Tackling Cancer Resistance by Immunotherapy: Updated Clinical Impact and Safety of PD-1/PD-L1 Inhibitors

Cancer therapy has been constantly evolving with the hope of finding the most effective agents with the least toxic effects to eradicate tumors. Cancer immunotherapy is currently among the most promising options, fulfilling this hope in a wide range of tumors. Immunotherapy aims to activate immunity to fight cancer in a very specific and targeted manner; however, some abnormal immune reactions known as immune-related adverse events (IRAEs) might occur. Therefore, many researchers are aiming to define the most proper protocols for managing these complications without interfering with the anticancer effect. One of these targeted approaches is the inhibition of the interaction between the checkpoint protein, programmed death-receptor 1 (PD-1), and its ligand, programmed death-ligand 1 (PD-L1), via a class of antibodies known as PD-1/PD-L1 inhibitors. These antibodies achieved prodigious success in a wide range of malignancies, including those where optimal treatment is not yet fully identified. In this review, we have critically explored and discussed the outcome of the latest PD-1 and PD-L1 inhibitor studies in different malignancies compared to standard chemotherapeutic alternatives with a special focus on the clinical efficacy and safety. The approval of the clinical applications of nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab in the last few years clearly highlights the hopeful future of PD-1/PD-L1 inhibitors for cancer patients. These promising results of PD-1/PD-L1 inhibitors have encouraged many ongoing preclinical and clinical trials to explore the extent of antitumor activity, clinical efficacy and safety as well as to extend their applications.

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Behcet’s-like syndrome following pembrolizumab: An immune-related adverse event associated with programmed death receptor-1 inhibitor therapy

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155219877219 ◽

2019 ◽

Vol 26 (4) ◽

pp. 995-999 ◽

Cited By ~ 1

Author(s):

Steffi Thomas ◽

Chay Bae ◽

Tabanor Joy-Ann ◽

William Traverse

Keyword(s):

Adverse Events ◽

Metastatic Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Death Receptor ◽

Programmed Death ◽

Organ Systems ◽

Wide Range ◽

The Right

Introduction The landscape for the treatment of metastatic melanoma has been revolutionized with the introduction immune checkpoint inhibitors. Immune checkpoint inhibitors have now become the standard of care for the treatment of cancers. These immune agents including programmed death receptor-1 inhibitors, programmed death-ligand 1 inhibitors and cytotoxic T-lymphocyte antigen-4 inhibitors have shown promising results but have been associated with numerous immune-related complications. Pembrolizumab, a programmed death receptor-1 inhibitor, has been associated with a number of immune-related adverse events affecting multiple organ systems including integument, ocular, endocrine, cardiovascular, pulmonary, renal, gastrointestinal, and musculoskeletal system. Case report We present a case of an 88-year-old Caucasian male with metastatic melanoma of the face with metastasis to the right fifth cranial nerve and into the right cavernous sinus. He underwent resection of the melanoma and was placed on pembrolizumab at 2 mg/kg every three weeks. Interestingly, 24 months on pembrolizumab therapy, he developed corneal erosions, oral and genital ulcerations. Management and outcome Patient completed his 24 months of pembrolizumab and was started on prednisone and colchicine with improvement in his symptoms. At his follow-up eight months, he had recurrence of an oral ulcer. Discussion Here we present a rare case of an elderly male on pembrolizumab who suffered from corneal erosions, oral and genital ulcers, a syndrome similar to Behcet’s disease. Given that pembrolizumab and other immune checkpoint inhibitors are being utilized in the treatment of cancers, physicians should be aware of the wide range immune-related adverse events including the possible Behcet’s-like syndrome presentation.

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Efficacy and safety of programmed death receptor-1 (PD-1) blockade in metastatic uveal melanoma (UM).

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.9507 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. 9507-9507 ◽

Cited By ~ 5

Author(s):

Katy K. Tsai ◽

Alexander Noor Shoushtari ◽

Rodrigo Ramella Munhoz ◽

Zeynep Eroglu ◽

Josep M. Piulats ◽

...

