scholarly journals Chromosomal Instability May Not Be a Predictor for Immune Checkpoint Inhibitors from a Comprehensive Bioinformatics Analysis

Life ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 276
Author(s):  
Chiao-En Wu ◽  
Da-Wei Yeh ◽  
Yi-Ru Pan ◽  
Wen-Kuan Huang ◽  
Ming-Huang Chen ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Predictive Value ◽  
Chromosomal Instability ◽  
Immune Checkpoint Inhibitors ◽  
Bioinformatics Analysis ◽  
Checkpoint Inhibitors ◽  
P Value ◽  
Cancer Type ◽  
Significant Difference ◽  
The Impact

Immune checkpoint inhibitors (ICIs) have become the standard of care in various cancers, although their predictive tools have not yet completely developed. Here, we aimed to exam the role of 70-gene chromosomal instability signature (CIN70) in cancers, and its association with previous predictors, tumor mutation burden (TMB), and microsatellite instability (MSI), for patients undergoing ICIs, as well as the possible predictive value for ICIs. We examined the association of CIN70 with TMB and MSI, as well as the impact of these biomarkers on the survival of 33 cancer cohorts from The Cancer Genome Atlas (TCGA) databank. The predictive value of the ICIs of CIN70 in previously published reports was also validated. Using the TCGA dataset, CIN70 scores were frequently (either positively or negatively) associated with TMB, but were only significantly associated with MSI status in three types of cancer. In addition, our current study showed that all TMB, MSI, and CIN70 had their own prognostic values for survival in patients with various cancers, and that they could be cancer type-specific. In two validation cohorts (melanoma by Hugo et al. and urothelial cancer by Snyder et al.), no significant difference of CIN70 scores was found between responders and non-responders (p-value = 0.226 and 0.108, respectively). In addition, no overall survival difference was noted between patients with a high CIN70 and those with a low CIN70 (p-value = 0.106 and 0.222, respectively). In conclusion, the current study, through a comprehensive bioinformatics analysis, demonstrated a correlation between CIN70 and TMB, but CIN70 is not the predictor for cancer patients undergoing ICIs. Future prospective studies are warranted to validate these findings.

scholarly journals Association between the type of thyroid dysfunction induced by immune checkpoint inhibitors and prognosis in cancer patients

2021 ◽  
Author(s):  
Han-sang Baek ◽  
Chaiho Jeong ◽  
Kabsoo Shin ◽  
Jaejun Lee ◽  
Dong-Jun Lim ◽  
...  
Keyword(s):  
Subclinical Hypothyroidism ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Thyroid Dysfunction ◽  
Checkpoint Inhibitors ◽  
Hazard Ratio ◽  
Cancer Type ◽  
Significant Difference ◽  
The Difference ◽  
Lower Hazard

Abstract Background Immune checkpoint inhibitors (ICIs) cause thyroid immune-related adverse effects (irAEs). However, associations between each type of thyroid immune-related adverse effect (irAE) and the anti-tumor effect of ICI remains unknown. This study aimed to determine the effects of each type of thyroid dysfunction on patient survival. Methods Patients who initiated ICI treatment from January 2015 to December 2019 in Seoul St. Mary’s Hospital were retrospectively analyzed. Thyroid dysfunction was classified into four types: newly developed overt or subclinical hypothyroidism, thyrotoxicosis, worsened hypothyroidism, and subclinical hyperthyroidism. Patients were divided into two groups according to the presence or absence of thyroid dysfunction. Results Among the 196 patients, 66 (33.7%) developed thyroid irAEs. There was no significant difference in age, sex, or cancer type between the two groups. The overall survival in patients with thyroid irAEs was significantly higher than that in patients without thyroid irAEs (38 months vs. 13 months, respectively, p = 0.005). After adjusting for confounding factors, the hazard ratio for mortality in the thyroid irAE group compared to the no thyroid irAE group was 0.520 (p = 0.007). Newly developed overt or subclinical hypothyroidism patients showed a significantly lower hazard ratio for morbidity of 0.309 (p = 0.001). Patients with thyrotoxicosis showed a worse hazard ratio for morbidity than those without thyroid irAE, although the difference was not statistically significant. Conclusions It was verified that ICI treatment-induced thyroid dysfunction was associated with better survival, even in the real-world practice. Thus, endocrinologists should cooperate with oncologists to monitor patients treated with ICIs.

