scholarly journals Immune Checkpoint Inhibitors in the Treatment of Renal Cancer: Current State and Future Perspective

2020 ◽  
Vol 21 (13) ◽  
pp. 4691
Author(s):  
Daniele Lavacchi ◽  
Elisa Pellegrini ◽  
Valeria Emma Palmieri ◽  
Laura Doni ◽  
Marinella Micol Mela ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Gene Expression Pattern ◽  
Gene Expression Signature ◽  
Future Perspective ◽  
Immune Gene

Systemic treatment of renal cancer (RCC) has undergone remarkable changes over the past 20 years with the introduction of immunotherapeutic agents targeting programmed cell death (PD-1)/programmed death-ligand 1 (PD-L1) axis, as a single-agent or combined with anti-CTLA-4 monoclonal antibodies (MoAbs) or a multi-target vascular endothelial growth factor-(VEGF) tyrosine kinase inhibitor (TKI). In this paper, we review the main evidence on the use of Immune Checkpoint Inhibitors (ICIs) for RCC treatment from the first demonstration of activity of a nivolumab single agent in a phase I trial to the novel combination strategies (anti-PD-1 plus anti-CTLA4 or anti-PD-1 plus TKI). In addition, we discuss the use of anti-PD-1/PD-L1 agents in patients with non-clear cells and rare histological subtype RCC. Then, we critically examine the current findings in biomarkers that have been proposed to be prognostic or predictive to the response of immunotherapy including immune gene expression signature, B7-H1 expression, PBRM1 loss of function, PD-L1 expression, frame shift indel count, mutations in bromodomain-containing genes in patients with MiT family translocation RCC (tRCC), high expression of the T-effector gene signature, and a high myeloid inflammation gene expression pattern. To date, a single biomarker as a predictor of response has not been established. Since the dynamic behavior of the immune response and the different impact of ICI treatment on patients with specific RCC subtypes, the integration of multiple biomarkers and further validation in clinical trials are needed.

scholarly journals The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

2021 ◽  
Vol 22 (14) ◽  
pp. 7511
Author(s):  
Albina Fejza ◽  
Maurizio Polano ◽  
Lucrezia Camicia ◽  
Evelina Poletto ◽  
Greta Carobolante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Effective Treatment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Hypoxia ◽  
Melanoma Cells ◽  
Vessel Normalization ◽  
Melanoma Patients

The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings,the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2−/− mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy.

scholarly journals Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors

2020 ◽  
Author(s):  
Adam C. Palmer ◽  
Benjamin Izar ◽  
Peter K. Sorger
Keyword(s):  
Clinical Trials ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Combination Therapies ◽  
Anti Tumor Activity

ABSTRACTHundreds of clinical trials are testing whether combination therapies can increase the anti-tumor activity of Immune Checkpoint Inhibitors (ICIs). We find that the benefits of recently reported and approved combinations involving ICIs are fully accounted for by increasing the chance of a single-agent response (drug independence), with no requirement for additive or synergistic efficacy. Thus, the degree of success of combinations involving ICIs with other therapies is largely predictable.

scholarly journals Future Perspective of Chemotherapy and Pharmacotherapy in Thymic Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5239
Author(s):  
Rui Kitadai ◽  
Yusuke Okuma
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Thymic Carcinoma ◽  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
Cytotoxic Agents ◽  
Future Perspective ◽  
Driver Mutations ◽  
Thymic Epithelial Cells ◽  
Thymic Epithelial Tumors

Thymic carcinoma is a rare cancer that arises from thymic epithelial cells. Its nature and pathology differ from that of benign thymoma, presenting a poorer prognosis. If surgically resectable, surgery alone or surgery followed by chemoradiotherapy or radiotherapy is recommended by the National Comprehensive Cancer Network Guidelines. Metastatic and refractory thymic carcinomas require systemic pharmacotherapy. Combined carboplatin and paclitaxel, and cisplatin and anthracycline-based regimens have been shown a fair response rate and survival to provide a de facto standard of care when compared with other drugs employed as first-line chemotherapy. Cytotoxic agents have been pivotal for treating thymic carcinoma, as little is known regarding its tumorigenesis. In addition, genetic alterations, including driver mutations, which play an important role in treatments, have not yet been discovered. However, molecular pathways and biomarker studies assessing thymic epithelial tumors have been reported recently, resulting in the development of new agents, such as molecular targeted agents and immune checkpoint inhibitors. As treatment options are currently limited and the prognosis remains poor in metastases and recurrent thymic carcinoma, genetic alterations need to be assessed. In the present review, we focused on the current role of targeted therapies and immune checkpoint inhibitors in treating thymic carcinoma.

scholarly journals Efficacy of immune checkpoint inhibitors for in-transit melanoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000440 ◽  
Author(s):  
Emilia Nan Tie ◽  
Julia Lai-Kwon ◽  
Michael Alexander Rtshiladze ◽  
Lumine Na ◽  
James Bozzi ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Progression Free Survival ◽  
Distant Metastases ◽  
Mek Inhibitor ◽  
Disease Recurrence ◽  
In Transit

