Dataset Information

Immunotherapy combined with local therapy in the late-line treatment of repair-proficient (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer.

ABSTRACT: Colorectal cancer (CRC) is one of the most common malignancies, and at the initial visit, most patients are diagnosed with metastatic CRC (mCRC). However, immunotherapy is only and highly effective in a very small proportion of patients with mCRC having mismatch repair defect (dMMR)/high microsatellite instability, and the majority of the patients with mCRC having mismatch repair proficient (pMMR)/microsatellite stability (MSS) cannot benefit from it. At present, many clinical studies of immunotherapy combined with tyrosine kinase inhibitors (TKIs) are trying to regulate the immune microenvironment of pMMR/MSS mCRC, transforming a "cold tumor" into a "hot tumor," which has not only surprising effects but also certain limitations, i.e., the response could not be specific to metastasis. Therefore, regarding the bottleneck encountered by immunotherapy in patients with patients pMMR/MSS mCRC, this study summarized current research and possible mechanisms of immunotherapy combined with local therapy for metastasis, including radiotherapy, ablation, and transcatheter arterial chemoembolization.

SUBMITTER: Ding Y

PROVIDER: S-EPMC10695980 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Immunotherapy combined with local therapy in the late-line treatment of repair-proficient (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer.

Ding Yuwei Y Weng Shanshan S Zhu Ning N Mi Mi M Xu Ziheng Z Zhong Liping L Yuan Ying Y

Heliyon 20231110 11

Colorectal cancer (CRC) is one of the most common malignancies, and at the initial visit, most patients are diagnosed with metastatic CRC (mCRC). However, immunotherapy is only and highly effective in a very small proportion of patients with mCRC having mismatch repair defect (dMMR)/high microsatellite instability, and the majority of the patients with mCRC having mismatch repair proficient (pMMR)/microsatellite stability (MSS) cannot benefit from it. At present, many clinical studies of immunot ...[more]

PMID: 38058653

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Project description:BackgroundNeoadjuvant immunotherapy (NIT) has been endorsed by clinical guidelines for the management of DNA mismatch repair deficiency/microsatellite instability-high (dMMR/MSI-H) locally advanced rectal cancer (LARC). Nonetheless, the therapeutic efficacy of NIT in mismatch repair-proficient/microsatellite stable (pMMR/MSS) non-metastatic rectal cancer (RC) remain pending matters. Therefore, a meta-analysis was carried out to assess the efficacy and safety of NIT in patients with non-metastatic pMMR/MSS RC.MethodsPubMed, Embase, Web of Science, the Cochrane Library, ClinicalTrials.gov, ASCO and ESMO were searched to obtain related studies up to July 2024. Two reviewers independently screened the included articles and extracted the pertinent data. The risk of publication bias was assessed by Begg or Egger tests and in cases of publication bias, the trim and fill method was applied. Heterogeneity was assessed using I 2 statistics.ResultsThirteen articles including 582 eligible patients were analyzed. The pooled pCR, MPR, cCR and anus preservation rate were 37%, 57%, 26% and 77% separately and the incidence of irAEs≥3 grades and TRAEs≥3 grades were 3% and 29%, respectively. Non-metastatic pMMR/MSS RC receiving the short-course radiotherapy (SCRT) in neoadjuvant setting exhibited superior pooled pCR and MPR than long-course radiotherapy (LCRT) without upregulating the incidence of adverse effects. Furthermore, patients with MSS RC underwent neoadjuvant treatment with anti-PD-1 inhibitors demonstrated higher pooled pCR, MPR, cCR compared to those receiving PD-L1 inhibitors. Additionally, yielded improved pooled MPR and anal preservation rates compared to sequential immuno-radiotherapy (63.4% vs 51.2% and 88.5% vs 69.9%), without raising the incidence of irAEs≥3 grade. Interestingly, RC patients with lymph node metastasis showed a higher pooled pCR than those without lymph node metastasis (43% vs 35%).ConclusionNIT was linked to favorable response rates and anal preservation, alongside an acceptable safety profile. Non-metastatic pMMR/MSS RC patients receiving SCRT, PD-1 inhibitors, or concurrent immuno-radiotherapy in the neoadjuvant setting exhibited enhanced outcomes. This meta-analysis provides evidence for further exploration and application of NIT in non-metastatic pMMR/MSS RC and highlights the potential for organ preservation with this approach. The relatively small sample size and the uneven quality of included studies may have had some impact on the generality of the results. Therefore, further analysis with a higher number of high-quality studies is needed to verify the conclusions.Systematic review registrationhttps://inplasy.com/, identifier: INPLASY202470110.

