplulimab () is an intravenously administered anti-PD-1 antibody being developed by Shanghai Henlius Biotech, Inc. for the treatment of solid tumours. Anti-PD-1... (Review)
Review
Serplulimab () is an intravenously administered anti-PD-1 antibody being developed by Shanghai Henlius Biotech, Inc. for the treatment of solid tumours. Anti-PD-1 immunotherapies, such as serplulimab, can stimulate immune responses by relieving PD-1-related immunosuppression. Serplulimab received its first approval on 25 Mar 2022 in China for the treatment of adult patients with advanced unresectable or metastatic microsatellite instability-high (MSI-H) solid tumours that have failed to respond to previous standard treatments. This article summarizes the milestones in the development of serplulimab leading to this first approval in the treatment of MSI-H solid tumours in adults.
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; China; Humans; Immune Checkpoint Inhibitors; Microsatellite Instability; Neoplasms
PubMed: 35796953
DOI: 10.1007/s40265-022-01740-0 -
Frontiers in Immunology 2023Immunotherapy has transformed treatment for various types of malignancy. However, the benefit of immunotherapy is limited to a minority of patients with... (Review)
Review
Immunotherapy has transformed treatment for various types of malignancy. However, the benefit of immunotherapy is limited to a minority of patients with mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) (dMMR-MSI-H) colorectal cancer (CRC). Understanding the complexity and heterogeneity of the tumor immune microenvironment (TIME) and identifying immune-related CRC subtypes will improve antitumor immunotherapy. Here, we review the current status of immunotherapy and typing schemes for CRC. Immune subtypes have been identified based on TIME and prognostic gene signatures that can both partially explain clinical responses to immune checkpoint inhibitors and the prognosis of patients with CRC. Identifying immune subtypes will improve understanding of complex CRC tumor heterogeneity and refine current immunotherapeutic strategies.
Topics: Humans; Immunotherapy; Prognosis; Colorectal Neoplasms; Microsatellite Instability; Tumor Microenvironment
PubMed: 37876934
DOI: 10.3389/fimmu.2023.1259461 -
British Journal of Cancer Oct 2023Colorectal cancer (CRC) is a common and deadly disease. Unfortunately, immune checkpoint inhibitors (ICIs) fail to elicit effective anti-tumour responses in the vast... (Review)
Review
Colorectal cancer (CRC) is a common and deadly disease. Unfortunately, immune checkpoint inhibitors (ICIs) fail to elicit effective anti-tumour responses in the vast majority of CRC patients. Patients that are most likely to respond are those with DNA mismatch repair deficient (dMMR) and microsatellite instability (MSI) disease. However, reliable predictors of ICI response are lacking, even within the dMMR/MSI subtype. This, together with identification of novel mechanisms to increase response rates and prevent resistance, are ongoing and vitally important unmet needs. To address the current challenges with translation of early research findings into effective therapeutic strategies, this review summarises the present state of preclinical testing used to inform the development of immuno-regulatory treatment strategies for CRC. The shortfalls and advantages of commonly utilised mouse models of CRC, including chemically induced, transplant and transgenic approaches are highlighted. Appropriate use of existing models, incorporation of patient-derived data and development of cutting-edge models that recapitulate important features of human disease will be key to accelerating clinically relevant research in this area.
Topics: Animals; Mice; Humans; Translational Research, Biomedical; Medical Oncology; Brain Neoplasms; Colorectal Neoplasms; Microsatellite Instability; DNA Mismatch Repair
PubMed: 37563222
DOI: 10.1038/s41416-023-02392-x -
Hematology/oncology Clinics of North... Jun 2022Colorectal cancer is a common malignancy that is frequently able to evade immune defenses. Although this may contribute to promoting and propagating cancer growth,... (Review)
Review
Colorectal cancer is a common malignancy that is frequently able to evade immune defenses. Although this may contribute to promoting and propagating cancer growth, recent advances suggest that for some tumors, particularly those with high levels of microsatellite instability and hypermutability from DNA mismatch repair defects, immunotherapy is effective to control tumor progression. Unfortunately, the overwhelming majority of patients have poor antitumoral immune cell penetration and fewer molecular defects within the cancer to successfully mount an anticancer defense. Studies, primarily in early phases of investigation, are underway to evaluate new combinations of immune checkpoint inhibitors, other targeted therapies, cellular therapies, and vaccines.