Keyword(s):

Uveal Melanoma ◽

Death Receptor ◽

Efficacy And Safety ◽

Programmed Death

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Current Trends in Treatment for Acid-Dependent Diseases: Clinical Efficacy and Safety of Rabeprazole

Russian Journal of Gastroenterology Hepatology Coloproctology ◽

10.22416/1382-4376-2021-31-4-55-63 ◽

2021 ◽

Vol 31 (4) ◽

pp. 55-63

Author(s):

O. D. Lopina ◽

B. K. Nurgalieva ◽

T. L. Lapina

Keyword(s):

Clinical Efficacy ◽

Minimal Risk ◽

Efficacy And Safety ◽

System A ◽

Current Trends ◽

Antisecretory Effect ◽

Comparative Review ◽

Wide Range ◽

Pleiotropic Action ◽

H Pylori

Aim. A comparative review of the rabeprazole properties vs. other PPIs, its efficacy and safety in treatment for aciddependent diseases.Key points. Rabeprazole provides a rapid proton pump blockade in parietal cells due to its high dissociation constant (pKa). A lower rabeprazole metabolic dependence on cytochrome P-450 enzyme system renders its antisecretory effect predictable and reduces the risk of interactions with other drugs metabolised through this system. A faster antisecretory effect and higher acid-suppressive activity of rabeprazole determine its better clinical efficacy in treatment for such acid-dependent diseases as gastroesophageal reflux disease and peptic ulcer. This makes rabeprazole (Pariet) a preferred drug in course and maintenance therapies for acid-dependent diseases, as well as in H. pylori eradication.Conclusion. The rabeprazole properties of high acid suppression potential, persistent antisecretory effect from first day of therapy, non-enzymatic metabolism and pleiotropic action determine its high efficacy in treatment for a wide range of acid-dependent diseases at a minimal risk of drug interaction.

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1268P JASPER: Efficacy and safety of first-line (1L) niraparib plus a programmed death receptor 1 inhibitor (PD-1i) in patients with advanced non-small cell lung cancer (NSCLC)

Annals of Oncology ◽

10.1016/j.annonc.2020.08.1582 ◽

2020 ◽

Vol 31 ◽

pp. S819-S820

Author(s):

S.S. Ramalingam ◽

E. Thara ◽

S. Rao ◽

M.M. Awad ◽

A. Dowlati ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Death Receptor ◽

Small Cell ◽

Efficacy And Safety ◽

Small Cell Lung ◽

First Line ◽

Programmed Death

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Comparisons of Underlying Mechanisms, Clinical Efficacy and Safety Between Anti-PD-1 and Anti-PD-L1 Immunotherapy: The State-of-the-Art Review and Future Perspectives

Frontiers in Pharmacology ◽

10.3389/fphar.2021.714483 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yating Zhao ◽

Liu Liu ◽

Liang Weng

Keyword(s):

Clinical Efficacy ◽

Clinical Performance ◽

Underlying Mechanism ◽

Efficacy And Safety ◽

The Past ◽

Real World Evidence ◽

Wide Range ◽

Novel Biomarkers ◽

Cancer Types ◽

Underlying Mechanisms

Over the past decade, diverse PD-1/PD-L1 blockades have demonstrated significant clinical benefit in across a wide range of tumor and cancer types. With the increasing number of PD-1/PD-L1 blockades available in the market, differences between the clinical performance of each of them started to be reported. Here, we provide a comprehensive historical and biological perspective regarding the underlying mechanism and clinical performance of PD-1/PD-L1 blockades, with an emphasis on the comparisons of their clinical efficacy and safety. The real-world evidence indicated that PD-1 blockade may be more effective than the PD-L1, though no significant differences were found as regards to their safety profiles. Future head-to-head studies are warranted for direct comparison between them. Finally, we summarize the yet to be elucidated questions and future promise of anti-PD-1/PD-L1 immunotherapy, including a need to explore novel biomarkers, novel combinatorial strategies, and their clinical use on chronic infection.

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Clinical Efficacy of Hydroxychloroquine or Chloroquine in Patients with COVID-19: An Umbrella Review

Pharmaceutical Sciences ◽

10.34172/ps.2021.66 ◽

2021 ◽

Author(s):

Kavous Shahsavarinia ◽

Morteza Ghojazadeh ◽

Sarvin Sanaie ◽

Leila Vahedi ◽

Mahta Ahmadpour ◽

...

