scholarly journals Combination therapy with immune checkpoint inhibitors (ICIs); a new frontier

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Somayeh Vafaei ◽  
Angelina O. Zekiy ◽  
Ramadhan Ado Khanamir ◽  
Burhan Abdullah Zaman ◽  
Arman Ghayourvahdat ◽  
...  

AbstractRecently, immune checkpoint inhibitors (ICIs) therapy has become a promising therapeutic strategy with encouraging therapeutic outcomes due to their durable anti-tumor effects. Though, tumor inherent or acquired resistance to ICIs accompanied with treatment-related toxicities hamper their clinical utility. Overall, about 60–70% of patients (e.g., melanoma and lung cancer) who received ICIs show no objective response to intervention. The resistance to ICIs mainly caused by alterations in the tumor microenvironment (TME), which in turn, supports angiogenesis and also blocks immune cell antitumor activities, facilitating tumor cells' evasion from host immunosurveillance. Thereby, it has been supposed and also validated that combination therapy with ICIs and other therapeutic means, ranging from chemoradiotherapy to targeted therapies as well as cancer vaccines, can capably compromise tumor resistance to immune checkpoint blocked therapy. Herein, we have focused on the therapeutic benefits of ICIs as a groundbreaking approach in the context of tumor immunotherapy and also deliver an overview concerning the therapeutic influences of the addition of ICIs to other modalities to circumvent tumor resistance to ICIs.

2021 ◽  
Vol 9 (2) ◽  
pp. e001945 ◽  
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gerry Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Cho Wing Li ◽  
Roland Leung ◽  
...  

BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p<0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs.ConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.


Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5103
Author(s):  
Maximilian Haist ◽  
Henner Stege ◽  
Saskia Pemler ◽  
Jaqueline Heinz ◽  
Maria Isabel Fleischer ◽  
...  

Immune checkpoint inhibitors (ICI) significantly improved the prognosis of advanced melanoma patients. However, many patients do not derive long-term benefit from ICI therapy due to primary and acquired resistance. In this regard, it has been shown that coagulation factors contribute to cancer immune evasion and might therefore promote resistance to ICI. In particular, recent observations in murine systems demonstrated that myeloid-derived factor Xa (FXa) impedes anti-tumor immunity in the tumor microenvironment and that the oral FXa inhibitor (FXa-i) rivaroxaban synergizes with ICI. The synergistic effect of FXa inhibitors with clinical ICI therapy is unknown. We performed a retrospective study of 280 metastatic melanoma patients who were treated with ICI and stratified them for concomitant anticoagulation (AC) by medical chart review. Data on baseline patient characteristics, specific AC treatment, ICI therapy, other tumor-targeting therapies, and clinical outcomes were analyzed. Of 280 patients who received ICI, 76 received concomitant AC during initial ICI therapy. Patients on AC were treated either with heparins (n = 29), vitamin K antagonists (VKA) (n = 20), or FXa-i (n = 27). Patients requiring AC during ICI therapy showed no significantly reduced objective response rate (ORR) (p = 0.27), or progression-free (PFS; median PFS 4 vs. 4 months; p = 0.71) or overall survival (OS; median OS: 39 vs. 51 months; p = 0.31). Furthermore, patients who underwent AC did not show significantly more bleeding complications (p = 0.605) than those who were not anticoagulated. Remarkably, stratification of patients by the class of AC revealed that patients receiving FXa-i were more likely to obtain CR (26.9 vs. 12.6%, p = 0.037), and showed better ORR (69.2 vs. 36.4%, p = 0.005), PFS (median PFS: 12 months vs. 3 months; p = 0.006), and OS (median OS not reached vs. 42 months; p = 0.09) compared to patients not receiving FXa-i. Patient demographics and tumor characteristics in this patient subcohort did not significantly differ from patients not on FXa-i. In summary, our study provides first clinical evidence that the clinical application of FXa-i may enhance the efficacy of ICI therapy via the restoration of anti-tumor immunity, while patients who received FXa-i were not more likely to encounter bleeding complications.