Project description:BackgroundMonotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells.MethodsOpen-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts (NCT03428126). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, requiring a response in two or more pts to proceed to stage 2. Tumor biopsies were collected at baseline (BL) and early on-treatment (OT) at week 4.ResultsTwenty nine treated pts include 48% females, median age 48 years (range 28-75), and median prior therapies 2 (range 1-5). No grade (G) 4 or 5 treatment-related adverse events (TRAE). The most common TRAE of any grade was acneiform rash, 17% being G3. One of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an overall response rate of 3.4%. Seven pts had stable disease (SD) and five pts (1 PR, 4 SD) demonstrated decrease in total carcinoembryonic antigen ng/mL (best percentage reduction: 94%, 95%, 42%, 34%, and 22%, respectively). Median progression-free survival was 3.2 mo (range 1.1-9.3 months). Three pts with both liver and lung metastases demonstrated discrepant responses in which clinical benefit was present in the lung metastases but not liver metastases. Comparison of BL and 4-week OT tumor tissue flow cytometry demonstrated no changes in T-cell infiltration but upregulation expression of PD-1 and Tim3 on CD8 T cells. However, expression of PD-1 and Tim3 as single markers and as coexpressed markers was observed to increase OT relative to BL (p=0.03, p=0.06 and p=0.06, respectively).ConclusionsT+D demonstrated acceptable tolerability in pts with refractory MSS mCRC. The response rate in the first stage of the study did not meet efficacy criteria to proceed to the second stage. Specific site of metastatic disease may impact outcomes in novel immunotherapy combination trials.Trial registration numberNCT03428126.

Project description:IntroductionImmunotherapy is currently the most promising antitumor treatment approach. However, the colon cancer immunotherapy indication dMMR/MSI-H do not cover all colon cancer patients suitable for immunotherapy. We performed transcriptome-wide expression profile analyses of pMMR/MSS colon adenocarcinoma (COAD) specimens from TCGA database to identify a genetype signature associated with tumor immune microenvironment types (TIMTs).MethodsTCGA database was used to identify tumor genotypes suitable for antitumor immunotherapy. We analyzed RNA-sequencing profiles of 338 COAD targeted to the pMMR/MSS group from TCGA public dataset. The ESTIMATE and the CIBERSORT were used to analyze the pMMR/MSS COAD immune microenvironment between APC wild and APC mutation. Furthermore, we further verified the relationship between APC genotype and TIMTs and the efficacy of immunotherapy in 42 colon cancer specimens.ResultsWe identified that in APC-wt/MSS colon cancer, the expressions of PD-1, PD-L1, CTLA4, and CYT (GZMA and PRF1) were increased. The TMB, Immunoscore, and the proportion of CT8+ T cell infiltration also were identified increasing in these patients. And pathway enrichment analysis for differentially expressed genes (DEGs) between APC-wt and APC-mt MSS COAD was done to further explore their biological function. Similarly, the significant pathways for DEGs were mainly enriched in the immune response, extracellular matrix, and cell adhesion which involved in immune response. Specimens from 42 colon cancer patients, including 22 APC-mt/MSS and 20 APC-wt/MSS, were immunohistochemically evaluated for expression of CD8 and PD-L1. And APC-wt/MSS tumors showed significantly higher expression of CD8 and PD-L1 than APC-mt/MSS tumor. Moreover, APC-wt was compared with APC-mt MSS/pMMR colon cancer (DOR, 45% and 26.7%, respectively; P < 0.05).ConclusionBased on the results, we found that more colon cancers of APC-wt/MSS are classified by TMIT I. And APC-wt/MSS colon cancer patients are more likely to benefit from antitumor immunotherapy.

Dataset Information

Immunotherapy combined with local therapy in the late-line treatment of repair-proficient (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer.

Publications

Immunotherapy combined with local therapy in the late-line treatment of repair-proficient (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer.

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