Browse
Submit Data
Databases
API
Help

Dataset Information

25 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pathological Tumor Response Following Immune Checkpoint Blockade for Deficient Mismatch Repair Advanced Colorectal Cancer.

ABSTRACT: Immune checkpoint inhibition (CPI) for metastatic colorectal cancer (mCRC) with deficient mismatch repair (dMMR) demonstrates high clinical activity that appears durable, but the impact of CPI on pathological tumor response is unknown. In this retrospective analysis, our objective was to assess pathological response and clinical outcomes in dMMR mCRC patients treated with CPI prior to surgical resection of primary and/or metastatic tumor. Among 121 advanced dMMR mCRC patients treated with CPI at 2 institutions between November 2016 and December 2018, 14 underwent surgery. Pathologic complete response was noted in the resected specimens of 13 patients despite the presence of residual tumor on preoperative imaging in 12 of those patients. With median follow-up of 9 months, no patients have had disease relapse or progression. For this small retrospective study, the data suggest that residual radiographic tumor may not require systematic resection following response to anti-PD1-based therapy. However, larger prospective studies are warranted.

SUBMITTER: Ludford K

PROVIDER: S-EPMC7850519 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair-Deficient Colorectal Cancer.

Project description:Immunotherapy with checkpoint inhibitors, such as the programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab, are effective in a variety of tumors, yet not all patients respond. Tumor microsatellite instability-high (MSI-H) has emerged as a biomarker of response to checkpoint blockade, leading to the tissue agnostic approval of pembrolizumab in MSI-H cancers. Here we describe a patient with MSI-H colorectal cancer that was treated with this immune checkpoint inhibitor and exhibited progression of disease. We examined this intrinsic resistance through genomic, transcriptional, and pathologic characterization of the patient's tumor and the associated immune microenvironment. The tumor had typical MSI-H molecular features, including a high neoantigen load. We also identified biallelic loss of the gene for β2-microglobulin (B2M), whose product is critical for antigen presentation. Immune infiltration deconvolution analysis of bulk transcriptome data from this anti-PD-1-resistant tumor and hundreds of other colorectal cancer specimens revealed a high natural killer cell and M2 macrophage infiltration in the patient's cancer. This was confirmed by single-cell transcriptome analysis and multiplex immunofluorescence. Our study provides insight into resistance in MSI-H tumors and suggests immunotherapeutic strategies in additional genomic contexts of colorectal cancer.

| S-EPMC6679789 | biostudies-literature

Mismatch Repair Deficiency and Response to Immune Checkpoint Blockade.

Project description:: More than 1.6 million new cases of cancer will be diagnosed in the U.S. in 2016, resulting in more than 500,000 deaths. Although chemotherapy has been the mainstay of treatment in advanced cancers, immunotherapy development, particularly with PD-1 inhibitors, has changed the face of treatment for a number of tumor types. One example is the subset of tumors characterized by mismatch repair deficiency and microsatellite instability that are highly sensitive to PD-1 blockade. Hereditary forms of cancer have been noted for more than a century, but the molecular changes underlying mismatch repair-deficient tumors and subsequent microsatellite unstable tumors was not known until the early 1990s. In this review article, we discuss the history and pathophysiology of mismatch repair, the process of testing for mismatch repair deficiency and microsatellite instability, and the role of immunotherapy in this subset of cancers.Mismatch repair deficiency has contributed to our understanding of carcinogenesis for the past 2 decades and now identifies a subgroup of traditionally chemotherapy-insensitive solid tumors as sensitive to PD-1 blockade. This article seeks to educate oncologists regarding the nature of mismatch repair deficiency, its impact in multiple tumor types, and its implications for predicting the responsiveness of solid tumors to immune checkpoint blockade.

| S-EPMC5061538 | biostudies-other

Mismatch repair-deficient prostate cancer with parenchymal brain metastases treated with immune checkpoint blockade.

