PARP inhibitors and immunotherapy in ovarian and endometrial cancers

2021 ◽  
pp. 20210002
Author(s):  
Rowan Miller ◽  
Amy Lewis ◽  
Melanie E Powell
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Advanced Ovarian Cancer ◽  
Parp Inhibitors ◽  
Platinum Sensitive ◽  
Endometrial Cancers ◽  
Novel Target ◽  
Defective Dna Repair

Advanced ovarian and endometrial cancers have historically been associated with poor prognosis and few treatment options, limited to single or doublet chemotherapy regimens. The introduction of novel target therapies has transformed the management of these cancers. In contrast to chemotherapy, which inhibits DNA replication and mitosis, targeted therapies target cancer signalling pathways, stroma, immune-microenvironment and vasculature in tumours tissues. The most notable advances in gynaecological cancers have come from the introduction of PARP inhibitors and immune checkpoint inhibitors for ovarian and endometrial cancer respectively. Several PARP inhibitors, which target defective DNA repair have been approved as maintenance therapy for advanced ovarian cancer in both the first line and platinum sensitive relapsed settings. Immune checkpoint inhibitors such as anti PD-1/PD-L1 antibodies have proven successful in advanced mismatch repair deficient endometrial cancers with use now being investigated beyond this population. This review will explore the biological rationale and clinical evidence behind the use of PARP inhibitors and immunotherapy in ovarian and endometrial cancers.

scholarly journals Ovarian Cancer in the Era of Immune Checkpoint Inhibitors: State of the Art and Future Perspectives

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4438
Author(s):  
Brigida Anna Maiorano ◽  
Mauro Francesco Pio Maiorano ◽  
Domenica Lorusso ◽  
Evaristo Maiello
Keyword(s):  
Ovarian Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
High Recurrence Rate ◽  
Female Population ◽  
First Choice

Background: Ovarian cancer (OC) represents the eighth most common cancer and the fifth leading cause of cancer-related deaths among the female population. In an advanced setting, chemotherapy represents the first-choice treatment, despite a high recurrence rate. In the last ten years, immunotherapy based on immune checkpoint inhibitors (ICIs) has profoundly modified the therapeutic scenario of many solid tumors. We sought to summarize the main findings regarding the clinical use of ICIs in OC. Methods: We searched PubMed, Embase, and Cochrane Databases, and conference abstracts from international congresses (such as ASCO, ESMO, SGO) for clinical trials, focusing on ICIs both as monotherapy and as combinations in the advanced OC. Results: 20 studies were identified, of which 16 were phase I or II and 4 phase III trials. These trials used ICIs targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, aterolizumab, durvalumab), and CTLA4 (ipilimumab, tremelimumab). There was no reported improvement in survival, and some trials were terminated early due to toxicity or lack of response. Combining ICIs with chemotherapy, anti-VEGF therapy, or PARP inhibitors improved response rates and survival in spite of a worse safety profile. Conclusions: The identification of biomarkers with a predictive role for ICIs’ efficacy is mandatory. Moreover, genomic and immune profiling of OC might lead to better treatment options and facilitate the design of tailored trials.

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.

scholarly journals New drug developments in metastatic gastric cancer

2018 ◽  
Vol 11 ◽  
pp. 175628481880807 ◽  
Author(s):  
Aaron C. Tan ◽  
David L. Chan ◽  
Wasek Faisal ◽  
Nick Pavlakis
Keyword(s):  
Gastric Cancer ◽  
Clinical Trials ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
Metastatic Gastric Cancer ◽  
New Era

Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.

scholarly journals Immune-related adverse events of immune checkpoint inhibitors: a brief review

2018 ◽  
Vol 25 (5) ◽  
Author(s):  
G. Myers
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Health Care Professionals ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Hematologic Malignancies ◽  
T Cell Response ◽  
Proactive Management ◽  
Organ Systems

Immune checkpoint inhibitors (icis) such as inhibitors of ctla-4, PD-1, and PD-L1, given as monotherapy or combination therapy have emerged as effective treatment options for immune-sensitive solid tumours and hematologic malignancies. The benefits of icis can be offset by immune-related adverse events (iraes) that leave all organ systems vulnerable and subsequently increase the risk for morbidity and mortality.Because of fluctuating onset and prolonged duration, the toxicities associated with iraes represent a shift from the understanding of conventional anticancer toxicities. The ctla-4 and PD-1/PD-L1 inhibitors modulate T-cell response differently, resulting in distinct toxicity patterns, toxicity kinetics, and dose–toxicity relationships. Using individualized patient education, screening, and assessment for the early identification of iraes is key to proactive management and is therefore key to improving outcomes and prolonging therapy.Management of iraes is guided by appropriate grading, which sets the stage for the treatment setting (outpatient vs. inpatient), ici treatment course (delay vs. discontinuation), supportive care, corticosteroid use, organ specialist consultation, and additional immunosuppression. Health care professionals in oncology must work collaboratively with emergency and community colleagues to facilitate an understanding of iraes in an effort to optimize seamless care.

