scholarly journals Unknown primary tumors: is there a future therapeutic role for immune checkpoint inhibitors?

2016 ◽  
Vol 12 (4) ◽  
pp. 429-431 ◽  
Author(s):  
Hampig Raphael Kourie ◽  
Gil Awada ◽  
Ahmad Hussein Awada
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Unknown Primary ◽  
Therapeutic Role ◽  
Primary Tumors ◽  
Unknown Primary Tumors

The genomic landscape of metastatic clear cell renal cell carcinoma (ccRCC) after treatment with systemic therapy.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 675-675
Author(s):  
Johannes Van Der Mijn ◽  
Kenneth Eng ◽  
Evan Fernandez ◽  
Clara Oromendia ◽  
Tuo Zhang ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Systemic Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Vegf Inhibitors ◽  
Cell Renal Cell Carcinoma ◽  
Primary Tumors ◽  
Anti Vegf ◽  
Genomic Landscape

675 Background: The most frequent genomic alterations in patients (pts) with ccRCC have been identified in primary tumors. Here we investigated the genomic landscape of ccRCC in a cohort enriched for metastatic tumors after treatment with systemic therapy. Methods: We prospectively enrolled pts with ccRCC in a clinical study in which Whole-Exome Sequencing (WES) of normal and tumor tissue was performed. Clinical features, treatment outcome and survival were evaluated. Results: Forty-five pts with ccRCC with a median age of 65 years (range 38–86) were enrolled. According to the Heng risk criteria, 15 pts (33.3%) were classified as favorable-risk 23 pts (51.1%) were intermediate-risk and 7 pts (15.6%) were poor-risk. Pts received a median number of 3 lines (range 0–9) of therapy including cytokines (n=7), anti-VEGF (n=36), mTOR inhibitors (n=10) and/or immune checkpoint inhibitors (n=23). The median progression free survival (PFS) after treatment was 3.5 months (0.7-13.1), 11.1 months (1.1–54.2), 2.7 months (0.7-36.2) and 4.9 months (1.4–29.2) after cytokines, VEGF-, mTOR- and immune checkpoint inhibitors, respectively. The median overall survival (OS) from start of treatment to last follow up was 2.2 years (range 0.2–14.9 years). A total of 68 samples were sequenced. These included 9 (12.5%) primary tumors, 38 (55.9%) collected after treatment with anti-VEGF, 16 (23.5%) after mTOR- and 8 (11.8%) after immune checkpoint inhibitor. VHL, KDM5C, SETD2 and PBRM1 were the most frequent somatic mutations detected in this cohort. In two cases with a short and long response to VEGF targeted therapy (PFS 2.8 versus 50.3 months) rapid autopsies were performed which allowed multiregional (n=7, n=4) sampling. The multiregional sequencing in the rapid autopsy case with a prolonged response to VEGF targeted therapy revealed recurrent KDM5C mutations. Conclusions: We present the genomic landscape of metastatic ccRCC after treatment with systemic therapy. We report an increased frequency of KDM5C mutations, previously described to be associated with a favorable response to VEGF-inhibitors.

Human leukocyte antigen expression in paired primary lung lesions and brain metastases in non-small cell lung cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 43-43
Author(s):  
Jarrett Failing ◽  
Marie-Christine Aubry ◽  
Aaron Scott Mansfield
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Human Leukocyte ◽  
Small Cell ◽  
Small Cell Lung ◽  
Primary Tumors ◽  
Primary Nsclc

