scholarly journals Mutations Status of Chemokine Signaling Pathway Predict Prognosis of Immune Checkpoint Inhibitors in Colon Adenocarcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Anqi Lin ◽  
Wentao Xu ◽  
Peng Luo ◽  
Jian Zhang
Keyword(s):  
Signaling Pathway ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Colon Adenocarcinoma ◽  
Cox Regression Analysis ◽  
Chemokine Signaling ◽  
Number Of Patients ◽  
Chemokine Signaling Pathway ◽  
The Relationship

In recent years, tumor immunotherapy has become an important treatment program and popular research focus. However, the use of immune checkpoint inhibitors (ICI) in the treatment of colorectal cancer still has limitations due to the current markers only being able to predict the prognosis of a small number of patients. As the chemokine signaling pathway can promote the anti-tumor response of the immune system by recruiting immune cells, we explored the relationship between mutations in the chemokine signaling pathway and the prognosis of colon adenocarcinoma (COAD) patients receiving ICI treatment. To analyze the relationship between chemokine mutation status and the prognosis of patients receiving ICI treatment, clinical and mutation data, with immunotherapy, for a COAD cohort was obtained from “cbioportal.” Then, combining this with COAD cohort data from The Cancer Genome Atlas (TCGA) database, the panorama of gene mutation, immunogenicity, and difference in tumor microenvironment (TME) of chemokine pathways with different mutation statuses were analyzed. High-mut status has been proved to be a prognostic indicator of COAD patients receiving ICI treatment by Univariate and Multivariate Cox regression analysis. CIBERSORT analysis showed that the infiltration degree of M1 macrophages, neutrophils, and activated natural killer (NK) cells was higher in those with high-mut status. Immunogenicity of the high-mut group was also significantly increased, with the mutation number of tumor mutation burden (TMB), neoantigen load (NAL), DNA damage repair (DDR) pathway and microsatellite instability biomarker (MSI-H) being significantly higher. In this study, we found that the mutation state of chemokine pathways is closely associated with the prognosis of COAD patients undergoing ICI treatment. The higher number of TMB, NAL, and DDR mutations and inflammatory TME, may be the mechanism of behind a better prognosis. This discovery provides a possible idea for ICI therapy of COAD.

scholarly journals 363 Vactosertib and durvalumab as second or later line treatment for PD-L1 positive non-small cell lung cancer: interim result

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A388-A388
Author(s):  
Byoung Chul Cho ◽  
Ki Hyeong Lee ◽  
Ji-Youn Han ◽  
Byoung Yong Shim ◽  
Hye Ryun Kim ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Objective Response Rate ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Anti Tumor Activity

BackgroundTargeting transforming growth factor-β (TGF-β) is reported to augment the efficacy of immune checkpoint inhibitors (ICIs) through either enhanced anti-tumor immunity or the correction of tumor microenvironment (TME). Therefore, the combination of vactosertib, a highly selective TGF-β RI kinase inhibitor, and durvalumab is anticipated to improve anti-tumor activity of the ICI. A phase 1b/2a study was conducted to evaluate the combination of vactosertib and durvalumab in patients with advanced NSCLC who progressed after platinum-based chemotherapy.MethodsPatients were treated with vactosertib at a dose of 200 mg twice daily (five days on and two days off) and durvalumab at a dose of 1500 mg every four weeks. Eligible patients were ≥19 years old with good performance status (ECOG 0–1) and have no prior exposure to immune checkpoint inhibitors or other TGF- β R1 kinase inhibitors. The objectives of this analysis were to evaluate the safety, antitumor activity including objective response rate (ORR), duration of response (DOR), and time to response (TTR) as well as circulating pharmacodynamic biomarkers related to TGF-β signaling. Response was assessed per RECIST (v1.1).ResultsBy August 4 2020, twenty-six PD-L1 positive (SP263 assay) patients were analyzed. Median age was 61.5 years (range 48–83), 69.2% were male, median number of previous lines of chemotherapy was 1 (range 1–4), and all patients were PD-L1 positive (15 patients with PD-L1≥25% and 11 patients with PD-L1 1–24%). The most frequently reported treatment-related adverse events (TRAE) were itching (38.5%) and skin rash (34.6%), but no Gr≥3 itching and rash were observed. Each case of the following was reported as Grade 3 TRAEs: adrenal insufficiency, anemia, and pneumonitis; Grade 4 TRAE, CPK increase, was observed in one patient. Objective response rate was 30.8% and 40.0% in patients with PD-L1≥1% and ≥25% respectively. Circulating PAI-1 and CTGF evaluated in 15 patients decreased significantly on Cycle 1 day 5. Ongoing biomarker results will be presented.ConclusionsThe combination of vactosertib and durvalumab has demonstrated a manageable safety profile and encouraging anti-tumor activity as a potential therapeutic strategy in patients with advanced NSCLC. The efficacy outcomes of this combination in a larger number of patients with advanced NSCLC will be followed.Trial RegistrationNCT03732274Ethics ApprovalThe study was approved by Ethics Board of Severance Hospital (4-2018-0892), National Cancer Center (NCC2019-0057), St. Vincent’s Hospital (VC19MDDF0205), and Chungbuk National University Hospital (2019-08-015).