2021 ◽  
Vol 12 ◽  
Author(s):  
Yuqian Feng ◽  
Huimin Jin ◽  
Kaibo Guo ◽  
Yuying Xiang ◽  
Yiting Zhang ◽  
...  

Background: Combination therapy with immune checkpoint inhibitors (ICIs) has been widely used for clinical treatment in recent years, which has a better survival benefit. However, not all patients can derive clinical benefit from combination immunotherapy. Therefore, it is necessary to explore the biomarkers of combination immunotherapy.Methods: We retrieved articles from electronic databases including PubMed, EMBASE and Cochrane. The statistical analysis was performed using RevMan software. Progression free survival (PFS), overall survival (OS) and objective response rate (ORR) were the outcome indicators. In the unselect population, we compared combination therapy with other treatments. In addition, we also conducted subgroup analysis on PFS, OS and ORR according to PD-L1 status.Results: Seven studies were included in the analysis for a total of 3,515 cases. In the unselected population, we found that combination therapy has longer PFS, OS, and better ORR than other treatments for cancer patients. The longer PFS was showed in PD-L1 ≥ 5% cases (HR = 0.64, 95% CI: 0.56–0.76; p &lt; 0.001) than PD-L1 ≥ 1% cases (HR = 0.72, 95% CI: 0.66–0.79; p &lt; 0.001), while ORR and OS have not related to the status of PD-L1.Conclusion: This study supported the efficacy of combination therapy with immune checkpoint inhibitors (ICIs), and also showed that PFS in patients with malignant tumors is positively correlated with PD-L1 expression. Due to the limited number of trials included, more high-quality clinical randomized controlled trials should be conducted to confirm the review findings.


2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Rilan Bai ◽  
Lingyu Li ◽  
Xiao Chen ◽  
Naifei Chen ◽  
Wei Song ◽  
...  

Objective. We aimed to retrospectively analyze the predictors of immune checkpoint inhibitors (ICIs)-efficacy in patients with advanced pancancer who were treated with various ICIs in the real world and focused on the correlation between ICIs-efficacy and immune-related adverse events (irAEs). Methods. We retrospectively analyzed data from 103 patients with advanced pancancer treated receiving various ICIs in the First Hospital of Jilin University from January 1, 2016 to August 1, 2020. Survival probabilities of progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier curves and log-rank tests and the multivariate Cox proportional hazards model. Receiver-operating characteristic curve was used to determine a cutoff value for parameters and area under the curve. Correlations between the two variables were analyzed by logistic regression. Results. All patients were analyzed for survival predictors of OS, while 87 of 103 patients experienced evaluable disease progression of immunotherapy and were included in the analysis of predictors of PFS. First, we found that lower platelet (cutoff = 201.5 × 109/L) and lactate dehydrogenase (LDH) (cutoff = 227 U/L) were independently associated with significantly improved PFS, while lower platelet-lymphocyte ratio (cutoff = 206.5), absolute monocyte count (cutoff = 0.62 × 109/L), and LDH (cutoff = 194.5 U/L) were significantly and independently associated with better OS. In the analysis of the immune cell subgroup, a lower absolute countof CD8+CD28−suppressor T cells was an independent factor associated with better PFS (6.60 vs.4.13 months (mo), hazard ratios (HR) = 3.17, p  = 0.0038), and OS (29.4 vs. 9.57 mo, HR = 3.05, p  = 0.03). Second, the results of the analysis for irAEs showed that patients with any grade irAEs had higher objective response rate (30% vs. 10%, HR = 4.34, p  = 0.009), disease control rate (69.7% vs. 50%, HR = 2.3, p  = 0.028), PFS (8.37 vs. 3.77 mo, HR = 2.02, p  = 0.0038), and OS (24.77 vs.13.83 mo, HR = 1.84, p  = 0.024). Moreover, the groups with irAEs of grade ≥2 and with “multi-site” irAEs had significantly better PFS and OS ( p  < 0.05) compared with the other groups. We also proved that endocrine irAEs (usually thyroid dysfunction) were significantly associated with better mPFS ( p  = 0.01), and hepatic irAEs were significantly associated with better mOS ( p  = 0.023). Conclusions. This retrospective study explored the availability and effectiveness of some cost-effective and readily available blood biochemical parameters in routine clinical practice to predict the ICIs-efficacy and demonstrated the predictive role of different categories of irAEs on efficacy.