Keyword(s):

Clinical Efficacy ◽

Systematic Reviews ◽

Respiratory Infections ◽

Meta Analysis ◽

The Novel ◽

Efficacy And Safety ◽

Umbrella Review ◽

Wide Range ◽

Novel Coronavirus

Background Many of the known coronaviruses cause a wide range of respiratory infections in humans, and the novel coronavirus is no exception to this rule. Although no drug has yet been discovered to prevent or treat this disease, chloroquine (CQ) and hydroxychloroquine (HCQ) have been widely used in studies showing different results. Methods The present study is an umbrella study. The search was conducted for the articles published from January 2020 to November 2020 using the keywords ("COVID-19" OR "SARS-CoV-2" AND "Hydroxychloroquine" OR "Chloroquine" AND "Systematic Review" OR "Metanalysis"). This study was limited to human samples and systematic reviews with or without meta-analysis. The quality of the articles was also evaluated independently by two researchers. Results To evaluate the clinical efficacy of HCQ and CQ, a total of 176 papers and 643569 cases ranging from patients with mild pneumonia to intubated critically ill patients were evaluated. Finally, 8 studies were included. Conclusion There are conflicting results regarding HCQ or CQ efficacy and safety in the systematic reviews. More evidence is needed to confirm whether these drugs are useful in COVID-19 infection, and their usage as the standard care cannot be recommended based on the majority of the studies included in this umbrella review.

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Results of studying the clinical efficacy and safety of tofacitinib in the treatment of psoriatic arthritis

Modern Rheumatology Journal ◽

10.14412/1996-7012-2019-2-112-118 ◽

2019 ◽

Vol 13 (2) ◽

pp. 112-118 ◽

Cited By ~ 1

Author(s):

T. V. Korotaeva ◽

E. Yu. Loginova

Keyword(s):

Psoriatic Arthritis ◽

Clinical Efficacy ◽

Signal Transmission ◽

Current Data ◽

Life Questionnaire ◽

Inadequate Response ◽

Medical Monitoring ◽

Efficacy And Safety ◽

Tnf Α ◽

Wide Range

The paper reviews of the data available in the literature on the clinical efficacy and safety of tofacitinib (TOFA) in the treatment of psoriatic arthritis (PsA). It considers the mechanism of action of TOFA, which is mainly in the selective inhibition of signal transmission due to its effect on the activity of JAK3 and/or JAK1, the enzymes that ensure the function of turning on and turning off the signals transmitted by cytokines. TOFA is noted to directly or indirectly act on a wide range of a number of molecules that play an important role in the pathogenesis of PsA.The paper analyzes the current data on the clinical efficacy of TOFA in treating PsA, which have been obtained in the 12-month OPAL Broaden study including patients with PsA and an inadequate response to synthetic disease-modifying anti-rheumatic drugs and in the 6-month OPAL Beyond study enrolling those with PsA and an inadequate response to tumor necrosis factor-α (TNF-α) inhibitors. It is noted that the results of these studies confirmed the efficacy of the drug in treating PsA not only according to the data of objective (medical) monitoring, but also to the subjective characteristics of pain, to the global assessment of disease activity, fatigue, as well as the mental and physical components of the SF-36 quality of life questionnaire.It is concluded that the current findings allow JAK inhibitors to be recommended as a new pathogenetically sound approach to treating PsA and suggest that TOFA has benefits in managing patients unresponsive to therapy with TNF-α inhibitors.

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Targeting Tim-3 in Cancer With Resistance to PD-1/PD-L1 Blockade

Frontiers in Oncology ◽

10.3389/fonc.2021.731175 ◽

2021 ◽

Vol 11 ◽

Author(s):

Tian Tian ◽

Zhaoming Li

Keyword(s):

Drug Resistance ◽

Immune Checkpoint ◽

Malignant Tumors ◽

Clinical Success ◽

Death Receptor ◽

Cancer Recurrence ◽

Acquired Drug Resistance ◽

Adaptive Resistance ◽

Programmed Death ◽

Wide Range

Programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) blocking therapy has completely changed the treatment pattern of malignant tumors. It has been tested in a wide range of malignant tumors and achieved clinical success. It might be a promising cancer treatment strategy. However, one of the important disadvantages of PD-1/PD-L1 blocking therapy is that only a few patients have a positive response to it. In addition, primary or acquired drug resistance can also lead to cancer recurrence in patients with clinical response. Therefore, it is very important to overcome the resistance of PD-1/PD-L1 blocking therapy and improve the overall response rate of patients to the immunotherapy. T cell immunoglobulin and mucin domain molecule 3 (Tim-3) belongs to the co-inhibitory receptor family involved in immune checkpoint function. Due to adaptive resistance, the expression of Tim-3 is up-regulated in PD-1/PD-L1 blocking therapy resistant tumors. Therefore, blocking the immune checkpoint Tim-3 might antagonize the resistance of PD-1/PD-L1 blocking therapy. This review systematically introduces the preclinical and clinical data of combined blockade of Tim-3 and PD-1/PD-L1 in cancer immunotherapy, and discusses the prospect of overcoming the drug resistance of PD-1/PD-L1 blockade therapy through blockade of Tim-3.

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