scholarly journals Immune Checkpoint Inhibitor Monotherapy is Associated With Less Cardiac Toxicity Than Combination Therapy

2021 ◽  
Author(s):  
Eugene B. Cone ◽  
Lorine Haeuser ◽  
Stephen Reese ◽  
Maya Marchese ◽  
David-Dan Nguyen ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
World Health ◽  
Reporting Odds Ratio ◽  
Pharmacovigilance Database ◽  
Health Organization

Abstract Background: Treatment options for many cancers include immune checkpoint inhibitor (ICI) monotherapy and combination therapy with impressive clinical benefit across cancers. We sought to define the comparative cardiac risks of ICI combination and monotherapy.Methods: We used VigiBase, the World Health Organization pharmacovigilance database, to identify cardiac ADRs (cADRs), such as carditis, heart failure, arrhythmia, myocardial infarction, and valvular dysfunction, related to ICI therapy. To explore possible relationships, we used the reporting odds ratio (ROR) as a proxy of relative risk. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more ADRs are observed than expected due to chance.Results: We found 2278 cADR for ICI monotherapy and 353 for ICI combination therapy. Combination therapy was associated with significantly higher odds of carditis(ROR 6.9, 95% CI: 5.6–8.3) versus ICI monotherapy (ROR 5.0, 95% CI: 4.6-5.4).Carditis in ICI combination therapy was fatal in 23.4% of reported ADRs, compared to15.8% for ICI monotherapy (P = 0.058).Conclusions: Using validated pharmacovigilance methodology, we found increased odds of carditis for all ICI therapies, with the highest odds for combination therapy.Given the substantial risk of severe ADR and death, clinicians should consider these findings when prescribing checkpoint inhibitors.

First-Line Immunotherapy Combinations in Advanced Renal Cell Carcinoma – A Rapid Review and Meta-Analysis

Kidney Cancer ◽  
2021 ◽  
pp. 1-11
Author(s):  
Jason Shpilsky ◽  
Paul J. Catalano ◽  
David F. McDermott
Keyword(s):  
Renal Cell Carcinoma ◽  
Combination Therapy ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Advanced Renal Cell Carcinoma

Background: Combination or multi-agent therapy including immune checkpoint inhibitors has shifted the landscape of the treatment of advanced/metastatic renal cell carcinoma. There are several approved immune checkpoint inhibitor (ICI) combinations featuring antibodies against programmed cell death protein 1 (PD-1) receptor or its ligand 1 (PD-L1) combined with other immune checkpoint inhibitors, multi-targeted tyrosine kinase inhibitors (TKIs), or other agents active in renal cell carcinoma. Objective: This study aims to compile the evidence of available first-line combination therapies compared to sunitinib monotherapy in advanced renal cell carcinoma. Methods: A systematic literature search was conducted according to the PRISMA statement to identify all randomized Phase III clinical trial data in previously untreated metastatic renal cell carcinoma featuring an immune checkpoint inhibitor combination compared against sunitinib. A two-stage selection process was utilized to determine eligible studies. Of a total of 124 studies and 94 additional abstracts, 6 studies were considered for final analysis. These studies were evaluated for progression free survival (PFS), overall survival (OS), Grade III or higher adverse events (AEs), objective response rate (ORR), and complete response rate (CRR). Results: 6 studies with 5,121 patients met our search criteria. For OS, ICI combination therapy was favored over sunitinib with an estimated combined hazard ratio of 0.74 (0.67–0.81 95% CI). For PFS, ICI combination therapy was favored over sunitinib with an estimated combined hazard ratio of 0.65 (0.52–0.82, 95% CI). The combination of nivolumab and ipilimumab had the longest duration of response and less incidence of grade III or higher adverse events compared to the combination of anti-PD-1/PD-L1 with TKI. The combination of anti-PD-1/PD-L1 with TKI had higher rates of overall response and longer PFS than the combination of nivolumab/ipilimumab. Conclusions: This meta-analysis supports the recommendation of immune checkpoint inhibitor combination therapy over sunitinib monotherapy for previously untreated advanced renal cell carcinoma by virtue of improved PFS and OS. The choice of which ICI combination therapy to use may be guided by patient-specific characteristics including IMDC risk status, adverse effect profile, and need for early response.

scholarly journals Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuyin Fu ◽  
Yujia Peng ◽  
Shengyan Zhao ◽  
Jun Mou ◽  
Lishi Zeng ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Kinase Inhibitor ◽  
Tumor Regression ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Combination Strategy ◽  
M2 Phenotype