43 Background: Human leukocyte antigens (HLA) are crucial for cytotoxic T cell responses to cancer. Loss of HLA expression is a mechanism of tumor immune escape and may contribute to resistance to immunotherapy. In patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors we have observed discordant responses between brain metastases and extracranial disease and reported on differential PD-L1 expression and clonal T cell infiltration between paired primary lung lesions and brain metastases. In this project we sought to evaluate whether HLA expression was retained in metastatic NSCLC. Methods: Adult patients with paired primary NSCLC and brain metastases were identified from our institution’s tissue registry. HLA-A cell membrane expression on tumor cells was determined by immunohistochemistry with an anti-HLA-A antibody. Tumors with greater than 10% HLA expression were considered positive. Agreement statistics (κ) and Fisher’s exact test were used for analysis. Results: 51 patients with paired primary NSCLC and brain lesions were identified. The median HLA expression was 20% in the primary tumors (IQR 0-65%) and 10% in the brain metastases (IQR 5-40%). 27 primary tumors and 24 brain metastases were positive for HLA expression. There was disagreement in HLA positivity between paired lesions in 11 patients (22%, 95% CI 12-35%)(κ = 0.57, 95% CI 0.35-0.79)(p = 0.0001). There was no significant difference in the time between the primary tumor and brain metastasis resections in patients with HLA expression disagreement compared to those with HLA expression agreement. None of the patients received immune checkpoint inhibitors for treatment of these lesions. Conclusions: We found significant differences in HLA-A expression on tumor cells in nearly one quarter of paired primary lung cancers and brain metastases. Differences in HLA expression may help explain the discrepancies in response to immune checkpoint inhibitors at different sites of disease and warrants further study.

scholarly journals Biologic subtypes of melanoma predict survival benefit of combination anti-PD1+anti-CTLA4 immune checkpoint inhibitors versus anti-PD1 monotherapy

2021 ◽  
Vol 9 (1) ◽  
pp. e001642
Author(s):  
April A N Rose ◽  
Susan M Armstrong ◽  
David Hogg ◽  
Marcus O Butler ◽  
Samuel D Saibil ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Primary Tumor ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Advanced Melanoma ◽  
Unknown Primary ◽  
Tumor Type ◽  
Multivariable Analyses ◽  
Primary Tumor Type

PurposeAnti-programmed cell death protein 1 (PD1)±anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint inhibitors (ICIs) are standard therapeutic options for metastatic melanoma. We assessed whether biologic subtype according to primary tumor type or genomic subtype can function as predictive biomarkers for anti-PD1±anti-CTLA4 ICI in patients with advanced melanoma.MethodsWe performed a single-center retrospective cohort analysis of patients who received anti-PD1±anti-CTLA4 ICI for advanced melanoma between 2012 and 2019. Primary tumor type, BRAF and NRAS mutation status, and other covariates were abstracted from chart review. Log-rank tests and multivariable Cox regression models were used to assess differences in clinical progression-free (cPFS) and overall survival (OS).ResultsWe identified 230 patients who received 249 lines of anti-PD1±anti-CTLA4 ICI for unresectable or metastatic disease. Of these patients, 74% were cutaneous, 11% mucosal, 8% unknown primary and 7% acral. BRAF and NRAS mutations were identified in 35% and 28% of patients, respectively. In multivariable analyses of the entire cohort, acral or mucosal primary tumor type, >3 metastatic sites, elevated LDH were predictive of shorter cPFS and OS. Combination ICI therapy was associated with longer cPFS (HR 0.57, 95% CI 0.38 to 0.86, p=0.007) and OS (HR 0.42, 95% CI 0.28 to 0.65, p<0.001). Combination ICI was significantly associated with longer OS in unknown primary and mucosal melanoma. There was a non-significant trend toward longer OS with anti-PD1+anti-CTLA4 in cutaneous melanoma, but not in acral melanoma. In multivariable analyses, combination ICI was associated with longer OS in NRAS (HR 0.24, 95% CI 0.10 to 0.62, p=0.003, n=69) and BRAF V600E/K (HR 0.47, 95% CI 0.24 to 0.90, p=0.024, n=86) mutant melanoma but not BRAF/NRAS wild-type (n=94) melanoma.ConclusionsIn our cohort, primary melanoma tumor type and genomic subtype were independent predictive markers of cPFS and OS for patients with metastatic melanoma receiving anti-PD1 ICI. Primary tumor type and genomic subtype—including NRAS—should be further evaluated in prospective clinical trials to determine their value as predictive markers. Biologic subtypes may facilitate clinical decision-making when recommending combination ICI treatment (anti-PD1±anti-CTLA4) versus anti-PD1 alone for patients with metastatic melanoma.