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 ◽  
...  

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).


2021 ◽  
Vol 11 ◽  
Author(s):  
Lucas V. dos Santos ◽  
Carina M. Abrahão ◽  
William N. William

Preclinical data suggest that head and neck squamous cell carcinomas (HNSCC) may evade immune surveillance and induce immunosuppression. One mechanism of immune evasion involves the expression of programmed death ligand-1 (PD-L1) in tumor and immune cells, which is, to date, the only biomarker routinely used in clinical practice to select patients with advanced HNSCCs more likely to benefit from anti-PD-1 therapy. Nonetheless, PD-L1 expression alone incompletely captures the degree of sensitivity of HNSCCs to PD-1 inhibitors. Most patients exposed to anti-PD-1 antibodies do not respond to therapy, suggesting the existence of mechanisms of de novo resistance to immunotherapy. Furthermore, patients that initially respond to PD-1 inhibitors will eventually develop acquired resistance to immunotherapy through mechanisms that have not yet been completely elucidated. In this article, we will provide an overview of the immune landscape of HNSCCs. We will briefly describe the clinical activity of inhibitors of the PD-1/PD-L1 axis in this disease, as well as biomarkers of benefit from these agents that have been identified so far. We will review pre-clinical and clinical work in cancers in general, and in HNSCCs specifically, that have characterized the mechanisms of de novo and acquired resistance to immunotherapy. Lastly, we will provide insights into novel strategies under investigation to overcome resistance to immune checkpoint inhibitors.


2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao-Juan Chen ◽  
Aiqun Ren ◽  
Liang Zheng ◽  
En-Dian Zheng ◽  
Tao Jiang

This study aimed to investigate the predictive value of liver metastases (LM) in patients with various advanced cancers received immune-checkpoint inhibitors (ICIs). First, clinical and survival data from a published cohort of 1,661 patients who received ICIs therapy were downloaded and analyzed. Second, a retrospective review of 182 patients with advanced non-small-cell lung cancer (NSCLC) who received PD-1/PD-L1 monotherapy was identified. Third, a meta-analysis of published trials was performed to explore the impact of LM on the efficacy of anti-PD-1/PD-L1 based therapy in advanced lung cancers. Pan-cancer analysis revealed that patients with LM had significantly shorter overall survival (OS) than those without LM (10 vs. 20 months; P &lt; 0.0001). Subgroup analysis showed that the presence of LM was associated with markedly shorter OS than those without LM in ICI monotherapy group (P &lt; 0.0001), but it did not reach the statistical significance in ICI-based combination therapy (P = 0.0815). In NSCLC, the presence of LM was associated with significantly inferior treatment outcomes in both pan-cancer and real-world cohort. Interestingly, ICI-based monotherapy and combination therapy could simultaneously prolong progression-free survival (PFS) and OS than chemotherapy in patients without LM. However, ICI-based monotherapy could not prolong PFS than chemotherapy in patients with LM while ICI-based combination therapy could dramatically prolong both PFS and OS. Together, these findings suggested that the presence of LM was the negative predictive factor in cancer patients received ICIs monotherapy, especially in NSCLC. ICI-based combination therapy might overcome the intrinsic resistance of LM to ICIs while the optimal combinatorial strategies remain under further investigation.


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