Impact of concurrent ACE inhibitors and ARBs on outcomes with immune-checkpoint inhibitors (ICIs) for patients (pts) with metastatic renal cell carcinoma (mRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 354-354
Author(s):  
Pier Vitale Nuzzo ◽  
Catherine Curran ◽  
Elio Adib ◽  
Dory Freeman ◽  
Amin Nassar ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Transforming Growth Factor ◽  
Checkpoint Inhibitors ◽  
Angiotensin Receptor Blockers ◽  
P Value ◽  
Line Treatment ◽  
Concurrent Administration ◽  
Best Response ◽  
The Impact

354 Background: The renin-angiotensin system (RAS) is involved in regulation of angiogenesis and cell proliferation and may improve drug delivery by enhancing tumor perfusion partly by downregulating transforming growth factor (TGF)-β. Since (TGF)-β appears to be associated with resistance in patients receiving immune checkpoint inhibitors (ICIs), we investigated whether angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) may enhance the outcomes of mRCC pts receiving ICI. Methods: Data from mRCC pts who received ICIs at the Dana-Farber Cancer Institute (DFCI) was obtained. Data for ACEI and ARB administration was collected with concurrent administration defined as ongoing therapy from the time of starting ICI . The Kaplan-Meier method and Cox were used to evaluate the impact of concurrent ACEI/ARB on overall survival (OS). Results: Data was available for 134 pts. The mean age was 63 years (Range 37-85)). 94 (70%) pts were male. The therapies included Nivolumab+/-Other (104), Atezolizumab+/-Other (21), Pembrolizumab+/-Other (8) and Durvalumab +Tremelimumab (1). 35 (25%) pts received ICI as first line treatment, 52 (39%) received as second line treatment, and 48 (36%) received as third line or higher. Out of the 134 pts, 39 (29%) had been treated with an ACEI or ARB during ICI treatment. Out of the 39 pts who had ACEI or ARB, 2 (5%) had complete response (CR) as best response, 11 (28%) had partial response (PR), 17 (46%) had stable disease (SD) and 9 (23%) had progressive disease (PD). Out of the 95 pts who did not receive ACEI or ARB, 3 pts (3%) had CR as their best response to ICI, 19 (21%) had PR, 39 (43%) had SD, and 29 (32%) had PD, (5 patients’ best response were unevaluable). The median OS for those who had ACEI/ARBs and did not have ACEI/ARBs was 32 months and 20 months respectively. Univariable analysis revealed that patients who received ACEI/ARBs had improved OS (Logrank p-value = 0.002; HR = 2.5 [95%CI: 1.4 - 4.5]). Conclusions: In this hypothesis-generating study, concurrent ACEI/ARBs are associated with better outcomes for mRCC pts receiving ICIs. Given the availability of ACEI/ARBs, it is important to validate this result in a larger dataset and after controlling for known prognostic factors.

scholarly journals 1769. The Impact of Checkpoint Inhibitor Immunotherapy on Infections in Lung Cancer Patients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S652-S652
Author(s):  
Alexandre Malek ◽  
Johny Fares ◽  
Melissa Khalil ◽  
Ray Y Hachem ◽  
Anne-Marie Chaftari ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Infectious Complications ◽  
Control Group ◽  
Conventional Chemotherapy ◽  
Significant Difference ◽  
Tract Infections ◽  
The Impact