Immunotherapy for advanced melanoma: current situation in Japan

2020 ◽  
Vol 51 (1) ◽  
pp. 3-9
Author(s):  
Junji Kato ◽  
Hisashi Uhara
Keyword(s):  
Uveal Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Advanced Melanoma ◽  
Current Evidence ◽  
Clinical Effects ◽  
Durable Response ◽  
Term Survival

Abstract Treatment with immune checkpoint inhibitors provides long-term survival for patients with advanced melanoma. Improvements in the overall survival of advanced melanoma patients have been achieved with anti-PD-1 monotherapy and anti-PD-1+ CTLA4 combination therapy, but there are still many issues to resolve. Acral, mucosal and uveal melanoma have been less responsive to immune checkpoint inhibitors than cutaneous melanoma. For patients who have achieved a good response, it is still not known how long the anti-PD-1 therapy should be administered. Moreover, there is limited treatment for patients who relapse during or after adjuvant anti-PD-1 therapy. Here, we review the current evidence regarding the clinical effects of immunotherapy for advanced melanoma. Moreover, we review previous studies of acral, mucosal and uveal melanoma, and we discuss the recent findings regarding durable response after the cessation of anti-PD-1 therapy, and treatment options for recurrence after adjuvant therapy.

scholarly journals Immunobiology of Thymic Epithelial Tumors: Implications for Immunotherapy with Immune Checkpoint Inhibitors

2020 ◽  
Vol 21 (23) ◽  
pp. 9056
Author(s):  
Valentina Tateo ◽  
Lisa Manuzzi ◽  
Andrea De Giglio ◽  
Claudia Parisi ◽  
Giuseppe Lamberti ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Cancer Biology ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Thymic Epithelial Tumors ◽  
Epithelial Tumors ◽  
New Treatment ◽  
Light Side ◽  
Thoracic Malignancies

Thymic epithelial tumors (TETs) are a group of rare thoracic malignancies, including thymic carcinomas (TC) and thymomas (Tm). Autoimmune paraneoplastic diseases are often observed in TETs, especially Tms. To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options are available for relapsed/refractory TETs. In the last few years, the deepening of knowledge on thymus’ immunobiology and involved altered genetic pathways have laid the foundation for new treatment options in these rare neoplasms. Recently, the immunotherapy revolution has landed in TETs, showing both a dark and light side. Indeed, despite the survival benefit, the occurrence of severe autoimmune treatment-related adverse events has risen crescent uncertainty about the feasibility of immunotherapy in these patients, prone to autoimmunity for their cancer biology. In this review, after summarizing immunobiology and immunopathology of TETs, we discuss available data on immune-checkpoint inhibitors and future perspectives of this therapeutic strategy.

scholarly journals An overview of immune checkpoint inhibitors in breast cancer

2020 ◽  
Vol 1 (6) ◽  
Author(s):  
Federica Miglietta ◽  
Maria Silvia Cona ◽  
Maria Vittoria Dieci ◽  
Valentina Guarneri ◽  
Nicla La Verde
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Novel Treatment ◽  
Near Future ◽  
Triple Negative Subtype

Although breast cancer is not traditionally considered an immunogenic type of tumor, the combination of immunotherapy and chemotherapy has recently emerged as a novel treatment option in triple-negative subtype in the advanced setting and other similar combinations of immune checkpoint inhibitors with chemotherapy are expected to become part of the neoadjuvant management in the near future. In addition, encouraging results have been observed with the combination of immune checkpoint blockade with diverse biological agents, including anti-HER2 agents, CDK 4/6 inhibitors, PARP-inhibitors. The present review summarized the available evidence coming from clinical trials on the role of immune checkpoint inhibitors in the management of breast cancer, both in advanced and early setting.

Gastroenteropancreatic Neuroendocrine Neoplasms (GEP NENs) : The Role of Checkpoint Inhibitors

2022 ◽  
Vol 22 ◽  
Author(s):  
Giulia Arrivi ◽  
Nicola Fazio
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Response Assessment ◽  
Neuroendocrine Neoplasms ◽  
Precision Oncology ◽  
Disease Characteristics

Background: The treatment options for GEP-NENs includes various drugs and is based on grading, morphology and location of the primary Objective: The aim of our work is to investigate the clinical impact of new immune checkpoint inhibitors in order to define a new possible strategy of use within GEP-NENs. Method: A scientific literature search from 2015 to January 2020 was performed by using PubMed and Embase: reviews and prospective or retrospective studies with a minimum of twenty patients were selected; conference proceedings were included Results: several studies have been conducted to assess the role of immune checkpoint inhibitors in NENs, but nowadays the current knowledge in this field is mainly based on a phase I-II studies. Immunotherapy showed limited antitumor activity, but higher response rate was reported in poor-differentiated neuroendocrine tumors. No specific biomarkers were identified for patient selection and response assessment Conclusion: Immunotherapy appears as a powerful possibility to help our patients, but nowadays we see many gaps in this field. We must balance therapeutic possibility offered by precision oncology with the understanding the limitations of application of testing and treatment in clinical practice. Future efforts should focus on research of the best patients to candidate for immunotherapy in term of disease characteristics and previous treatments, and how to select them with accurate biomarkers.