Project description:Parenchymal brain metastases from prostate cancer are unusual and are associated with poor prognosis. Given the rarity of this entity, little is known about its molecular and histologic characteristics. Here we describe a patient with metastatic castration-resistant, mismatch repair-deficient (dMMR) prostate cancer with parenchymal brain metastases. Analysis of a brain metastasis revealed MLH1 loss consistent with dMMR, yet few tumor-infiltrating lymphocytes (TILs). He was treated with immune checkpoint blockade (ICB) and exhibited an extra-central nervous system (CNS) systemic response but CNS progression. Subsequent assessment of a brain metastasis following ICB treatment surprisingly showed increased TIL density and depletion of macrophages, suggestive of an enhanced antitumor immune response. Post-treatment tumoral DNA sequencing did not reveal acquired mutations that might confer resistance to ICB. This is the first description of ICB therapy for a patient with prostate cancer with parenchymal brain metastases, with pre- and post-treatment immunogenomic analyses.

| S-EPMC8327884 | biostudies-literature

Genomic Determinants of De Novo Resistance to Immune Checkpoint Blockade in Mismatch Repair-Deficient Endometrial Cancer.

Project description: Not available

| S-EPMC7269172 | biostudies-literature

Immunotherapy with immune checkpoint inhibitors in colorectal cancer: what is the future beyond deficient mismatch-repair tumours?

Project description:Following initial success in melanoma and lung tumours, immune checkpoint inhibitors (ICIs) are now well recognized as a major immunotherapy treatment modality for multiple types of solid cancers. In colorectal cancer (CRC), the small subset that is mismatch-repair-deficient and microsatellite-instability-high (dMMR/MSI-H) derive benefit from immunotherapy; however, the vast majority of patients with proficient MMR (pMMR) or with microsatellite stable (MSS) CRC do not. Immunoscore and the consensus molecular subtype classifications are promising biomarkers in predicting therapeutic efficacy in selected CRC. In pMRR/MSS CRC, biomarkers are also needed to understand the molecular mechanisms governing immune reactivity and to predict their relationship to treatment. The continuous development of such biomarkers would offer new perspectives and more personalized treatments by targeting oncological options, including ICIs, which modify the tumour-immune microenvironment. In this review, we focus on CRC and discuss the current status of ICIs, the role of biomarkers to predict response to immunotherapy, and the approaches being explored to render pMMR/MSS CRC more immunogenic through the use of combined therapies.

| S-EPMC7034232 | biostudies-literature

Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers.

Project description:Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with the mutator phenotype of MMRd fosters enhanced immune surveillance of these cancers. In addition, recent findings suggest that MMRd tumors have increased cytosolic DNA, which triggers the cGAS STING pathway, leading to interferon-mediated immune response. Unfortunately, approximately 30% of MMRd CRC exhibit primary resistance to CPIs, while a substantial fraction of tumors acquires resistance after an initial benefit. Profiling of clinical samples and preclinical studies suggests that alterations in the Wnt and the JAK-STAT signaling pathways are associated with refractoriness to CPIs. Intriguingly, mutations in the antigen presentation machinery, such as loss of MHC or Beta-2 microglobulin (B2M), are implicated in initial immune evasion but do not impair response to CPIs. In this review, we outline how understanding the mechanistic basis of immune evasion and CPI resistance in MMRd CRC provides the rationale for innovative strategies to increase the subset of patients benefiting from CPIs.

| S-EPMC8199207 | biostudies-literature

Deficient mismatch repair system in patients with sporadic advanced colorectal cancer.