Abstract Background Immune checkpoint inhibitors (ICI) therapy has ushered cancer treatment into a potentially curative era. However, infectious complications remain largely unknown and the few studies that described infectious complications associated with ICI had no comparative control groups. We assessed the rate of infections in patients with non-small cell lung cancer (NSCLC) treated with ICI plus conventional chemotherapy (CC) vs. CC alone. Methods We performed a comparative single-center retrospective cohort study of patients with NSCLC who received de novo treatment with either Pembrolizumab or Nivolumab, and/or Ipilimumab combined with CC including Pemetrexed and Carboplatin vs. patients treated with CC alone between August 2016 and January 2019. We excluded all patients who were switched from CC to ICI or vice-versa. We evaluated patients’ characteristics, treatment modality, immune-related adverse events (irAEs), and outcome. Infections were defined by clinical signs and symptoms, microbiologic documentation, and/or imaging studies. Results A group of 126 patients who received ICI concurrently with CC were compared with 126 patients who received CC alone (control group). Patients in the ICI group were more likely to have stage IV NSCLC compared with the control group (P < 0.0001). Pembrolizumab was most commonly used as a single ICI agent in 107 patients (85%), followed by Ipilimumab and Nivolumab as dual therapy (9%). Confirmed infections were identified in 20 (16%) patients in the ICI group and 18 (14%) in the control group (P = 0.7). The control group had a higher rate of multiple infections at different times compared with the ICI group (P = 0.014). However, there was no significant difference in the types of infections (bacterial, fungal or viral) that occurred between the two groups. The irAEs were reported in 14 (11%) patients, 13 of them received corticosteroids with a median duration of 32 days (range, 15–64 days). Out of these patients, three (21%) developed confirmed infections of which two were viral upper respiratory tract infections and one was a bacterial urinary tract infection. Conclusion Patients with NSCLC treated with the combination of Immune Checkpoint Inhibitors plus Conventional Chemotherapy have comparable risk of developing infections compared with those on Conventional Chemotherapy alone. Disclosures All authors: No reported disclosures.

scholarly journals Timing of immune checkpoint inhibitors for metastatic patients over 75 years of age: the earlier the better

2020 ◽  
Author(s):  
Thierry Landre ◽  
Gaetan Des Guetz ◽  
Kader Chouahnia ◽  
Virginie Fossey-Diaz ◽  
Stéphane Culine
Keyword(s):  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Significant Difference ◽  
Line Setting ◽  
The Impact

Abstract Background The impact of ageing on Immune Checkpoint Inhibitors (ICIs) effectiveness remains controversial. However, data from clinical studies do not show any difference between patients over 65 years and those under 65 years. We focused our study on patients over 75 and looked at the potential impact of timing in the use of ICIs. Methods We performed a meta-analysis of published randomized control trials (RCTs) concerning ICIs versus standard therapy in patients with advanced solid tumors. Overall Survival (OS) among the older (≥75 years) was compared with that of younger patients (< 75 years). Hazard ratios (HRs) with their 95% confidence interval (CI) were collected and pooled. Results Fifteen phase III studies evaluating anti-PD-1(nivolumab or pembrolizumab), anti-PD-L1 (atezolizumab or avelumab) or anti-CTLA-4 (ipilimumab) were included. Patients were enrolled for Non-Small-Cell-Lung-Cancer, Renal-Cell-Carcinoma, Melanoma, Head-and-Neck-Squamous-Cell-Carcinoma or Gastric Cancer. Eight studies assessed treatment in first-line setting and seven in the second line. The median age was 64 years, with 906 patients over 75 years of age and 5233 youngers. In first-line setting, HRs for death were 0.78 (95% CI: 0.61-0.99) in patients ≥75 years versus 0.84 (95% CI: 0.71-1.00) in younger. In second line setting, HRs for death were 1.02 (95% CI: 0.77-1.36) in patients ≥75 years versus 0.68 (95% CI: 0.61-0.75) in younger with a statistically significant difference observed between subgroups (p interaction = 0.009). Conclusions ICIs appears to be effective in patients over 75 years of age. However, the survival benefit is mainly observed in first-line treatment.

scholarly journals Neutrophil to lymphocyte ratio influences impact of steroids on efficacy of immune checkpoint inhibitors in lung cancer brain metastases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Adam Lauko ◽  
Bicky Thapa ◽  
Mayur Sharma ◽  
Baha’eddin Muhsen ◽  
Addison Barnett ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Neutrophil To Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Significant Difference ◽  
The Impact

