Genetic ancestry and clinical outcomes to immune checkpoint inhibitors among seven common cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10536-10536
Author(s):  
Amin Nassar ◽  
Elio Adib ◽  
Sarah Abou Alaiwi ◽  
Elie Akl ◽  
Talal El Zarif ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
East Asian ◽  
Genetic Ancestry ◽  
Sequencing Data ◽  
Histologic Subtype ◽  
Cancer Types

10536 Background: Prior studies and clinical trials report associations between self-reported race and clinical outcomes to Immune Checkpoint Inhibitors (ICIs). However, comprehensive studies of ancestry-associated differences in clinical outcomes have not been performed. We derived genetic ancestry scores and assessed clinical outcomes in 1341 patients with cancer treated with ICIs. Methods: Patients at the Dana-Farber Cancer Institute treated with ICIs only and with relevant cancer types and targeted exome sequencing data (Oncopanel) were included. Relevant cancer types included colorectal adenocarcinoma (CRC), esophagogastric adenocarcinoma (EGC), head and neck squamous cell carcinoma (HNSCC), melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma (UC). We developed a bioinformatics pipeline to infer fine-scale genetic ancestry for each patient (n=1341) directly from tumor sequencing data by leveraging off and on-target sequenced reads and external ancestry reference panels. Three ancestry scores were determined (African, East Asian, European). Overall survival (OS) and time-to-treatment failure (TTF) were compared by Cox logistic regression between ancestral populations. Hazard ratio (HR) was derived using multivariable analysis, adjusted for single versus combination therapy, prior lines of therapy, and tumor mutational burden (TMB, as percentiles). Results: Median follow-up was 37.8 months (m; interquartile range: 35.7-39.5m). Common cancer types included CRC (n=52), EGC (n=114), HNSCC (n=88), melanoma (n=274), NSCLC (n=571), RCC (n=99), and UC (n=143). A higher East Asian ancestry (EAS) was significantly associated with worse OS ( p=0.03) and TTF ( p=0.002) in patients with RCC, independent of the histologic subtype (Table). There was no significant association between any of the three ancestral populations and clinical outcomes in the other 6 cancer types. Conclusions: We described clinical outcomes to ICIs across three global populations in 7 cancers. As the medical field re-evaluates the use of self-reported race in clinical decision-making, we utilize a novel ancestry pipeline that can be readily applied to tumor-only sequencing panels and better characterize non-white populations. We find no ancestry differences in clinical outcomes except in patients with RCC treated with ICIs which will require future validation. We plan to analyze genomic correlates of response by ancestry in each of the cancer types to better understand these diverge clinical behaviors.[Table: see text]

scholarly journals Exploration of Feasible Immune Biomarkers for Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma Treatment in Real World Clinical Practice

2020 ◽  
Vol 21 (20) ◽  
pp. 7621
Author(s):  
Hui-Ching Wang ◽  
Tsung-Jang Yeh ◽  
Leong-Perng Chan ◽  
Chin-Mu Hsu ◽  
Shih-Feng Cho
Keyword(s):  
Squamous Cell Carcinoma ◽  
Clinical Practice ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Clinical Outcomes ◽  
Squamous Cell ◽  
Real World ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

Recurrent locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC) is associated with dismal prognosis because of its highly invasive behavior and resistance to conventional intensive chemotherapy. The combination of targeted therapy and conventional chemotherapy has significantly improved clinical outcomes. In recent years, the development of immunotherapies, such as immune checkpoint inhibitors (ICIs), has further increased treatment responses and prolonged survival. However, the limited response rate, risk of immunotherapy-related adverse effects and high cost of immunotherapy make the identification of predictive markers to optimize treatment efficacy a critical issue. Biomarkers are biological molecules that have been widely utilized to predict treatment response to certain treatments and clinical outcomes or to detect disease. An ideal biomarker should exhibit good predictive ability, which can guide healthcare professionals to achieve optimal treatment goals and bring clinical benefit to patients. In this review, we summarized the results of recent and important studies focused on HNSCC ICI immunotherapy and discussed potential biomarkers including their strengths and limitations, aiming to gain more insight into HNSCC immunotherapy in real world clinical practice.

