scholarly journals Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer: An Overview on Efficacy and Future Perspectives

Diagnostics ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 146 ◽  
Author(s):  
Fulvio Borella ◽  
Eleonora Ghisoni ◽  
Gaia Giannone ◽  
Stefano Cosma ◽  
Chiara Benedetto ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Therapeutic Approaches ◽  
Medical Treatments ◽  
New Therapeutic Approaches ◽  
Early Phase Trials ◽  
Improve Patient

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological cancers. Despite improvements in medical treatments, the prognosis for EOC remains poor, and there is an urgent need for new therapeutic strategies. Immune checkpoint inhibitors (CPIs) have dramatically improved survival of several cancers and are under evaluation in OC. Unfortunately, CPIs have shown globally unsatisfactory results. The aim of this manuscript is to critically review the results from early-phase trials with CPIs in terms of safety and activity, discuss the possible reasons for disappointing results and the new therapeutic approaches to improve patient outcomes.

scholarly journals Expectations and Challenges of First-Line Maintenance Therapy for Advanced Ovarian Cancer

Medicina ◽  
2021 ◽  
Vol 57 (5) ◽  
pp. 501
Author(s):  
Tadahiro Shoji ◽  
Chie Sato ◽  
Hidetoshi Tomabechi ◽  
Eriko Takatori ◽  
Yoshitaka Kaido ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Checkpoint ◽  
Clinical Studies ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Advanced Ovarian Cancer ◽  
Targeted Drugs ◽  
First Line ◽  
Double Blind ◽  
Platinum Based Chemotherapy

The incidence of ovarian cancer, which has had a poor prognosis, is increasing annually. Currently, the prognosis is expected to improve with the use of molecular-targeted drugs and immune checkpoint inhibitors as maintenance therapies after the first-line chemotherapy. The GOG218 and ICON7 studies reported the usefulness of bevacizumab and the SOLO-1 and PRIMA (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy) studies have reported the usefulness of olaparib and niraparib, respectively. The ATHENA study investigating the usefulness of rucaparib is currently ongoing. Although clinical studies of immune checkpoint inhibitors are lagging in the field of gynecology, many clinical studies using programmed death cell-1 (PD-1) and PD-1 ligand 1 (PD-L1) antibodies are currently ongoing. Some biomarkers have been identified for molecular-targeted drugs, but none have been identified for immune checkpoint inhibitors, which is a challenge that should be addressed in the future.

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 Immune Checkpoint Inhibitors: A New Opportunity in the Treatment of Ovarian Cancer?

2016 ◽  
Vol 17 (7) ◽  
pp. 1169 ◽  
Author(s):  
Gloria Mittica ◽  
Sofia Genta ◽  
Massimo Aglietta ◽  
Giorgio Valabrega
Keyword(s):  
Ovarian Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

scholarly journals Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6180
Author(s):  
Maria Gracia-Hernandez ◽  
Zuleima Munoz ◽  
Alejandro Villagra
Keyword(s):  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Epigenetic Alterations ◽  
Therapeutic Approaches ◽  
Extrinsic Factors ◽  
Epigenetic Drugs ◽  
Epigenetic Modifiers ◽  
Melanoma Patients

Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma’s susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients.

Clinical outcome of sequential chemotherapy after immune checkpoint inhibitors in advanced ovarian cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5580-5580
Author(s):  
Luisa Bonilla ◽  
Amit M. Oza ◽  
Stephanie Lheureux ◽  
Sam Saibil ◽  
Shiyi Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Low Grade