AbstractSteroids are often utilized to manage patients with non-small cell lung cancer brain metastases (NSCLCBM). Steroids and elevated neutrophil-to-lymphocyte ratio (NLR) have been associated with decreased overall survival (OS) in patients treated with immune checkpoint inhibitors (ICI). We retrospectively investigated patients treated with ICI after the diagnosis of NSCLCBM at a single tertiary care institution examing the impact of steroids and NLR. Overall survival (OS) and intracranial progression-free survival (PFS) were analyzed. 171 patients treated with ICI for NSCLCBM were included. Thirty-six received steroids within 30 days of the start of ICI, and 53 patients had an NLR ≥ 5 before the start of ICI. Upfront steroids was associated with decreased OS on multivariable analysis (median OS 10.5 vs. 17.9 months, p = .03) and intracranial PFS (5.0 vs. 8.7 months, p = .045). NLR ≥ 5 was indicative of worse OS (10.5 vs. 18.4 months, p = .04) but not intracranial PFS (7.2 vs. 7.7 months, p = .61). When NLR and upfront steroids are modeled together, there is a strong interaction (p = .0008) indicating that the impact of steroids depended on the patient’s NLR. In a subgroup analysis, only in patients with NLR < 4 was there a significant difference in OS with upfront steroids (26.1 vs. 15.6 months, p = .032). The impact of steroids on the efficacy of ICI in patients with NSCLCBM is dependent on the patient's NLR underscoring its importance in these patients. Patients with a low NLR, steroid use decreases the efficacy of ICI. These results can inform clinicians about the impact of steroids in patients treated with ICI.

Characteristics of hospitalizations among patients receiving immune checkpoint inhibitors at a community teaching hospital

2019 ◽  
Vol 26 (1) ◽  
pp. 60-66
Author(s):  
Brendan Rasor ◽  
Rachel Henderson ◽  
Kin Chan
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Cancer Type ◽  
Preventable Admissions ◽  
The Impact ◽  
Reason For Admission

Purpose As immune checkpoint inhibitors continue to acquire new indications, it is important to understand the impact their use has on patients. This study adds to current literature by presenting an analysis of hospitalizations in this population. The primary objective was to assess the reasons for an emergency department visit or hospital admission in patients who receive immune checkpoint inhibitors. Secondary objectives included identifying the frequency of suspected or confirmed immune related adverse events, types of immune related adverse events, number of preventable admissions, duration of immunotherapy, and length of stay. Methods This study was a retrospective, multi-center, chart review of patients hospitalized after receiving an immune checkpoint inhibitor. The population included patients aged 18 and above who received at least one dose of an immune checkpoint inhibitor at a network facility and had a documented admission within one year following the initiation of immunotherapy. Descriptive statistics were performed along with inferential comparisons and a Poisson regression to determine if the immune checkpoint blocker or cancer type predicted admission or reason for admission. Results The 99 patients who met inclusion criteria had a total of 202 admissions. Of these patients, 56 (56.6%) had multiple admissions within the year following initiation of immunotherapy. The most common diagnoses on initial admissions were shortness of breath, pain, and pneumonia. A total of 104 admissions (51.5%) were considered potentially preventable. Suspected or confirmed immune related adverse events were identified in 15.6% of all admissions. There were no significant predictors of admissions or reason for admission. Conclusion Reasons for admission in the study population were comparable to those identified in the general cancer population, with immune related adverse events being associated with a minority of both total and potentially preventable admissions.