scholarly journals Risk factors for pneumonitis in advanced extrapulmonary cancer patients treated with immune checkpoint inhibitors

2021 ◽  
Author(s):  
Yasuki Uchida ◽  
Daisuke Kinose ◽  
Yukihiro Nagatani ◽  
Sachiko Tanaka-Mizuno ◽  
Hiroaki Nakagawa ◽  
...  
Keyword(s):  
Risk Factors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Lung Metastases ◽  
Smoking Status ◽  
Medical Science ◽  
Significant Risk ◽  
Primary Tumors ◽  
Smoking Index

Abstract Background Immune-mediated pneumonitis has a high mortality rate; however, little is known about the related risk factors. We analyzed the risk factors for pneumonitis, such as smoking and lung metastasis (LM), among extrapulmonary primary tumors. Methods We retrospectively collected data of 110 patients treated with immune checkpoint inhibitors (ICIs) (nivolumab/pembrolizumab) for extrapulmonary primary tumors at the Shiga University of Medical Science Hospital, between January 2015 and December 2019. The frequency of pneumonitis was evaluated based on the time between the start of ICI treatment and the onset of symptomatic or all pneumonitis. The severity of pneumonitis was graded according to the Common Terminology Criteria for Adverse Events, version 5.0. We analyzed the risk factors, such as the absence or presence of interstitial lung disease (ILD) and lung metastases (LMs), or other clinical factors, including smoking status before ICI administration. Results The Cox proportional hazards regression analysis revealed that the smoking index and presence of ILD were significant factors for an increased rate of all pneumonitis (hazard ratio [HR] = 20.3, 95% confidence interval [CI] = 20.0–20.4; p = 0.02 and HR = 4.3, 95% CI = 1.2–12.1; p = 0.03, respectively). LM was significantly related to an increased rate of symptomatic pneumonitis (HR = 6.8, 95% CI = 1.3–124.2; p = 0.02). Conclusions Smoking index and ILD were the significant risk factors for ICI-induced pneumonitis. LM was a significant risk factor for ICI-induced symptomatic pneumonitis. Therefore, pre-screening for ILD and LM and the recognition of patients’ smoking histories are important for determining the risk of ICI-induced pneumonitis and allowing safe ICI administration.

scholarly journals LMD-10. The role of immune checkpoint inhibitors in leptomeningeal disease: a systematic review

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii9-iii9
Author(s):  
Paolo Palmisciano ◽  
Ali S Haider ◽  
Chibueze D Nwagwu ◽  
Waseem Wahood ◽  
Navraj S Sagoo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Median Overall Survival ◽  
Checkpoint Inhibitors ◽  
Leptomeningeal Disease ◽  
Mri Findings ◽  
Primary Tumors ◽  
Advanced Malignancy