5580 Background: Immunomodulation through check point inhibition is an important treatment strategy in many cancers. In ovarian cancer (OC) response rates with immune checkpoint inhibitors (ICI) alone are around 10%. Chemotherapy antitumoural effect is driven by cytotoxicity and immunomodulatory effect. ICI treatment reduces tumour induced immune-tolerance improving immunocompetence, essential for chemotherapy effect. We chose to investigate clinical outcomes of chemotherapy post ICI in women with OC. Methods: The Tumor Immunotherapy Program (TIP) database at the Princess Margaret Cancer Centre identified patients with OC treated with chemotherapy after ICI from 2011 to 2018. Evaluation of clinical outcomes including response rate (RR), progression free survival (PFS) and overall survival (OS) was assessed for pre ICI, ICI and post ICI. Results: 40 women with OC were treated with chemotherapy after ICI. 90% had high grade serous histology, 7.5% carcinosarcoma and 2.5% low grade serous. Median number of pre ICI treatment lines was 3 (1-8) and 2 (1-6) in the post ICI setting. Median time of ICI initiation from diagnosis was 3 years. At ICI all patients had PS 0-1 and treated in clinical trials. 2% of the patients had platinum refractory disease, 88% had platinum resistant disease and 10% platinum sensitive disease. 50% were treated with ICI single agent, 16% were treated with ICI combined with chemotherapy, 14% ICI combo and 17% ICI in combination with other agents. Patients were treated for a median of 3 cycles (1-26). 8% experienced PR, 18% SD, no CR were seen. 67% of the patients discontinued treatment due to PD, 25% due to toxicity. Last treatment in pre ICI RR was 35%. First treatment in post ICI RR was 30%. RR for each treatment used in post ICI was 9% for liposomal doxorubicin, 25% for single agent platinum, 29% for weekly paclitaxel and 67% for chemotherapy with bevacizumab. Median PFS in the last pre ICI treatment was 6.5m and 5m in the first post ICI treatment. Median PFS and OS for all the population was 53m and 54m respectively. Conclusions: ICI are associated with modest activity in OC, planned clinical trials exploring systematic sequential therapy integrating ICI, targeted agents and chemotherapy are needed.

Emerging role of immune checkpoint inhibitors in the treatment of ovarian cancer

2020 ◽  
Vol 25 (4) ◽  
pp. 445-453 ◽  
Author(s):  
Domenica Lorusso ◽  
Valentina Ceni ◽  
Margherita Muratore ◽  
Vanda Salutari ◽  
Camilla Nero ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

scholarly journals The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Anwaar Saeed ◽  
Robin Park ◽  
Weijing Sun
Keyword(s):  
Immune Checkpoint ◽  
Early Phase ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Gastroesophageal Junction ◽  
Single Agent ◽  
Antiangiogenic Agents ◽  
Targeted Agents ◽  
Early Phase Trials ◽  
Dual Blockade

AbstractSeveral targeted therapies have shown efficacy in patients with advanced gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJC), including anti-angiogenic agents and immune checkpoint inhibitors. Ramucirumab, an anti-VEGFR2 antibody, has shown efficacy in GC, but the benefits are limited, in part due to MET-mediated resistance. Other VEGF targeted agents like VEGF tyrosine kinase inhibitors (TKIs) with broad multi-kinase inhibitory spectrum like regorafenib and cabozantinib have also shown modest single agent activity in early phase trials. For immune checkpoint inhibitors, pembrolizumab (anti-PD-1) monotherapy confers survival advantage as 3rd line therapy for the PD-L1 expressing GC and GEJC population and has been approved for use in this setting. Extensive tumor microenvironment immune modulatory effects from antiangiogenic agents have been demonstrated from preclinical data which support the clinical study rationale of dual blockade of VEGF and immune checkpoint. In addition, FDA has approved combinations of anti-VEGF/VEGFR with anti-PD-1/PD-L1 agents in hepatocellular carcinoma and renal cell carcinoma. Promising clinical activity has been demonstrated in patients with refractory GC/GEJC when treated with dual blockade combination with antiangiogenic agents and immune checkpoint inhibitors like PD-1/PD-L1 inhibitors in several phase I/II trials. This review highlights the trials investigating these novel combinations as well as their preclinical rationale.

scholarly journals Controversies on the possible role of immune checkpoint inhibitors in pediatric cancers: balancing irAEs and efficacy

2021 ◽  
pp. 030089162110102
Author(s):  
Olga Nigro ◽  
Andrea Ferrari ◽  
Michela Casanova ◽  
Daniel Orbach ◽  
Amaury Leruste ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Pediatric Patients ◽  
Checkpoint Inhibitors ◽  
Patients With Cancer ◽  
Pediatric Cancers ◽  
Early Phase Trials ◽  
Younger Age ◽  
Tumor Mutational Burden ◽  
Functional Inactivation