Impact of age in advanced renal cell carcinoma treated with immune checkpoint inhibitors.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 702-702
Author(s):  
Alberto Carretero-González ◽  
David Lora ◽  
Lucía Carril Ajuria ◽  
Maria Cruz Martin Soberón ◽  
Daniel Castellano ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Elderly Patients ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Randomized Clinical Trials ◽  
Checkpoint Inhibitors ◽  
P Value ◽  
The Impact

702 Background: Immune checkpoint inhibitors (ICIs) are beneficial in a subset of metastatic renal cell carcinoma (mRCC) patients. Elderly patients are usually under-represented in pivotal trials. Importantly, aging has been pointed as a potential detrimental factor for the benefit with ICIs as a consequence of the “immunosenescence” which could decrease the efficacy of these treatments. Methods: We assessed the potential role of aging according to Cochrane Collaboration's Guidelines. Search of randomized clinical trials (RCTs) comparing ICIs (monotherapy or in combination with other therapies) to standard of care (SoC) in mRCC patients was performed. Trials must have included subgroup analysis evaluating the selected outcome (overall survival-OS-) in different subsets of patients according to age. Additionally, a retrospective series of mRCC patients treated with ICIs from our institution was also reviewed to assess the impact of age. Results: A total of 3415 patients (4 studies) were included in the meta-analysis (ICIs arm: 1709 patients; SoC arm: 1706 patients). Altogether, OS results favored ICIs. Older patients (aged more than 75 years-old) seem to present a less clear benefit with ICIs compared to SoC in comparison with younger patients (aged up to 75 years-old; p-value for difference between subgroups: 0.006) (Table). No differences between subgroups were found when considering 65 years-old as the borderline (p-value: 0.179). A similar trend was found in our series, with a numerically better median OS in patients younger than 65 years-old compared to those older than 65 years-old (31,6 vs. 23,6 months); the effect of age on outcomes was maintained along all International Metastatic RCC Database Consortium (IMDC) score subgroups. Conclusions: Elderly patients with mRCC, particularly older than 75 years-old, could benefit to a lesser extent compared to younger counterparts from receiving ICIs.[Table: see text]

RNF43 mutations to predict survival from treatment with immune checkpoint inhibitors and are associated with a high tumor mutation burden in bladder cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16528-e16528
Author(s):  
Liping Li ◽  
Mengmei Yang ◽  
Mengli Huang
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Negative Regulator ◽  
Wilcoxon Test ◽  
Wild Type ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
The Impact

e16528 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1/L1 have been approved as first-line treatment for cisplatin-ineligible patients and as second-line therapy for patients with metastatic urothelial carcinoma of the bladder. Biomarkers can help select patients who are more likely to response to ICIs. RNF43 is an E3 ubiquitin ligase that acts as a negative regulator of Wnt/β-catenin signaling pathway. In colorectal cancer (CRC) patients treated with immune checkpoint inhibitors (ICIs), RNF43 mutations predicted longer overall survival (OS). The impact of RNF43 mutations on the efficiency of ICIs in bladder cancer(BLC) remains to be explored. Methods: We downloaded the mutation and clinical data of 211 BLC patients treated with ICIs from the immunotherapeutic cohort published by Samstein et al. (2019). OS analyses were conducted using Kaplan-Meier curves and log-rank tests. Wilcoxon test was used for the comparison of TMB. We also downloaded a TCGA cohort for prognostic analysis. The correlations between RNF43 and immune infiltrates were analyzed in the TIMER2.0 database. Statistical significance was set at p = 0.05. Results: RNF43 mutations were identified in 4.3%(9/211) and 3%(13/438) BLC patients in the immunotherapeutic and TCGA cohort, respectively. In the immunotherapeutic cohort, patients with RNF43 mutations had significantly longer OS (25 months vs 8 months; p = 0.015) and higher tumor mutation burden(TMB, 42.3 vs 7.9; p = 3.15E-06) than RNF43-wild-type patients. Different from this, no significant difference was found in OS between RNF43-mutant and RNF43-wild-type BLC patients with standard treatment in the TCGA cohort (p = 0.696). These results indicated that RNF43 was not a prognostic factor but a predictive biomarker of survival in BLC treated with ICIs. No difference was observed in subsets of immune cells between RNF43-mutant and the RNF43-wide-type BLC patients, including neutrophils, macrophages, CD8+ T cells, Tregs, B cells and NK cells. Conclusions: RNF43 mutations may be a predictor of survival benefit from ICIs in bladder cancer and correlated with higher TMB. Further studies in other ICI-treated cohorts are needed to confirm these results.

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