BackgroundThe efficacy of immune checkpoint inhibitors (ICI) in metastatic melanoma is well established. However, there are limited data regarding their efficacy in in-transit melanoma (ITM). This study assessed the efficacy of ICI in patients with ITM.MethodsA retrospective review of patients with ITM commenced on an ICI between March 2013 and February 2018 at three tertiary centers in Australia. Patients were excluded if they had previous or synchronous distant metastases. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were based on a composite of radiological and clinical assessments.ResultsFifty-four patients were included: 27 (50%) female; median age 75 (range 26–94); 12 (22%) stage IIIB, 40 (74%) stage IIIC and 2 (4%) stage IIID; 10 (19%) BRAF mutant. Forty (74%) received single-agent anti-PD-1 (pembrolizumab or nivolumab), 8 (15%) single agent anti-CTLA-4 (ipilimumab), 5 (9%) combination anti-PD-1/anti-CTLA-4 (ipilimumab and nivolumab or pembrolizumab) and 1 (2%) combination anti-PD-L1 (atezolizumab) and MEK inhibitor (cobimetinib). The median follow-up was 15 months (2–46).ORR to ICI was 54%: 14 (26%) complete responses; 15 (28%) partial responses; 9 (17%) stable disease; 16 (30%) progressive disease. Thirteen (46%) responders had only one ITM lesion. ORR was 58% for single-agent anti-PD-1, 38% for single-agent anti-CTLA4 and 40% for anti-PD-1/anti-CTLA-4. The median PFS was 11.7 months (6.6-not reached). 1-year and 2-year PFS were 48% and 39%, respectively,. Fourteen progressed locoregionally and 11 progressed distantly. The median OS was not reached. 1-year and 2-year OS were 85% and 63%, respectively. No clinicopathological features were associated with ORR.Conclusions and relevanceICI produce objective responses in ITM and should be considered in patients with unresectable ITM or disease recurrence.

scholarly journals Immune checkpoint inhibitors in renal cell carcinoma

2017 ◽  
Vol 131 (21) ◽  
pp. 2627-2642 ◽  
Author(s):  
Kirsty Ross ◽  
Rob J. Jones
Keyword(s):  
Renal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
Optimal Timing ◽  
New Class ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Immune Manipulation

The immune system has long been known to play a critical role in the body’s defence against cancer, and there have been multiple attempts to harness it for therapeutic gain. Renal cancer was, historically, one of a small number of tumour types where immune manipulation had been shown to be effective. The current generation of immune checkpoint inhibitors are rapidly entering into routine clinical practice in the management of a number of tumour types, including renal cancer, where one drug, nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody (mAb), is licensed for patients who have progressed on prior systemic treatment. Ongoing trials aim to maximize the benefits that can be gained from this new class of drug by exploring optimal timing in the natural course of the disease as well as combinations with other checkpoint inhibitors and drugs from different classes.

A living systematic review of immune checkpoint inhibitors in cancer patients: A novel platform for evidence synthesis in oncology.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6596-6596
Author(s):  
Irbaz Bin Riaz ◽  
Rabbia Siddiqi ◽  
Saad Malik ◽  
Elizabeth Jane Cathcart-Rake ◽  
Ognjen Gajic ◽  
...  
Keyword(s):  
Systematic Review ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Clinical Decision Making ◽  
Checkpoint Inhibitors ◽  
Evidence Synthesis ◽  
Meta Analysis ◽  
Single Agent ◽  
Phase 2 ◽  
New Evidence

6596 Background: Several previous systematic reviews and meta-analyses have attempted to summarize toxicity of Immune checkpoint inhibitors (ICIs). However, very soon after each one of these reviews has been published, it became outdated. ICIs are currently used in 14 different cancers and data is rapidly evolving from new clinical trials. A living Systematic review, which is defined as a systematic review that is continually updated to incorporate relevant new evidence as it becomes available, is necessary in this situations. Therefore, we performed an updated systematic review and a meta-analysis which will serve as a foundation of a living Systematic review. Methods: MEDLINE, EMBASE and Cochrane were searched to identify phase 2 and 3 RCTs of PD-1/PD-L1 ICIs. Included studies compared either immunotherapy alone or combination with existing standard of care treatment and reported data for AE’s of interest. DerSimonian-Laird random effects Meta-Analysis was performed to derive pooled odds Ratio (OR) estimates for AE’s of interest. An infrastructure of a living systematic review is being developed and it includes monthly literature searches, cumulative meta-analysis and an online reporting platform. Results: We screened 6746 studies and 31 phase 3 and 2 phase 2 RCTs (n = 21,421) were included in the analysis. 22 RCTs used PD-1/PD-L1 ICIs as a single agent and 11 as a combination therapy. Selected toxicity estimates are summarized in a table. Conclusions: The meta-analysis updates previously published toxicity estimates and provides additional information about the risk of toxicities in single versus combination regimens. We have initiated the first living systematic review in oncology that will be continuously updated, incorporating relevant new evidence as it becomes available, and will provide accurate and up to date toxicity estimates to support clinical decision making. [Table: see text]