Pediatric cancers are not the equivalent of adult cancers occurring at a younger age and the prospect of immunotherapy in children has not been received with the same enthusiasm as in the adult setting. Although most pediatric malignancies are considered immunologically cold, we are learning more about PD-L1 expression, tumor mutational burden, and microsatellite instability in several pediatric cancers. The side effects of immunotherapy are an important consideration. Immune checkpoint inhibitors (ICIs) engender a unique constellation of inflammatory toxicities known as immune-related adverse events (irAEs). Three early-phase trials—KEYNOTE-051, iMATRIX, and ADVL1412—were the first to describe irAEs in pediatric patients and ICIs were well tolerated. There was concern about unknown late irAEs in pediatric patients, as they have much more time to develop than in adult or elderly patients. Academic clinicians, biopharmaceutical companies, and parents’ advocates concluded that no benefit could be expected from further monotherapy trials employing other ICIs with the same mechanism of action until more scientific knowledge becomes available. On the other hand, ICIs could be useful in combination with other therapies to prevent the functional inactivation of several pathways in the hostile microenvironment. Future clinical studies on ICIs in children need to build on strong biological premises, taking into account the distinctive immunobiology of pediatric cancers vis-à-vis ICI-responsive adult cancers. We need to gain and share experiences of new therapies for managing pediatric patients with cancer, clarifying to what extent we can extrapolate the data obtained in adults.

scholarly journals Pembrolizumab in Combination with Bevacizumab and Oral Cyclophosphamide in Heavily Pretreated Platinum-Resistant Ovarian Cancer

2021 ◽  
Author(s):  
Angeliki Andrikopoulou ◽  
Michalis Liontos ◽  
Efthymia Skafida ◽  
Konstantinos Koutsoukos ◽  
Kleoniki Apostolidou ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Disease Stage ◽  
Oral Cyclophosphamide ◽  
First Line ◽  
Platinum Resistant ◽  
Heavily Pretreated

Abstract Background: Immune checkpoint inhibitors (ICIs) have been widely implemented in the treatment of solid tumors. Although epithelial ovarian carcinoma is considered as scarcely immunogenic, the presence of tumor-infiltrating T lymphocytes (TILs) in the ovarian tumor microenvironment (TME) could increase sensitivity to immune checkpoint inhibitors (ICIs). Combinations of ICIs with chemotherapy, anti-VEGF compounds and PARP inhibitors are under evaluation in ovarian cancer. Recently, a Phase II study evaluated the efficacy of Pembrolizumab in Combination with bevacizumab and oral cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian cancer.Methods: Herein, we present a retrospective study of all patients who received pembrolizumab in combination with bevacizumab and oral cyclophosphamide for recurrent platinum-resistant heavily pretreated ovarian cancer in the Oncology Unit of Alexandra University Hospital.Results: Median age at diagnosis was 54.5 years (SD; 8.9; range: 44–72). All patients were diagnosed with high-grade serous ovarian carcinoma (HGSC). Initial disease stage was FIGO IIIC (8/10; 80%), IIIB (1/10; 10%) and IIC (1/10; 10%)). Patients were heavily pretreated with a median of 6 (range: 4–9) prior lines of systemic therapy. All patients have experienced disease progression on first-line platinum-based chemotherapy and median PFS to first-line treatment was 20.1 months (95%CI; 11.4 – 28.7). Patients received a median of 4 cycles of pembrolizumab in combination with cyclophosphamide and bevacizumab (range 2-11). ORR was 20% (2/10) with two patients achieving partial response (PR) and two patients achieving stable disease (SD) while disease control rate (DCR) was 40% (4/10). Median PFS was 2.7 months (95%; 0.6 – 4.8) and 6-month PFS rate 20%. Conclusions: Though our data reflect a small population, we here demonstrate that the combination of pembrolizumab with bevacizumab and oral cyclophosphamide is an effective alternative in platinum-resistant recurrent ovarian carcinoma. This novel combination provides a promising alternative in heavily pretreated patients that have otherwise limited treatment options.

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