Project description:A deficient mismatch repair system (dMMR) is present in 10-20% of patients with sporadic colorectal cancer (CRC) and is associated with a favourable prognosis in early stage disease. Data on patients with advanced disease are scarce. Our aim was to investigate the incidence and outcome of sporadic dMMR in advanced CRC. Data were collected from a phase III study in 820 advanced CRC patients. Expression of mismatch repair proteins was examined by immunohistochemistry. In addition microsatellite instability analysis was performed and the methylation status of the MLH1 promoter was assessed. We then correlated MMR status to clinical outcome. Deficient mismatch repair was found in only 18 (3.5%) out of 515 evaluable patients, of which 13 were caused by hypermethylation of the MLH1 promoter. The median overall survival in proficient MMR (pMMR), dMMR caused by hypermethylation of the MLH1 promoter and total dMMR was 17.9 months (95% confidence interval 16.2-18.8), 7.4 months (95% CI 3.7-16.9) and 10.2 months (95% CI 5.9-19.8), respectively. The disease control rate in pMMR and dMMR patients was 83% (95% CI 79-86%) and 56% (30-80%), respectively. We conclude that dMMR is rare in patients with sporadic advanced CRC. This supports the hypothesis that dMMR tumours have a reduced metastatic potential, as is observed in dMMR patients with early stage disease. The low incidence of dMMR does not allow drawing meaningful conclusions about the outcome of treatment in these patients.

| S-EPMC2634718 | biostudies-literature

Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer: a phase I study

Project description:Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. All patients completed treatment without severe toxicity. A partial radiologic response was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on Magnetic Resonance Imaging (MRI). Pathologic response was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. Monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.

2024-07-19 | GSE268903 | GEO

Hyperprogression of a mismatch repair-deficient colon cancer in a humanized mouse model following administration of immune checkpoint inhibitor pembrolizumab.

Project description:Immunotherapy is an established treatment modality in oncology. However, in addition to primary or acquired therapy resistance with immune checkpoint blockade (ICB), hyperprogressive disease (HPD) or hyperprogression (HP) with acceleration of tumor growth occurs in a subset of patients receiving ICB therapy. A validated and predictive animal model would help investigate HPD/HP to develop new approaches for this challenging clinical entity. Using human cytotoxic T-cell line TALL-104 injected intraperitoneally into immunodeficient NCRU-nude athymic mice bearing mismatch repair-deficient (MMR-d) human colon carcinoma HCT116 p53-null (but not wild-type p53) tumor xenograft, we observed accelerated tumor growth after PD-1 blockade with pembrolizumab administration. There was increased colon tumor cell proliferation as determined by immunohistochemical Ki67 staining of tumor sections. There was no increase in MDM2 or MDM4/MDMX in the p53-null HCT116 cells versus the wild-type p53-expressing isogenic tumor cells, suggesting the effects in this model may be MDM2 or MDM4/MDMX-independent. Human cytokine profiling revealed changes in IFN-γ, TRAIL-R2/TNFRSF10B, TRANCE/TNFSF11/RANK L, CCL2/JE/MCP-1, Chitinase 3-like 1, IL-4 and TNF-α. This represents a novel humanized HPD mouse model with a link to deficiency of the p53 pathway of tumor suppression in the setting of MMR-d. Our novel humanized preclinical TALL-104/p53-null HCT116 mouse model implicates p53-deficiency in an MMR-d tumor as a possible contributor to HPD/HP and may help with evaluating therapeutic strategies in cancer immunotherapy to extend clinical benefits of ICB's in a broader patient population.

| S-EPMC8522841 | biostudies-literature

Immune Checkpoint Inhibitors and Mismatch Repair Status in Advanced Endometrial Cancer: Elective Affinities.

Project description:Since endometrial cancers (ECs) are frequently TMB-H and MSI-H/dMMR tumors, this element has provided the rationale for testing immune checkpoint inhibitors (ICIs), which have recently emerged as a potential game-changer. However, several questions remain to be addressed, including the identification of patients who may benefit from the addition of ICIs as well as those who do not need immunotherapy. In the current paper, we provide an overview of the clinical development of immunotherapy in advanced or recurrent EC, discussing the role of MMR and the "elective affinities" between ICIs and this predictive biomarker in this setting.

| S-EPMC9267485 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data