Abstract Background Leptomeningeal disease (LMD) is a devastating complication of advanced malignancy with a poor prognosis and limited therapeutic options. Whether immune checkpoint inhibitors (ICIs) alter disease course is unknown. Methods We searched PubMed, EMBASE, Scopus, Cochrane, and clinicaltrials.gov according to PRISMA guidelines to analyze the therapeutic role and toxicity profiles of ICIs in the management of LMD. Studies reporting clinical outcome data of patients with LMD treated with ICIs were included. A comprehensive review of clinical characteristics and survival analysis was conducted. Results We included 14 studies encompassing 61 patients. The median age at LMD diagnosis was 57 years (female=63.9%). Lung cancer (44.3%), breast cancer (27.9%), and melanoma (23.0%) were the most frequent primary tumors. Parenchymal brain metastases occurred in 37 patients, mostly treated with radiotherapy (83.3%). LMD most frequently presented with headache (42.1%) and was diagnosed by MRI findings (leptomeningeal T1-contrast enhancement: 96.7%) and/or positive cerebrospinal fluid cytology (86.5%). Patients received ICIs for a median duration of 7 months (range, 0.5–58.0): pembrolizumab (49.2%), nivolumab (32.8%), and/or ipilimumab (18.0%). The most common concurrent LMD treatments were radiotherapy (54.7%) and steroids (35.7%). Radiological responses at 6-months were complete (33.3%) and partial response (12.5%), stable disease (33.3%), and progression (20.8%). 22 patients developed ICI-related adverse events, mostly mild (100%) and uncommonly severe (15.6%). Median progression-free survival was 5.1 months, median overall survival was 6.3 months, and 12-month survival was 32.1%. Survival was correlated with ICIs (P=0.042), but not with primary tumors (P=0.144). Patients concurrently receiving steroids showed worse survival (P=0.040), with a median overall survival of 1.9 months. Conclusion ICI therapy shows promise and appears to be well-tolerated in patients with LMD. Concurrent use of steroids is associated with worse survival. The role of ICIs in the multimodal management of LMD and their combination with steroids requires further analysis.

scholarly journals Immune-related adverse events: a retrospective look into the future of oncology in the intensive care unit

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Adrien Joseph ◽  
Audrey Simonaggio ◽  
Annabelle Stoclin ◽  
Antoine Vieillard-Baron ◽  
Guillaume Geri ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Adverse Events ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Primary Tumors ◽  
Icu Admission ◽  
Paris Area

Abstract Background Immune checkpoint inhibitors have reshaped the standard of care in oncology. However, they have been associated with potentially life-threatening immune-related adverse events. With the growing indications of immune checkpoint inhibitors and their position as a pillar of cancer treatment, intensive care physicians will be increasingly confronted with their side effects. The outcome of patients with severe immune-related adverse events in the intensive care unit remains unknown. This retrospective multicentric study aims to describe the characteristics of patients admitted to the intensive care units of 4 academic hospitals in Paris area while receiving immune checkpoint inhibitor treatment between January 2013 and October 2019. Results Over the study period, 112 cancer patients who received immune checkpoint inhibitors were admitted to the intensive care unit within 60 days after the last dose. ICU admission was related to immune-related adverse events (n = 29, 26%), other intercurrent events (n = 39, 35%), or complications related to tumor progression (n = 44, 39%). Immune-related adverse events were pneumonitis (n = 8), colitis (n = 4), myocarditis (n = 3), metabolic disorders related to diabetes (n = 3), hypophysitis (n = 2), nephritis (n = 2), meningitis or encephalitis (n = 2), hepatitis (n = 2), anaphylaxis (n = 2) and pericarditis (n = 1). Primary tumors were mostly melanomas (n = 14, 48%), non-small-cell lung cancers (n = 7, 24%), and urothelial carcinomas (n = 5, 17%). Diagnosis of melanoma and a neutrophil/lymphocyte ratio < 10 were associated with immune-related diagnosis versus other reasons for ICU admission. During their ICU stay, immune-related adverse events patients needed vasopressors (n = 7), mechanical ventilation (n = 6), and extra-corporeal membrane oxygenation (n = 2). One-year survival was significantly higher for patients admitted for irAE compared to patients admitted for other reasons (p = 0.004). Conclusions Admission to the intensive care unit related to immune-related adverse event was associated with better outcome in cancer patients treated with immune checkpoint inhibitors. Our results support the admission for an intensive care unit trial for patients with suspected immune-related adverse events.

scholarly journals Potential protective and therapeutic role of immune checkpoint inhibitors against viral infections and COVID-19

Immunotherapy ◽  
2020 ◽  
Vol 12 (15) ◽  
pp. 1111-1114 ◽  
Author(s):  
Lidia Gatto ◽  
Enrico Franceschi ◽  
Vincenzo Di Nunno ◽  
Alba Ariela Brandes
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Viral Infections ◽  
Checkpoint Inhibitors ◽  
Therapeutic Role
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