scholarly journals SAT-411 Vitamin D Levels and Risk of Thyroid Immune Related Adverse Events in Patients on Immune Checkpoint Inhibitors

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Samantha Kass Newman ◽  
Amanda C Leiter ◽  
Emily Carroll ◽  
Brooks C Danielle ◽  
Jennifer Ben Shimol ◽  
...  
Keyword(s):  
Vitamin D ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Thyroid Disease ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cancer Type ◽  
Increased Risk ◽  
Cancer Types

Abstract Immune checkpoint inhibitors (ICI), such as monoclonal antibodies to cytotoxic T lymphocyte associated protein 4 (CTLA-4), programmed cell death 1 (PD-1) and PD ligand 1 (PD-L1) are recognized as effective cancer-directed therapies. Yet, ICI-induced activation of the immune system results in immune-related adverse events (irAEs) affecting many organs, including the thyroid. Separately, Vitamin D (Vit D) deficiency has been associated with increased risk of autoimmune thyroid disease. We hypothesized that patients who were Vit D deficient at the time of initiating ICI therapy would be more likely to develop thyroid irAEs. We retrospectively collected data for 411 patients who received ICIs at our institution between January 2011 and April 2017. We then identified 91 of these patients who had 25-OH Vit D levels obtained; 2 were excluded from analysis due to previous thyroidectomy. We recorded demographics, cancer type, Vit D level closest to the start date of ICI therapy, and thyroid irAEs. Patients were categorized as Vit D deficient (<20ng/mL), insufficient (20-29.9ng/mL) or sufficient (≥30ng/mL). We compared patient demographic and clinical characteristics between the VitD categories. Proportions were compared using Fisher’s Exact Test. Of the 89 patients, 48.3% were female and 51.7% were male. Mean age was 67.2 (SD±10.6) years with 57% white, 8% black, 10% hispanic, 7% Asian, and 18% other / unknown. 20% of patients had non-small cell lung cancer, 15% melanoma, 13% hepatocellular carcinoma, 12% multiple myeloma (MM), 8% renal cell carcinoma (RCC), 7% head and neck squamous cell carcinoma, 7% urothelial carcinoma and 18% other cancer types. 21.3% were Vit D deficient, 40.4% were insufficient, and 38.2% were sufficient. Patients with Vit D deficiency and insufficiency were younger (age 64.1± 11.7, 65.9±9.5 years, respectively) than the Vit D sufficiency group (70.1±10.5years, p=0.046). No significant differences between males and females were observed between Vit D categories. Across cancer types, the highest prevalence of Vit D deficiency was in RCC (42.9%) and MM (36.4%). Hispanic and Asian patients had the highest prevalence of Vit D deficiency (44.4% and 33.3%, respectively). 11 patients (12.4%) developed a thyroid irAE. Thyroid irAEs occurred in 5.3% with Vit D deficiency, 8.1% with Vit D insufficiency, and 20% with Vit D sufficiency, but the association was not statistically significant (p=0.2). In contrast to our hypothesis, Vit D deficiency was not associated with a higher rate of thyroid irAEs. In fact our data suggest that patients who are vitamin D sufficient at the time of starting ICI therapy may be at greater risk of developing thyroid irAEs. Our study is limited by small numbers and the retrospective nature of the study. Prospective studies should be performed to determine the significance of Vit D levels on ICI related thyroid disease.

Immune Checkpoint Inhibitors: Basics and Challenges

2019 ◽  
Vol 26 (17) ◽  
pp. 3009-3025 ◽  
Author(s):  
Bin Li ◽  
Ho Lam Chan ◽  
Pingping Chen
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Complete Response ◽  
Modern World ◽  
Basic Principles ◽  
Mutation Status ◽  
Anti Cancer ◽  
Cancer Types ◽  
Shed Light

Cancer is one of the most deadly diseases in the modern world. The last decade has witnessed dramatic advances in cancer treatment through immunotherapy. One extremely promising means to achieve anti-cancer immunity is to block the immune checkpoint pathways – mechanisms adopted by cancer cells to disguise themselves as regular components of the human body. Many review articles have described a variety of agents that are currently under extensive clinical evaluation. However, while checkpoint blockade is universally effective against a broad spectrum of cancer types and is mostly unrestricted by the mutation status of certain genes, only a minority of patients achieve a complete response. In this review, we summarize the basic principles of immune checkpoint inhibitors in both antibody and smallmolecule forms and also discuss potential mechanisms of resistance, which may shed light on further investigation to achieve higher clinical efficacy for these inhibitors.