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 Lessons From the Development of the Immune Checkpoint Inhibitors in Oncology

2018 ◽  
Vol 17 (4) ◽  
pp. 1012-1015 ◽  
Author(s):  
Denis L. Jardim ◽  
Débora de Melo Gagliato ◽  
Razelle Kurzrock
Keyword(s):  
Phase I ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Dose Finding ◽  
Priority Review ◽  
Marketing Approval ◽  
Phase I Trials ◽  
Clinical Cancer Research ◽  
Number Of Patients

Immunotherapies are becoming increasingly important in the treatment armamentarium of a variety of malignancies. Immune checkpoint inhibitors are the most representative drugs receiving regulatory approval over the past few years. In a recent study published in Clinical Cancer Research, we demonstrated that these agents are being developed faster than other prior anticancer therapies. All checkpoint inhibitors received priority review, being granted with at least one Food and Drug Administration expedited program. Hence, some of them are getting marketing approval after preliminary trials. The model continues to rely on phase I trials, designed with traditional models for dose definition, although a substantial number of patients are treated during the dose expansion cohorts. We demonstrated that efficacy and safety are reasonably predicted from the dose-finding portion of phase I trials with these agents, assuring a low treatment-related mortality for patients throughout the development process. In this article, we further discuss and summarize these findings and update some recent approval information for immune checkpoint inhibitors.

Gut Microbiota and Immune Checkpoint Inhibitors-Based Immunotherapy

2021 ◽  
Vol 21 ◽  
Author(s):  
Mingming Tian ◽  
Si Zhang ◽  
Yujen Tseng ◽  
Xizhong Shen ◽  
Ling Dong ◽  
...  
Keyword(s):  
Immune System ◽  
Gut Microbiota ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Recent Progress ◽  
Checkpoint Inhibitors ◽  
Antitumor Response ◽  
Number Of Patients ◽  
Cancer Types ◽  
Patients Experience

: Application of immune checkpoint inhibitors (ICIs) is a major breakthrough in the field of cancer therapy, which has displayed tremendous potential in various types of malignancies. However, their response rates range widely in different cancer types and a significant number of patients experience immune-related adverse effects (irAEs) induced by these drugs, limiting the proportion of patients who can truly benefit from ICIs. Gut microbiota has gained increasing attention due to its emerging role in regulating the immune system. In recent years, numerous studies have shown that gut microbiota can modulate antitumor response, as well as decrease the risk of colitis due to ICIs in patients receiving immunotherapy. The present review analyzed recent progress of relevant basic and clinical studies in this area and explored new perspectives to enhance the efficacy of ICIs and alleviate associated irAEs via manipulation of the gut microbiota.

Effect of antibiotic use prior to or concurrent with immune checkpoint inhibitors on outcomes in patients with Hodgkin lymphoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8030-8030
Author(s):  
Steven R Hwang ◽  
Alexandra Higgins ◽  
Betsy LaPlant ◽  
Matthew J. Maurer ◽  
Stephen M. Ansell ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cox Regression ◽  
Checkpoint Inhibitors ◽  
Retrospective Chart Review ◽  
Progression Free Survival ◽  
Antibiotic Use ◽  
Patient Specific ◽  
Cox Regression Analysis

8030 Background: There is growing interest in the identification of modifiable patient-specific factors that may predict response to immune checkpoint inhibitors (ICIs) in classical Hodgkin lymphoma (cHL). Recently, it has been proposed that antibiotic use could decrease the efficacy of ICIs in the treatment of advanced solid malignancies. The objective of our study is to assess whether antibiotic use prior to or concurrent with ICIs is associated with changes in outcomes in patients with cHL. Methods: Patients who received a PD-1 or CTLA-4 blocker for the treatment of cHL at Mayo Clinic Rochester between January 1, 2011 and October 20, 2018 were identified. We conducted a longitudinal retrospective chart review to identify those who received antibiotics within 30 or 90 days prior to initiation or concurrent with ICI therapy. Univariate cox regression analysis was used to assess for an association between antibiotic use and overall survival (OS) and progression-free survival (PFS) within these groups; a time-dependent variable was used for concurrent antibiotic use. Results: A total of sixty-two patients were identified (61% male, median age at ICI initiation 35 years [range: 19-87]). Median duration of follow up from ICI start was 38 months (range: 4-78). Twenty-one patients (34%) received antibiotics within 90 days of initiation of ICI, of which thirteen (21%) received antibiotics within 30 days. Thirty-five patients (57%) received antibiotics concurrently with ICI. Concurrent and prior antibiotic use within 90 days of ICI were both associated with inferior PFS (concurrent HR = 6.38 [95% CI 3.02-13.47]; 90-day HR = 2.21 [95% CI 1.10-4.47]) and OS (concurrent HR = 8.77 [95% CI 1.91-40.36]; 90-day HR = 2.96 [95% CI 1.09-8.04]). Conclusions: Antibiotic use is associated with inferior outcomes in patients with cHL treated with ICIs in this single institution cohort. This may reflect potential antibiotic effects on the gut microbiome (GMB) and immune system as has been suggested in prior studies. Further confirmatory studies and examination of potential confounding covariates are needed.