Immune checkpoint inhibitors have achieved unprecedented success in cancer immunotherapy. However, the overall response rate to immune checkpoint inhibitor therapy for many cancers is only between 20 and 40%, and even less for colorectal cancer (CRC) patients. Thus, there is an urgent need to develop an efficient immunotherapeutic strategy for CRC. Here, we developed a novel CRC combination therapy consisting of a multiple receptor tyrosine kinase inhibitor (Foretinib) and anti-PD-1 antibody. The combination therapy significantly inhibited tumor growth in mice, led to improved tumor regression without relapse (83% for CT26 tumors and 50% for MC38 tumors) and prolonged overall survival. Mechanistically, Foretinib caused increased levels of PD-L1 via activating the JAK2-STAT1 pathway, which could improve the effectiveness of the immune checkpoint inhibitor. Moreover, the combination therapy remodeled the tumor microenvironment and enhanced anti-tumor immunity by further increasing the infiltration and improving the function of T cells, decreasing the percentage of tumor-associated macrophages (TAMs) and inhibiting their polarization toward the M2 phenotype. Furthermore, the combination therapy inhibited the metastasis of CT26-Luc tumors to the lung in BALB/c mouse by reducing proportions of regulatory T-cells, TAMs and M2 phenotype TAMs in their lungs. This study suggests that a novel combination therapy utilizing both Foretinib and anti-PD-1 antibody could be an effective combination strategy for CRC immunotherapy.

Association of checkpoint inhibitor monotherapy with less cardiac toxicity than combination therapy.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 671-671 ◽  
Author(s):  
Eugene Blanchard Cone ◽  
Stephen Reese ◽  
Maya Marchese ◽  
Junaid Nabi ◽  
Kerry L. Kilbridge ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Adverse Events ◽  
Cardiac Toxicity ◽  
Checkpoint Inhibitors ◽  
Cardiac Risk ◽  
World Health ◽  
Reporting Odds Ratio ◽  
Cardiac Events ◽  
Nccn Guidelines ◽  
Health Organization

671 Background: Immune checkpoint inhibitors (ICIs) demonstrate impressive clinical benefit across a variety of cancers. NCCN guidelines for several cancers including renal cell carcinoma now support ICI monotherapy and combination therapy with ipilimumab. Cardiac toxicity is a rare but catastrophic adverse event associated with ICIs. We sought to define the comparative cardiac risk profile of ICI combination versus monotherapy in a real world setting. Methods: We used VigiBase, the World Health Organization database of case safety reports, which collects data from more than 130 countries to identify drug-associated adverse events. Using Medical Dictionary for Regulatory Activities terminology, we identified cardiac adverse events (AE) related to monotherapy (nivolumab, ipilimumab, pembrolizumab) or combination therapy (ipilimumab/nivolumab). To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more AEs are observed than expected due to chance. Results: We found 7,644, 25,016, and 14,681, and 5,191 AEs for ipilimumab, nivolumab, pembrolizumab, and combination therapy respectively. No signal existed for overall cardiac events, but combination therapy was associated with significantly higher odds of pericarditis or myocarditis (ROR 6.9, 95% CI 5.7—8.3) versus pembrolizumab (5.6, 4.9—6.4), nivolumab (5.1, 4.6-5.7), or ipilimumab monotherapy (1.9, 1.4-2.7). Pericarditis and myocarditis with combination therapy was fatal for 23% of reported AEs, compared to 14%, 14%, and 20% for ipilimumab, nivolumab, and pembrolizumab (p = 0.003) respectively. Conclusions: Using validated pharmacovigilance methodology, we found significantly increased odds of myocarditis and pericarditis for all ICI, with the highest odds for combination therapy. These adverse events were often fatal. Further research is needed to identify patients at high risk for immunotherapy related cardiac toxicity.

scholarly journals Cell-free DNA copy number variations predict efficacy of immune checkpoint inhibitor-based therapy in hepatobiliary cancers

2021 ◽  
Vol 9 (5) ◽  
pp. e001942
Author(s):  
Xu Yang ◽  
Ying Hu ◽  
Keyan Yang ◽  
Dongxu Wang ◽  
Jianzhen Lin ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Clinical Outcome ◽  
Risk Score ◽  
Immune Checkpoint ◽  
Copy Number ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Copy Number Variations ◽  
Risk Scores ◽  
Free Dna

BackgroundThis study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers.MethodsThree cohorts including 187 patients with hepatobiliary cancers were recruited from clinical trials at the Peking Union Medical College Hospital. Forty-three patients received combination therapy of programmed cell death protein 1 (PD-1) inhibitor with lenvatinib (ICI cohort 1), 108 patients received ICI-based therapy (ICI cohort 2) and 36 patients received non-ICI therapy (non-ICI cohort). The plasma cfDNA and blood cell DNA mutation profiles were assessed to identify efficacy biomarkers by a cancer gene-targeted next-generation sequencing panel.ResultsBased on the copy number variations (CNVs) in plasma cfDNA, the CNV risk score model was constructed to predict survival by using the least absolute shrinkage and selection operator Cox regression methods. The results of the two independent ICI-based therapy cohorts showed that patients with lower CNV risk scores had longer overall survival (OS) and progression-free survival (PFS) than those with high CNV risk scores (log-rank p<0.01). In the non-ICI cohort, the CNV risk score was not associated with PFS or OS. Furthermore, the results indicated that 53% of patients with low CNV risk scores achieved durable clinical benefit; in contrast, 88% of patients with high CNV risk scores could not benefit from combination therapy (p<0.05).ConclusionsThe CNVs in plasma cfDNA could predict the clinical outcome of the combination therapy of PD-1 inhibitor with lenvatinib and other ICI-based therapies in hepatobiliary cancers.