Preliminary safety, efficacy, and pharmacokinetics (PK) results of KN046 (bispecific anti-PD-L1/CTLA4) from a first-in-human study in subjects with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2554-2554 ◽  
Author(s):  
Jermaine Coward ◽  
Vinod Ganju ◽  
Ramin Behzadigohar ◽  
Kenneth Kwong ◽  
June Xu ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Human Study ◽  
Safety Data ◽  
Advanced Solid Tumors ◽  
Duration Of Treatment ◽  
Efficacy Evaluation

2554 Background: KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. KN046 has a wild type IgG1 Fc portion that preserves intact effector functions, such as depletion of Tregs in tumor microenvironments. This first-in-human study evaluated the safety, tolerability, PK and preliminary efficacy of KN046 in subjects with advanced solid tumors. Methods: This traditional “3+3” dose-escalation design study enrolled patients (pts) with advanced unresectable or metastatic solid tumors refractory or intolerant to standard therapies. Previous treatment from PD1 or PD-L1 immune checkpoint inhibitors was allowed. KN046 was administered intravenously Q2W. Dose limit toxicity (DLT) evaluation period is 28 days. The planned dose levels (DL) were 0.3, 1, 3, 5 and 10 mg/kg. Efficacy evaluation was performed by RECIST 1.1 every 8 weeks. Results: As of Dec 13, 2018, 10 pts had been enrolled (0.3 mg/kg, n = 1; 1 mg/kg, n = 3; 3 mg/kg, n = 3; and 5 mg/kg, n = 3). Median duration of treatment was 8 (range: 2-24) weeks. 1 DLT was observed at 5 mg/kg dose (a grade 3 immune-related hepatitis without elevation in total bilirubin; reversible in two weeks). The most common (≥30%) treatment-emergent AEs (TEAE) were Fatigue, Diarrhea, Nausea, Vomiting. Six immune-related TEAEs (Abdominal pain lower, Arthralgia, Hepatic function abnormal, Hyperthyroidism, Nausea and Transaminitis) were observed in 3 pts. One pt with NSCLC from 3 mg/kg cohort had confirmed completed response. Two pts (TNBC and nivolumab refractory RCC) from 1 mg/kg cohort had shown long-term stable disease ( > 12 weeks). Faster clearance of KN046 was observed at lower dose might be due to target-mediated clearance. T1/2 is approximately 7~9 days at doses of 3 mg/kg and above when saturation occurs. Conclusions: Single agent KN046 has an acceptable safety profile and is in line with previously reported safety data from other immune checkpoint inhibitors. Preliminary efficacy results are promising. PK data from initial 4 cohorts support Q2W schedule. The study is currently ongoing at dose level of 5 mg/kg Q2W. Clinical trial information: NCT03529526.

scholarly journals Tumor Suppressor Immune Gene Therapy to Reverse Immunotherapy Resistance

2021 ◽  
Author(s):  
Sunil Chada ◽  
Dora Wiederhold ◽  
Kerstin B. Menander ◽  
Beatha Sellman ◽  
Max Talbott ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Type I ◽  
Immune Gene ◽  
Gene Signatures ◽  
Complete Tumor

AbstractBackgroundWhile immune checkpoint inhibitors are becoming a standard of care for multiple types of cancer, the majority of patients do not respond to this form of immunotherapy. New approaches are required overcome resistance to immunotherapies.MethodsWe investigated the effects of adenoviral p53 (Ad-p53) gene therapy in combination with immune checkpoint inhibitors and selective IL2 or IL15 CD122/132 agonists in the aggressive B16F10 tumor model resistant to immunotherapies. To assess potential mechanisms action, pre and post Ad-p53 treatment biopsies were evaluated for changes in gene expression profiles by Nanostring IO 360 assays.ResultsSubstantial synergy of “triplet” Ad-p53 + CD122/132 + anti-PD-1 therapy resulted in potential curative effects associated with complete tumor remissions of both primary and contralateral tumors. Interestingly, contralateral tumors which were not injected with Ad-p53 showed robust abscopal effects resulting in statistically significant decreases in tumor size and increased survival (p<0.001). None of the monotherapies or doublet treatments induced complete tumor regressions. Ad-p53 treatment increased Type I Interferon, CD8+ T cell, immuno-proteosome antigen presentation and tumor inflammation gene signatures. Ad-p53 treatment also decreased immune suppressive TGF-beta, beta-catenin, macrophage, and endothelium gene signatures, which may contribute to enhanced immune checkpoint inhibitor (CPI) efficacy. Unexpectedly, a number of previously unidentified, strongly p53 down regulated genes associated with stromal pathways and IL10 expression identified novel anti-cancer therapeutic applications.ConclusionsThese results imply the ability of Ad-p53 to induce efficacious local and systemic anti-tumor immune responses with the potential to reverse resistance to immune checkpoint inhibitor therapy when combined with CD122/132 agonists and immune checkpoint blockade. Our findings further imply that Ad-p53 has multiple complimentary immune mechanisms of action which support future clinical evaluation of triplet Ad-p53, CD122/132 agonist and immune checkpoint inhibitor combination treatment.

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