scholarly journals Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

2020 ◽  
Vol 21 (17) ◽  
pp. 6176 ◽  
Author(s):  
Yolla Haibe ◽  
Ziad El Husseini ◽  
Rola El Sayed ◽  
Ali Shamseddine
Keyword(s):  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Immune Checkpoints ◽  
Therapeutic Approaches ◽  
Standard Chemotherapy ◽  
Primary Resistance ◽  
In The Beginning ◽  
Tumor Types

The treatment landscape in oncology has witnessed a major revolution with the introduction of checkpoint inhibitors: anti-PD1, anti-PDL1 and anti-CTLA-4. These agents enhance the immune response towards cancer cells instead of targeting the tumor itself, contrary to standard chemotherapy. Although long-lasting durable responses have been observed with immune checkpoints inhibitors, the response rate remains relatively low in many cases. Some patients respond in the beginning but then eventually develop acquired resistance to treatment and progress. Other patients having primary resistance never respond. Multiple studies have been conducted to further elucidate these variations in response in different tumor types and different individuals. This paper provides an overview of the mechanisms of resistance to immune checkpoint inhibitors and highlights the possible therapeutic approaches under investigation aiming to overcome such resistance in order to improve the clinical outcomes of cancer patients.

scholarly journals Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors

2021 ◽  
Vol 9 (2) ◽  
pp. e001945 ◽  
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gerry Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Cho Wing Li ◽  
Roland Leung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Acquired Resistance ◽  
Survival Rates ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Resistance ◽  
Advanced Hcc

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.

scholarly journals Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 735
Author(s):  
Simran Venkatraman ◽  
Jarek Meller ◽  
Suradej Hongeng ◽  
Rutaiwan Tohtong ◽  
Somchai Chutipongtanate
Keyword(s):  
Immune Checkpoint ◽  
Cancer Genomics ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Master Regulators ◽  
New Class ◽  
Public Datasets ◽  
Molecular Expression

The study of immune evasion has gained a well-deserved eminence in cancer research by successfully developing a new class of therapeutics, immune checkpoint inhibitors, such as pembrolizumab and nivolumab, anti-PD-1 antibodies. By aiming at the immune checkpoint blockade (ICB), these new therapeutics have advanced cancer treatment with notable increases in overall survival and tumor remission. However, recent reports reveal that 40–60% of patients fail to benefit from ICB therapy due to acquired resistance or tumor relapse. This resistance may stem from increased expression of co-inhibitory immune checkpoints or alterations in the tumor microenvironment that promotes immune suppression. Because these mechanisms are poorly elucidated, the transcription factors that regulate immune checkpoints, known as “master regulators”, have garnered interest. These include AP-1, IRF-1, MYC, and STAT3, which are known to regulate PD/PD-L1 and CTLA-4. Identifying these and other potential master regulators as putative therapeutic targets or biomarkers can be facilitated by mining cancer literature, public datasets, and cancer genomics resources. In this review, we describe recent advances in master regulator identification and characterization of the mechanisms underlying immune checkpoints regulation, and discuss how these master regulators of immune checkpoint molecular expression can be targeted as a form of auxiliary therapeutic strategy to complement traditional immunotherapy.

Non-coding RNA and immune-checkpoint inhibitors: friends or foes?

Immunotherapy ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 513-529
Author(s):  
Dmitrii Shek ◽  
Scott A Read ◽  
Liia Akhuba ◽  
Liang Qiao ◽  
Bo Gao ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Protein Translation ◽  
Immune Checkpoints ◽  
Signalling Pathways ◽  
Therapeutic Approaches ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Tumor Growth Suppression

Non-coding RNAs (ncRNAs) are an abundant component of the human transcriptome. Their biological role, however, remains incompletely understood. Nevertheless, ncRNAs are highly associated with cancer development and progression due to their ability to modulate gene expression, protein translation and growth pathways. Immune-checkpoint inhibitors (ICIs) are considered one of the most promising and highly effective therapeutic approaches for cancer treatment. ICIs are monoclonal antibodies targeting immune checkpoints such as CTLA-4, PD-1 and PD-L1 signalling pathways that stimulate T cell cytotoxicity and can result in tumor growth suppression. This Review will summarize existing knowledge regarding ncRNAs and their role in cancer and ICI therapy. In addition, we will discuss potential mechanisms by which ncRNAs may influence ICI treatment outcomes.