scholarly journals Combinatorial immunotherapies overcome MYC-driven immune evasion

2021 ◽  
Author(s):  
Joyce V. Lee ◽  
Filomena Houseley ◽  
Christina Yau ◽  
Daniel Van de Mark ◽  
Rachel Nakagawa ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Immune Evasion ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Mhc I ◽  
Number Of Patients ◽  
Tumor Outgrowth

For many human cancers, including triple negative breast cancer (TNBC), a modest number of patients benefit from immune checkpoint inhibitors, and few experience cancer remission. Expression of programed death-ligand 1 (PD-L1), tumor immune infiltration, or tumor mutation burden have been widely investigated for predicting cancer immunotherapy response. Whether specific oncogenes diminish response to immunotherapy and whether these effects are reversible remains poorly understood. We predicted that MYC, an oncogene that is frequently overexpressed and is associated with worse prognosis, may predict immunotherapy response in patients with TNBC. Here, we report that MYC-elevated TNBCs are resistant to immune checkpoint inhibitors. Using mouse models of TNBC and patient data we report that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor reduces MYC expression and increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, most mice experience complete tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and if strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.

scholarly journals The Emerging Role of the Gut Microbiome in the Cancer Response to Immune Checkpoint Inhibitors: A Narrative Review

2021 ◽  
Author(s):  
Ghada Araji ◽  
Julian Maamari ◽  
Fatima Ali Ahmad ◽  
Rana Zareef ◽  
Patrick Chaftari ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Therapeutic Interventions ◽  
The Impact ◽  
The Relationship ◽  
Gut Microbiota Composition

ABSTRACT The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the care of cancer patients. However, the response to ICI therapy exhibits substantial interindividual variability. Efforts have been directed to identify biomarkers that predict the clinical response to ICIs. In recent years, the gut microbiome has emerged as a critical player that influences the efficacy of immunotherapy. An increasing number of studies have suggested that the baseline composition of a patient's gut microbiota and its dysbiosis are correlated with the outcome of cancer immunotherapy. This review tackles the rapidly growing body of evidence evaluating the relationship between the gut microbiome and the response to ICI therapy. Additionally, this review highlights the impact of antibiotic-induced dysbiosis on ICI efficacy and discusses the possible therapeutic interventions to optimize the gut microbiota composition to augment immunotherapy efficacy.

Effect of influenza vaccination on immune-related adverse events in patients receiving single-agent immune checkpoint inhibitors for the treatment of cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18763-e18763
Author(s):  
Naga Malleswari Vutukuri ◽  
Calette Corcoran ◽  
Jill Comeau ◽  
Elizabeth Stephenson ◽  
Kavitha Beedupalli ◽  
...  
Keyword(s):  
Adverse Events ◽  
Influenza Vaccine ◽  
Influenza Vaccination ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Secondary Outcome ◽  
Number Of Patients ◽  
Influenza Vaccinations