scholarly journals Neoadjuvant immunotherapy in resectable head and neck cancer: oral cavity carcinoma as a potential research model

2021 ◽  
Vol 13 ◽  
pp. 175883592098406
Author(s):  
Vanesa Gutiérrez Calderón ◽  
Alexandra Cantero González ◽  
Laura Gálvez Carvajal ◽  
Yolanda Aguilar Lizarralde ◽  
Antonio Rueda Domínguez
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Cavity ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Surgical Resection ◽  
Squamous Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Research Model

Squamous cell carcinoma of oral cavity (OCSCC) accounts for approximately 25% of cases of head and neck squamous cell carcinoma (HNSCC). Tobacco and alcohol consumption are the main risk factors for both cancers. Surgical resection, combined with adjuvant radiotherapy or radiochemotherapy in patients with high risk of relapse, is the key element in management in the initial stages. However, despite the availability of aggressive multidisciplinary treatments, advanced resectable OCSCC carries poor prognosis; only half of the patients are disease-free 5 years after the surgery. Immunotherapy based on the use of immune checkpoint inhibitors has been proven to be effective in a wide variety of tumours, including recurrent and metastatic HNSCC. These positive results resulted in investigations into its effectiveness in earlier stages of the disease with OCSCC emerging as an interesting research model because of the accessible location of the tumours. This article reviews the potential advantages of emerging immunotherapeutic agents [mainly monoclonal antibodies against programmed cell death-1 ( PD-1) immune checkpoint inhibitors] as neoadjuvant treatment for OCSCC at locoregional stages as well as the ongoing clinical trials, challenges in evaluating tumour response, and possible predictive biomarkers of response with highlights regarding the role of oral microbiota as modulators of immune response. The efficacy and safety of anti- PD-1 drugs in these patients have been proven in preliminary trials. If there is a decrease in the relapse rate and an improvement in the overall survival after surgical resection in ongoing trials, preoperative immunotherapy may be established as a treatment option for patients with early stages of the disease.

scholarly journals Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Revati Sharma ◽  
Elif Kadife ◽  
Mark Myers ◽  
George Kannourakis ◽  
Prashanth Prithviraj ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanisms ◽  
Number Of Patients ◽  
Angiogenesis Pathway

AbstractVascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) have been the mainstay of treatment for patients with advanced renal cell carcinoma (RCC). Despite its early promising results in decreasing or delaying the progression of RCC in patients, VEGF-TKIs have provided modest benefits in terms of disease-free progression, as 70% of the patients who initially respond to the treatment later develop drug resistance, with 30% of the patients innately resistant to VEGF-TKIs. In the past decade, several molecular and genetic mechanisms of VEGF-TKI resistance have been reported. One of the mechanisms of VEGF-TKIs is inhibition of the classical angiogenesis pathway. However, recent studies have shown the restoration of an alternative angiogenesis pathway in modulating resistance. Further, in the last 5 years, immune checkpoint inhibitors (ICIs) have revolutionized RCC treatment. Although some patients exhibit potent responses, a non-negligible number of patients are innately resistant or develop resistance within a few months to ICI therapy. Hence, an understanding of the mechanisms of VEGF-TKI and ICI resistance will help in formulating useful knowledge about developing effective treatment strategies for patients with advanced RCC. In this article, we review recent findings on the emerging understanding of RCC pathology, VEGF-TKI and ICI resistance mechanisms, and potential avenues to overcome these resistance mechanisms through rationally designed combination therapies.

scholarly journals Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 989
Author(s):  
Heidar J. Albandar ◽  
Jacob Fuqua ◽  
Jasim M. Albandar ◽  
Salahuddin Safi ◽  
Samuel A. Merrill ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Survival Outcomes ◽  
Limited Data ◽  
Risk Of Death ◽  
Survival Difference ◽  
Histopathologic Diagnosis ◽  
Cancer Types

Introduction: There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge. Methods: We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011–2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy. Results: Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former. Conclusions: Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.

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