The emerging use of immune checkpoint blockade in the adjuvant setting for solid tumors: a review

Immunotherapy ◽  
2019 ◽  
Vol 11 (16) ◽  
pp. 1409-1422 ◽  
Author(s):  
Elissar Moujaess ◽  
Fady Gh Haddad ◽  
Roland Eid ◽  
Hampig Raphael Kourie
Keyword(s):  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Adjuvant Setting ◽  
Lung Cancers ◽  
Metastatic Setting ◽  
Postoperative Setting

The use of immune checkpoint inhibitors has been approved in the advanced and metastatic setting for many types of solid tumors. Nonetheless, their role in the adjuvant setting is limited to the treatment of surgically resected melanoma. Ipilimumab was the first immune checkpoint inhibitor approved for this indication, followed by nivolumab and pembrolizumab. Many ongoing trials are evaluating these molecules in the postoperative setting, alone or in combination with other therapies. Preliminary results are promising regarding the treatment of other cutaneous tumors, lung cancers, head and neck squamous cell carcinomas, bladder cancer and renal cell carcinomas. Some data assessing their use for the adjuvant treatment of esophageal, colorectal, ovarian cancer and other solid tumors are similarly emerging.

scholarly journals Enterococcus peptidoglycan remodeling promotes immune checkpoint inhibitor therapy

2020 ◽  
Author(s):  
Matthew E. Griffin ◽  
Juliel Espinosa ◽  
Jessica L. Becker ◽  
Jyoti K. Jha ◽  
Gary R. Fanger ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Molecular Mechanisms ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Mouse Tumor ◽  
Peptidoglycan Hydrolases ◽  
Checkpoint Inhibitor Therapy ◽  
Specific Species

AbstractThe antitumor efficacy of cancer immunotherapy has been correlated with specific species within the gut microbiota. However, molecular mechanisms by which these microbes affect host response to immunotherapy remain elusive. Here we show that specific members of the bacterial genus Enterococcus can promote anti-PD-L1 immunotherapy in mouse tumor models. The active enterococci express and secrete orthologs of the NlpC/p60 peptidoglycan hydrolase SagA that generate immune-active muropeptides. Expression of SagA in non-protective E. faecalis was sufficient to promote antitumor activity of clinically approved checkpoint targets, and its activity required the peptidoglycan sensor Nod2. Notably, SagA-engineered probiotics or synthetic muropeptides also promoted checkpoint inhibitor antitumor activity. Our data suggest that microbiota species with unique peptidoglycan remodeling activity may enhance immunotherapy and could be leveraged for next-generation adjuvants.One Sentence SummaryA conserved family of secreted NlpC/p60 peptidoglycan hydrolases from Enterococcus promote antitumor activity of immune checkpoint inhibitors.

scholarly journals Application of Immune Checkpoint Inhibitors in the Treatment of Cholangiocarcinoma

2021 ◽  
Vol 20 ◽  
pp. 153303382110399
Author(s):  
Fan-li Zeng ◽  
Jing-fang Chen
Keyword(s):  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Malignant Tumors ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
General Term ◽  
Distal Cholangiocarcinoma ◽  
Poor Outcomes ◽  
Defective Mismatch Repair

Cholangiocarcinoma is a general term for intrahepatic and extrahepatic malignant tumors deriving in the biliary system. According to the location, it is divided into intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma. Progressive cholangiocarcinoma yields poor outcomes with radiotherapy; therefore, there is an urgent need for new therapeutic breakthroughs. Immune checkpoint inhibitor (ICI) therapy brings the treatment for cancer into a new field, with the use of drugs targeting PD-1/PD-L1 and CTLA-4 considerably extending the survival of patients with melanoma, lung cancer, and other solid tumors. The FDA has approved the application of pembrolizumab for solid tumors with high microsatellite instability and defective mismatch repair, including cholangiocarcinoma. Moreover, the combination of ICIs with chemotherapy and radiation therapy showed good promise. The aim of the present study was to review the application of ICIs in the treatment of cholangiocarcinoma and to summarize the reported individualized immunotherapy-based protocols and ongoing clinical trials for clinical reference.