Topics: Colorectal Neoplasms; DNA Mismatch Repair; Humans; Immune Checkpoint Inhibitors; Immunologic Factors; Immunotherapy; Microsatellite Instability
PubMed: 35577706
DOI: 10.1016/j.hoc.2022.02.010 -
Current Opinion in Oncology Sep 2022Here, we reviewed the recent breakthroughs in the understanding of predictive biomarkers for immune checkpoint inhibitors (ICI) treatment. (Review)
Review
PURPOSE OF REVIEW
Here, we reviewed the recent breakthroughs in the understanding of predictive biomarkers for immune checkpoint inhibitors (ICI) treatment.
RECENT FINDINGS
ICI have revolutionized cancer therapy enabling novel therapeutic indications in multiple tumor types and increasing the probability of survival in patients with metastatic disease. However, in every considered tumor types only a minority of patients exhibits clear and lasting benefice from ICI treatment, and due to their unique mechanism of action treatment with ICI is also associated with acute clinical toxicities called immune related adverse events (irAEs) that can be life threatening. The approval of the first ICI drug has prompted many exploratory strategies for a variety of biomarkers and have shown that several factors might affect the response to ICI treatment, including tumors intrinsic factors, tumor microenvironment and tumor extrinsic or systemic factor. Currently, only three biomarkers programmed death-ligand 1 (PD-L1), tumor microenvironment and microsatellite instability had the US Food and Drug Administration-approbation with some limitations.
SUMMARY
The establishment of valid predictive biomarkers of ICI sensitivity has become a priority to guide patient treatment to maximize the chance of benefit and prevent unnecessary toxicity.
Topics: Humans; Immunotherapy; Microsatellite Instability; Neoplasms; Programmed Cell Death 1 Receptor; Tumor Microenvironment
PubMed: 35943441
DOI: 10.1097/CCO.0000000000000891 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... May 2021Lymphoma is one of the most common malignant tumor of the hematologic system. The genome instability is not only an important molecular basis for the development of...
Lymphoma is one of the most common malignant tumor of the hematologic system. The genome instability is not only an important molecular basis for the development of lymphoma, but also has important value in the diagnosis and prognosis of lymphoma. There are 2 types of genome instability: Microsatellite instability (MSI/MIN) at gene level and chromosomal instability at chromosome level. Through the study on genes associated with lymphoma, the unstable genes associated with lymphoma could be found, meanwhile the mechanism of its occurrence and development of lymphoma could be explored, and the important basis of molecular biology could also be provided in the field of current hot lymphoma precision medical research.
Topics: Genomic Instability; Humans; Lymphoma; Microsatellite Instability; Microsatellite Repeats; Neoplasms
PubMed: 34148893
DOI: 10.11817/j.issn.1672-7347.2021.190427 -
Pathologie (Heidelberg, Germany) Nov 2023Testing to detect mismatch repair deficiency (dMMR) and high-grade microsatellite instability (MSI-H) has become an integral part of the routine diagnostic workup for... (Review)
Review
Testing to detect mismatch repair deficiency (dMMR) and high-grade microsatellite instability (MSI-H) has become an integral part of the routine diagnostic workup for colorectal cancer (CRC). While MSI was initially considered to be a possible indicator of a hereditary disposition to cancer (Lynch syndrome, LS), today the prediction of the therapy response to immune checkpoint inhibitors (ICI) is in the foreground. Corresponding recommendations and testing algorithms are available for use in primary diagnosis (reviewed in: Rüschoff et al. 2021).Given the increasing importance for routine use and the expanding indication spectrum of ICI therapies for non-CRCs, such as endometrial, small intestinal, gastric, and biliary tract cancers, an updated review of dMMR/MSI testing is presented. The focus is on the challenges in the assessment of immunohistochemical stains and the value of PCR-based procedures, considering the expanded ICI indication spectrum. A practice-oriented flowchart for everyday diagnostic decision-making is provided that considers new data on the frequency and type of discordances between MMR-IHC and MSI-PCR findings, and the possible role of Next Generation Sequencing in clarifying them. Reference is made to the significance of systematic quality assurance measures (e.g., QuIP MSI portal and multicenter proficiency testing), including regular continued training and education.
Topics: Humans; DNA Mismatch Repair; Microsatellite Instability; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Multicenter Studies as Topic
PubMed: 37874379
DOI: 10.1007/s00292-023-01208-2