e18763 Background: Recent single-center, retrospective reviews have evaluated the effect of influenza vaccinations on the incidence and severity of immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICI). Methods and outcomes in these studies vary. The most common medication investigated was ipilimumab, an Anti-CTLA-4 monoclonal antibody. There is limited data evaluating the incidence of irAEs in those receiving the specific ICIs, program death-1 (PD-1) and program death ligand-1 (PD-L1) inhibitors. Methods: A retrospective chart review was conducted including patients 18 to 89 years old who received single-agent pembrolizumab, nivolumab, atezolizumab, or durvalumab at an academic medical center from August 2015 to August 2019. The primary objective was to evaluate the incidence of irAEs in those who received an influenza vaccine compared to those who did not. Electronic health records, and the Louisiana Immunization Network for Kids (LINKS), which now collects adult information, were utilized for data collection. Chi-square tests were used to evaluate all endpoints. Results: Of the 217 charts screened, 133 were included in this study Fifty-three patients were included in the influenza vaccination group and 80 patients in the group that did not receive influenza vaccinations. The median age in those who received an influenza vaccine and in those who did not were 61 years and 62 years, respectively. The most common cancer diagnoses were lung cancer and melanoma. Ninety-one percent of patients in the vaccination group versus 81% in the group who did not receive an influenza vaccine received either nivolumab or pembrolizumab (PD-1 inhibitors). There was no statistical difference in irAEs in those who received an influenza vaccine versus those who did not (30% versus 45%, p = 0.15). The only significant secondary outcome found was the rate of irAEs in patients receiving a PD-1 inhibitor versus a PD-L1 inhibitor regardless of vaccination (42.2% versus 11.1%, p = 0.03). The majority of irAEs were grade 1 or 2. Conclusions: Based on this study, receiving an influenza vaccine does not have an influence on the risk of irAEs in those receiving ICI, specifically PD-1 and PD-L1 inhibitors. These outcomes may have been affected by adherence issues with yearly influenza vaccinations, inaccurate vaccine records, and receiving vaccines out of state. The statistically significant secondary outcome may have been affected by the disproportionate number of patients who were receiving a PD-1 inhibitor in this study. Larger population studies are needed to validate these findings and identify both the risk and benefit of patients receiving their yearly influenza vaccine while receiving ICI.

Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance

2020 ◽  
Vol 16 (1) ◽  
Author(s):  
Sreya Bagchi ◽  
Robert Yuan ◽  
Edgar G. Engleman
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Annual Review ◽  
Publication Date ◽  
Number Of Patients ◽  
Cancer Types ◽  
Cell Changes

Immune checkpoint inhibitors (ICIs) have made an indelible mark in the field of cancer immunotherapy. Starting with the approval of anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) for advanced-stage melanoma in 2011, ICIs—which now also include antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1)—quickly gained US Food and Drug Administration approval for the treatment of a wide array of cancer types, demonstrating unprecedented extension of patient survival. However, despite the success of ICIs, resistance to these agents restricts the number of patients able to achieve durable responses, and immune-related adverse events complicate treatment. Thus, a better understanding of the requirements for an effective and safe antitumor immune response following ICI therapy is needed. Studies of both tumoral and systemic changes in the immune system following ICI therapy have yielded insight into the basis for both efficacy and resistance. Ultimately, by building on these insights, researchers should be able to combine ICIs with other agents, or design new immunotherapies, to achieve broader and more durable efficacy as well as greater safety. Here, we review the history and clinical utility of ICIs, the mechanisms of resistance to therapy, and local and systemic immune cell changes associated with outcome. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 16 is January 25, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals An Evaluation of the Use of Corticosteroids for the Management of Immune-Mediated Adverse Events in Cancer Patients Treated With Immune Checkpoint Inhibitors

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Adrian Tsui, PharmD ◽  
Linday Edmondson, PharmD, BCOP ◽  
Justin Julius, PharmD
Keyword(s):  
Adverse Events ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Retrospective Chart Review ◽  
Prescribing Practices ◽  
Immune Mediated ◽  
Number Of Patients ◽  
Secondary Endpoints

Immune checkpoint inhibitors (ICIs) have gained prominence for the treatment of a variety of malignancies. However, they are associated with the development of immune-mediated adverse events (IMAEs). Appropriate management of IMAEs and subsequent rechallenging of patients with ICI therapy remains an important area of research. The primary endpoint of this study was to evaluate the efficacy of current prescribing practices and adherence to guideline recommendations for IMAE management. The incidence of symptom resolution, number of patients reinitiated with ICI therapy, and IMAE recurrence upon ICI therapy reinitiation were explored as secondary endpoints. A retrospective chart review within the Allegheny Health Network was conducted in cancer patients treated with ICI therapy who developed a documented ICI-associated IMAE and subsequently received corticosteroid therapy. IRB approval was obtained for this study. Descriptive statistics were used to analyze both primary and secondary endpoints. The study sample was made up of 81 patients. Overall, 50 out of 81 patient cases (62%) were found to be discordant with guideline recommendations; the primary factors identified were inappropriate starting corticosteroid dosing (64%), initiation of a corticosteroid taper prior to IMAE resolution to at least grade 1 severity, and condensed corticosteroid taper (74%). The main IMAEs identified were colitis (28%), pneumonitis (27%), and skin-related inflammation (12%). 76 out of the 81 patients (94%) achieved IMAE resolution; 41 patients (54%) were rechallenged with ICI therapy, of which 14 patients (34%) developed IMAE recurrence. Future studies may focus on evaluating different immunosuppression strategies to optimize IMAE management.

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