Efficacy of immunotherapy in hepatocholangiocarcinoma (HCC-CC): Proof of concept.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16194-e16194
Author(s):  
Osama Diab ◽  
Maloree Khan ◽  
Saqib Abbasi ◽  
Anwaar Saeed ◽  
Anup Kasi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
Liver Cancers ◽  
First Line Treatment

e16194 Background: Hepatocholangiocarcinoma (HCC-CC) is a rare form of cancer with a poor prognosis. Of all primary liver cancers, the incidence of HCC-CC ranges from 0.4 to 14.2%. HCC-CC is a mixed carcinoma with findings of both hepatocellular carcinoma and cholangiocarcinoma. Immune checkpoint inhibitors are a potent first line treatment in hepatocellular carcinoma with multiple clinical trial showing effectiveness in cholangiocarcinoma. HCC-CC has limited proven treatment options as patients are generally excluded from clinical trials. In this study we reviewed outcomes of patients with HCC-CC who received immune checkpoint inhibitor in a single center. Methods: Records of patients who had a pathological confirmed HCC-CC by a subspecialized hepatic pathologist at the University of Kansas medical center were reviewed. We identified 6 patients with locally advanced unresectable or metastatic HCC-CC that received immune checkpoint inhibitor between February 2017 and January 2021. Baseline characteristics were obtained, as well as best response, line of therapy, and duration of response. Results: Of the six patients 4 (66%) received PD-1 inhibitor alone and 2 (34%) received combination therapy with CTLA-4 inhibitor for the treatment of HCC-CC. There were 3 (50%) females and 6 (100%) with prior hepatitis C infection. four (66%) patients had metastatic disease and 2 had locally unresectable advanced disease. Objective response rate was 83.3%. One patient achieved complete response and had a treatment holiday after receiving treatment for 2 years, and restarted immunotherapy upon relapse. Four patients had a partial response, of which two passed away after disease progression. One patient had stable disease on 2 different lines of immunotherapy then progressed. Of those who responded, one patient received immunotherapy, 3 (50%) received liver directed therapy and two received chemotherapy or Lenvatinib as first line treatment (Table). Conclusions: Immune checkpoint inhibitors demonstrate potential activity in patients with HCC-CC without unexpected side effect in this unmet need high-risk population. Larger studies are needed to confirm activity and efficacy in this setting.[Table: see text]

Immune checkpoint inhibitor sensitivity of DNA repair deficient tumors

Immunotherapy ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 1205-1213
Author(s):  
Pauline Rochefort ◽  
Françoise Desseigne ◽  
Valérie Bonadona ◽  
Sophie Dussart ◽  
Clélia Coutzac ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Immune Checkpoint ◽  
Genome Stability ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Excision Repair ◽  
Checkpoint Inhibitors ◽  
Repair Deficiency ◽  
Dna Repair Deficiency

Faithful DNA replication is necessary to maintain genome stability and implicates a complex network with several pathways depending on DNA damage type: homologous repair, nonhomologous end joining, base excision repair, nucleotide excision repair and mismatch repair. Alteration in components of DNA repair machinery led to DNA damage accumulation and potentially carcinogenesis. Preclinical data suggest sensitivity to immune checkpoint inhibitors in tumors with DNA repair deficiency. Here, we review clinical studies that explored the use of immune checkpoint inhibitor in patient harboring tumor with DNA repair deficiency.

Venous thromboembolism events in patients with advanced cancer on immune checkpoint inhibitors

Immunotherapy ◽  
2021 ◽  
Author(s):  
Adi Kartolo ◽  
Cynthia Yeung ◽  
Gordon T Moffat ◽  
Lilian Hanna ◽  
Wilma Hopman ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Advanced Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Cancer Management ◽  
Thromboembolism Events

Aim: To evaluate the correlation between venous thromboembolism events (VTEs) and immune checkpoint inhibitor (ICI)-based regimens. Methods: This is a retrospective study of 403 patients with advanced cancer on ICI-based regimens. Results: We report 8% VTE incidence post-ICI initiation over a median of 11.1 months of follow-up. Compared with single-agent ICI, dual-ICI was significantly correlated with higher incidence of VTE (odds ratio [OR]: 4.196, 95% CI: 1.527–11.529, p = 0.005), but chemotherapy–immuno-oncology combination was not (OR: 1.374, 95% CI: 0.285–6.632, p = 0.693). Subsequent systemic therapy post-ICI was also independently associated with higher VTE incidence (OR: 2.599, 95% CI: 1.169–5.777, p = 0.019). Conclusion: Our findings suggest potential underreporting of VTE incidence in ICI clinical trials. As dual-ICI is becoming more prevalent in cancer management, clinicians should maintain vigilance regarding VTE in patients with advanced cancer on ICI-based regimens.

Sign in / Sign up

Export Citation Format

Share Document