scholarly journals A Systematic Review of the Tumor-Infiltrating CD8+ T-Cells/PD-L1 Axis in High-Grade Glial Tumors: Toward Personalized Immuno-Oncology

2021 ◽  
Vol 12 ◽  
Author(s):  
Mahdi Abdoli Shadbad ◽  
Zahra Asadzadeh ◽  
Negar Hosseinkhani ◽  
Afshin Derakhshani ◽  
Nazila Alizadeh ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Cancer Therapies ◽  
High Grade ◽  
Glial Tumors ◽  
Anti Cancer ◽  
The Impact

Based on preclinical findings, programmed death-ligand 1 (PD-L1) can substantially attenuate CD8+ T-cell-mediated anti-tumoral immune responses. However, clinical studies have reported controversial results regarding the significance of the tumor-infiltrating CD8+ T-cells/PD-L1 axis on the clinical picture and the response rate of patients with high-grade glial tumors to anti-cancer therapies. Herein, we conducted a systematic review according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements to clarify the clinical significance of the tumor-infiltrating CD8+ T-cells/PD-L1 axis and elucidate the impact of this axis on the response rate of affected patients to anti-cancer therapies. Indeed, a better understanding of the impact of this axis on the response rate of affected patients to anti-cancer therapies can provide valuable insights to address the futile response rate of immune checkpoint inhibitors in patients with high-grade glial tumors. For this purpose, we systematically searched Scopus, Web of Science, Embase, and PubMed to obtain peer-reviewed studies published before 1 January 2021. We have observed that PD-L1 overexpression can be associated with the inferior prognosis of glioblastoma patients who have not been exposed to chemo-radiotherapy. Besides, exposure to anti-cancer therapies, e.g., chemo-radiotherapy, can up-regulate inhibitory immune checkpoint molecules in tumor-infiltrating CD8+ T-cells. Therefore, unlike unexposed patients, increased tumor-infiltrating CD8+ T-cells in anti-cancer therapy-exposed tumoral tissues can be associated with the inferior prognosis of affected patients. Because various inhibitory immune checkpoints can regulate anti-tumoral immune responses, the single-cell sequencing of the cells residing in the tumor microenvironment can provide valuable insights into the expression patterns of inhibitory immune checkpoints in the tumor micromovement. Thus, administrating immune checkpoint inhibitors based on the data from the single-cell sequencing of these cells can increase patients’ response rates, decrease the risk of immune-related adverse events development, prevent immune-resistance development, and reduce the risk of tumor recurrence.

Managing Resistance to Immune Checkpoint Inhibitors in Lung Cancer: Treatment and Novel Strategies

2022 ◽  
Author(s):  
Antonio Passaro ◽  
Julie Brahmer ◽  
Scott Antonia ◽  
Tony Mok ◽  
Solange Peters
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Primary Resistance ◽  
Previous Response ◽  
Immune Resistance ◽  
Clinical Resistance

A proportion of patients with lung cancer experience long-term clinical benefit with immune checkpoint inhibitors (ICIs). However, most patients develop disease progression during treatment or after treatment discontinuation. Definitions of immune resistance are heterogeneous according to different clinical and biologic features. Primary resistance and acquired resistance, related to tumor-intrinsic and tumor-extrinsic mechanisms, are identified according to previous response patterns and timing of occurrence. The clinical resistance patterns determine differential clinical approaches. To date, several combination therapies are under development to delay or prevent the occurrence of resistance to ICIs, including the blockade of immune coinhibitory signals, the activation of those with costimulatory functions, the modulation of the tumor microenvironment, and the targeting T-cell priming. Tailoring the specific treatments with distinctive biologic resistance mechanisms would be ideal to improve the design and results of clinical trial. In this review, we reviewed the available evidence on immune resistance mechanisms, clinical definitions, and management of resistance to ICIs in lung cancer. We also reviewed data on novel strategies under investigation in this setting.

Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for All Patients?

2019 ◽  
pp. 147-164 ◽  
Author(s):  
Charlene M. Fares ◽  
Eliezer M. Van Allen ◽  
Charles G. Drake ◽  
James P. Allison ◽  
Siwen Hu-Lieskovan
Keyword(s):  
Immune Checkpoint ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Mechanisms Of Resistance ◽  
Primary Resistance ◽  
Wide Range ◽  
Clinical Responses ◽  
Tumor Types

The emergence of immune checkpoint blockade therapies over the last decade has transformed cancer treatment in a wide range of tumor types. Unprecedented and durable clinical responses in difficult-to-treat cancer histologies have been observed. However, despite these promising long-term responses, the majority of patients fail to respond to immune checkpoint blockade, demonstrating primary resistance. Additionally, many of those who initially respond to treatment eventually experience relapse secondary to acquired resistance. Both primary and acquired resistance are a result of complex and constantly evolving interactions between cancer cells and the immune system. Many mechanisms of resistance have been characterized to date, and more continue to be uncovered. By elucidating and targeting mechanisms of resistance, treatments can be tailored to improve clinical outcomes. This review will discuss the landscape of immune checkpoint blockade response data, different resistance mechanisms, and potential therapeutic strategies to overcome resistance.

Cabozantinib in advanced HCC patients previously treated with immune checkpoint inhibitors: A territory-wide cohort study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16179-e16179
Author(s):  
Jeffrey Sum Lung Wong ◽  
Yawen Dong ◽  
Vikki Tang ◽  
Thomas Wai-Tong Leung ◽  
Cynthia SY Yeung ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Acquired Resistance ◽  
Previous Treatment ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Resistance ◽  
Grade 3

e16179 Background: Cabozantinib is licensed for use as second- or third-line treatment for sorafenib-exposed advanced hepatocellular carcinoma (aHCC) based on the phase III CELESTIAL trial. However, its use in the post-immune checkpoint inhibitors (ICI) setting has yet to be described. We evaluated the pattern of use, efficacy, survival and tolerability of cabozantinib in aHCC patients with previous treatment by ICIs. Methods: We did a multi-centre, territory-wide study analysing aHCC patients who received cabozantinib after prior ICIs. Objective response rate (ORR), disease control rate (DCR), time-to-progression (TTP), overall survival (OS) and treatment related adverse events (TRAEs) were assessed. Results: Thirty-one patients were included. The median age was 58.0 (range 41-85) and 77.4% had Child-Pugh A cirrhosis. 51.6% of patients received single agent cabozantinib and 48.4% received cabozantinib in combination with ICIs. ≥80% of patients received cabozantinib beyond the second-line and 93.5% of patients had prior TKIs. All patients received prior anti-PD-1 and 61.3% had prior anti-CTLA-4. The median follow-up was 15.2 months. For single agent cabozantinib patients, the ORR was 6.3%, DCR was 31.3% and median TTP was 3.5 months (95% C.I. 1.2-5.8). For cabozantinib-ICI combination patients, the ORR was 6.7%, DCR was 26.7% and median TTP was 2.3 months (95% C.I. 1.4-3.1). The overall median OS was 8.9 months (95% C.I. 5.7-11.9). Single agent cabozantinib patients had a significantly shorter OS compared to cabozantinib-ICI combination patients (8.3 months (95% C.I. 1.3-15.2) vs. 15.1 months (95% C.I. 11.1-19.2), p = 0.047). There was no significant difference in OS among patients with primary resistance to prior ICI regimes compared to those with acquired resistance (primary resistance 8.28 months (95% C.I. 5.04-11.5) vs. acquired resistance 8.90 months (95% C.I. 3.49-14.3), p = 0.472). Overall, 67.7% and 6.5% of patients experienced TRAEs of all grade and grade ≥3 respectively. The most common TRAE was hand-foot syndrome. 62.5% of single agent cabozantinib patients had any grade TRAE and no such patients had grade ≥3 TRAE. Conclusions: Cabozantinib had good anti-tumour activity and survival outcomes with acceptable toxicity in aHCC patients with previous treatment by ICIs.