scholarly journals SARS-CoV-2 infection and adverse events in patients with cancer receiving immune checkpoint inhibitors: an observational prospective study

2021 ◽  
Vol 9 (2) ◽  
pp. e001694
Author(s):  
Mario Mandala ◽  
Paul Lorigan ◽  
Matilde De Luca ◽  
Andrea Bianchetti ◽  
Barbara Merelli ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Antigen Expression ◽  
Serious Adverse Events ◽  
Exact Test ◽  
Cancer Subtypes ◽  
Patients With Cancer

BackgroundIn ambulatory patients with cancer with asymptomatic or pauci-symptomatic SARS-CoV-2 infection, the safety of targeted therapies (TTs), chemotherapy (CT) or immune checkpoint inhibitors (ICIs) therapy is still unknown.Material and methodsFrom the start of the first epidemic wave of SARS-CoV-2 in Bergamo, Italy, we have prospectively screened all consecutive outpatients who presented for treatment to the Oncology Division of the Papa Giovanni XXIII Hospital, Bergamo for SARS-CoV-2 antigen expression. We identified patients treated with ICIs and compared these to patients with the same cancer subtypes treated with TTs or CT.ResultsBetween March 5 and May 18, 293 consecutive patients (49% melanoma, 34% non-small cell lung cancer, 9% renal cell carcinoma, 8% other) were included in this study: 159 (54%), 50 (17%) and 84 (29%) received ICIs, CT or TTs, respectively. Overall 89 patients (30.0%) were SARS-CoV-2 positive. Mortality of SARS-CoV-2-positive patients was statistically significantly higher compared with SARS-CoV-2 negative patients (8/89 vs 3/204, respectively, Fisher’s exact test p=0.004). All deaths were due to COVID-19. Serious adverse events (SAEs) were more frequent in SARS-CoV-2-positive patients compared with SARS-CoV-2-negative cases (Cochran-Mantel-Haenszel (CMH) test p=0.0008). The incidence of SAEs in SARS-CoV-2 positive compared with SARS-CoV-2 negative patients was similar in ICI and CT patients (17.3% and 3.7% for positive and negative patients in ICIs and 15.4% and 2.7% in CT, Breslow-Day test p=0.891). No COVID-19-related SAEs were observed in the TTs patients.ConclusionsThe incidence of SAEs was higher for SARS-CoV-2-positive patients treated with ICIs and CT, mostly in advanced disease. No SAEs were observed in patients treated with TTs. SAEs were COVID-19 related rather than treatment related. Treatment with ICIs does not appear to significantly increase risk of SAEs compared with CT. This information should be considered when determining treatment options for patients.

Targeted therapies and checkpoint inhibitors in sarcoma

QJM ◽  
2021 ◽  
Author(s):  
M Vasella ◽  
E Gousopoulos ◽  
M Guidi ◽  
G Storti ◽  
S Y Song ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Suppressor Gene ◽  
Treatment Practice ◽  
Therapeutic Concepts

Abstract Sarcomas are defined as a group of mesenchymal malignancies with over 100 heterogeneous subtypes. As a rare and difficult to diagnose entity, micrometastasis is already present at the time of diagnosis in many cases. Current treatment practice of sarcomas consists mainly of surgery, (neo)adjuvant chemo- and/or radiotherapy. Although the past decade has shown that particular genetic abnormalities can promote the development of sarcomas, such as translocations, gain-of-function mutations, amplifications or tumor suppressor gene losses, these insights have not led to established alternative treatment strategies so far. Novel therapeutic concepts with immunotherapy at its forefront have experienced some remarkable success in different solid tumors while their impact in sarcoma remains limited. In this review, the most common immunotherapy strategies in sarcomas, such as immune checkpoint inhibitors, targeted therapy and cytokine therapy are concisely discussed. The programmed cell death (PD)-1/PD-1L axis and apoptosis-inducing cytokines, such as TNF-related apoptosis-inducing ligand (TRAIL), have not yielded the same success like in other solid tumors. However, in certain sarcoma subtypes, e.g. liposarcoma or undifferentiated pleomorphic sarcoma, encouraging results in some cases when employing immune checkpoint inhibitors in combination with other treatment options were found. Moreover, newer strategies such as the targeted therapy against the ancient cytokine macrophage migration inhibitory factor (MIF) may represent an interesting approach worth investigation in the future.

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