scholarly journals The Role of Immunotherapy in the Treatment of Adrenocortical Carcinoma

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 98
Author(s):  
Izabela Karwacka ◽  
Łukasz Obołończyk ◽  
Sonia Kaniuka-Jakubowska ◽  
Krzysztof Sworczak
Keyword(s):  
Immune Checkpoint ◽  
Adrenocortical Carcinoma ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Distant Metastases ◽  
Immune Checkpoints ◽  
High Tendency

Adrenocortical carcinoma (ACC) is a rare epithelial neoplasm, with a high tendency for local invasion and distant metastases, with limited treatment options. Surgical treatment is the method of choice. For decades, the mainstay of pharmacological treatment has been the adrenolytic drug mitotane, in combination with chemotherapy. Immunotherapy is the latest revolution in cancer therapy, however preliminary data with single immune checkpoint inhibitors showed a modest activity in ACC patients. The anti-neoplastic activity of immune checkpoint inhibitors such as anti-cytotoxic-T-lymphocyte-associated-antigen 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), and anti-PD-ligand-1 (PD-L1) antibodies in different solid tumors has aroused interest to explore the potential therapeutic effect in ACC as well. Multiple ongoing clinical trials are currently evaluating the role of immune checkpoint inhibitors in ACC (pembrolizumab, combination pembrolizumab and relacorilant, nivolumab, combination nivolumab and ipilimumab). The primary and acquired resistance to immunotherapy continue to counter treatment efficacy. Therefore, attempts are made to combine therapy: anti-PD-1 antibody and anti-CTLA-4 antibody, anti-PD-1 antibody and antagonist of the glucocorticoid receptor. The inhibitors of immune checkpoints would benefit patients with antitumor immunity activated by radiotherapy. Immunotherapy is well tolerated by patients; the most frequently observed side effects are mild. The most common adverse effects of immunotherapy are skin and gastrointestinal disorders. The most common endocrinopathy during anti-CTLA treatment is pituitary inflammation and thyroid disorders.

Evaluation of the impact of thyroiditis development in patients receiving immunotherapy with programmed cell death-1 inhibitors

2019 ◽  
Vol 25 (6) ◽  
pp. 1402-1411 ◽  
Author(s):  
Matthew Lei ◽  
Angela Michael ◽  
Seema Patel ◽  
Ding Wang
Keyword(s):  
Immune Checkpoint ◽  
Objective Response Rate ◽  
Immune Checkpoint Inhibitors ◽  
Tumor Response ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Free Survival ◽  
Tumor Types

Purpose We evaluated if the development of thyroiditis in patients who received treatment with immune checkpoint inhibitors across various tumor types was associated with tumor response. Methods In this retrospective, single-center, cross-sectional study, patients with various tumor types who received treatment with nivolumab or pembrolizumab as standard of care were evaluated. The primary endpoint was to evaluate the objective response rate in patients who developed thyroiditis compared with patients who did not develop thyroiditis. Secondary endpoints included disease control rate, progression-free survival, and overall survival. Results One hundred and three patients were included for analysis with a median follow-up duration of 12.8 months (range, 4.0–21.6). The data cutoff was 31 December 2016. The objective response rate was 38.2% among the 34 patients in the thyroiditis group and 17.4% in the 69 patients in the non-thyroiditis group (p = 0.028). Progression-free survival was longer in the thyroiditis group than in the non-thyroiditis group. The median progression-free survival was 10.1 months (95% CI, 1.6–18.5) in the thyroiditis group and 3.7 months (95% CI, 2.5–4.9) in the non-thyroiditis group (hazard ratio, 0.45; 95% CI, 0.27–0.76; p = 0.002). Conclusion Patients with various tumor types who received treatment with immune checkpoint inhibitors and developed thyroiditis had a higher objective response rate than those who did not develop thyroiditis. The development of thyroiditis should be investigated further in the context of prospective randomized trials as a surrogate marker for tumor response to treatment with immune checkpoint inhibitor therapies.

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