scholarly journals Immune-Checkpoint Inhibitors in Platinum-Resistant Ovarian Cancer

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1663
Author(s):  
Alice Indini ◽  
Olga Nigro ◽  
Csongor György Lengyel ◽  
Michele Ghidini ◽  
Angelica Petrillo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Single Agent ◽  
Clinical Trial Data ◽  
Parp Inhibitors ◽  
Platinum Resistance ◽  
Combination Strategies ◽  
Platinum Resistant

Platinum-resistant ovarian cancer (OC) has limited treatment options and is associated with a poor prognosis. There appears to be an overlap between molecular mechanisms responsible for platinum resistance and immunogenicity in OC. Immunotherapy with single agent checkpoint inhibitors has been evaluated in a few clinical trials with disappointing results. This has prompted exploration of immunotherapy combination strategies with chemotherapy, anti-angiogenics, poly (ADP-ribose) polymerase (PARP) inhibitors and other targeted agents. The role of immunotherapy in the treatment of platinum-resistant OC remains undefined. The aim of this review is to describe the immunobiology of OC and likely benefit from immunotherapy, discuss clinical trial data and biomarkers that warrant further exploration, as well as provide an overview of future drug development strategies.

scholarly journals [18F]Fluciclatide PET as a biomarker of response to combination therapy of pazopanib and paclitaxel in platinum-resistant/refractory ovarian cancer

2019 ◽  
Vol 47 (5) ◽  
pp. 1239-1251 ◽  
Author(s):  
Rohini Sharma ◽  
Pablo Oriol Valls ◽  
Marianna Inglese ◽  
Suraiya Dubash ◽  
Michelle Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Combination Therapy ◽  
Single Agent ◽  
Progression Free Survival ◽  
Platinum Resistance ◽  
Open Label ◽  
Intention To Treat ◽  
Resistant Refractory ◽  
Platinum Resistant ◽  
Pet Tracer

Abstract Background Angiogenesis is a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum-resistant/refractory ovarian cancer. Integrins αvβ3 and αvβ5 are both upregulated in tumor-associated vasculature. [18F]Fluciclatide is a novel PET tracer that has high affinity for integrins αvβ3/5, and was used to assess the anti-angiogenic effect of pazopanib. Patients and methods We conducted an open-label, phase Ib study in patients with platinum-resistant/refractory ovarian cancer. Patients received 1 week of single-agent pazopanib (800 mg daily) followed by combination therapy with weekly paclitaxel (80 mg/m2). Following completion of 18 weeks of combination therapy, patients continued with single-agent pazopanib until disease progression. Dynamic [18F]fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities, and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. Results Fourteen patients were included in the intention-to-treat analysis. Complete and partial responses were seen in seven patients (54%). Median progression-free survival (PFS) was 10.63 months, and overall survival (OS) was 18.5 months. Baseline [18F]fluciclatide uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and fibroblast growth factor (FGF) were predictive of greater reduction in SUV60,mean following pazopanib. Kinetic modeling of PET data indicated a reduction in K1 and Ki following pazopanib indicating reduced radioligand delivery and retention. Conclusions Combination therapy followed by maintenance pazopanib is effective and tolerable in platinum-resistant/refractory ovarian cancer. [18F]Fluciclatide-PET uptake parameters predict clinical outcome with pazopanib therapy indicating an anti-angiogenic response.

scholarly journals Immune checkpoint inhibitors in ovarian cancer: where do we stand?

2021 ◽  
Vol 13 ◽  
pp. 175883592110398
Author(s):  
Alexandra Leary ◽  
David Tan ◽  
Jonathan Ledermann
Keyword(s):  
Ovarian Cancer ◽  
Retrospective Studies ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Parp Inhibitors ◽  
Early Results ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Immune Oncology

Numerous retrospective studies have demonstrated that the density of intra-tumoral immune cell infiltration is prognostic in epithelial ovarian cancer (OC). These observations together with reports of programmed death ligand-1 (PD-L1) expression in advanced OC provided the rationale for investigating the benefit of programmed death-1 (PD1) or PD-L1 inhibition in OC. Unfortunately clinical trials to date evaluating PD1/PD-L1 inhibition in patients with relapsed OC have been disappointing. In this review we will discuss early results from single agent PD1/PD-L1 inhibitors and the strategies to enhance benefit from immune-oncology agents in OC, including proposing anti-PD-L1 in combination with other agents (cytotoxics, anti-angiogenics, poly(ADP-ribose) polymerase. (PARP) inhibitors, targeted therapies or other immunotherapies), as well as evaluating these agents earlier in the disease course, or in biomarker selected patients.

Mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian cancer (EOC) patients (pts): Activity and safety analyses in phase I pooled expansion cohorts.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5547-5547 ◽  
Author(s):  
Kathleen N. Moore ◽  
Ursula A. Matulonis ◽  
David M. O'Malley ◽  
Jason A. Konner ◽  
Lainie P. Martin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Folate Receptor ◽  
Single Agent ◽  
Phase Iii ◽  
Platinum Resistance ◽  
Low Grade ◽  
Antibody Drug Conjugate ◽  
Pivotal Phase ◽  
Platinum Resistant

5547 Background: The early clinical evaluation of mirvetuximab soravtansine (IMGN853), an ADC that comprises a FRα-binding antibody linked to the tubulin-disrupting maytansinoid DM4, has revealed encouraging signs of activity in pts with ovarian cancer. A pooled analysis of safety and efficacy was performed including individuals with platinum-resistant EOC, enrolled across three expansion cohorts of an ongoing phase I trial (NCT01609556), who met the eligibility criteria for the pivotal phase III study of IMGN853 (FORWARD I; NCT02631876). Methods: Pts were administered IMGN853 intravenously once every 3 weeks at 6 mg/kg using adjusted ideal body weight dosing. Responses were assessed according to RECIST 1.1 and adverse events (AEs) evaluated by CTCAE v4.0. Results: A total of 37 EOC pts treated as part of the three phase I expansion cohorts (pooled population; n = 113) met the FORWARD I enrollment criteria of moderate to high tumor FRα levels (≥ 50% of cells with ≥ 2+ FRα expression) and 1-3 prior lines of therapy. In this group of pts with platinum-resistant disease, confirmed objective tumor responses were observed in 17 individuals (1 complete response [CR] and 16 partial responses [PR]) for an overall response rate (ORR) of 46% (95% CI, 29.5, 63.1) and a median PFS of 6.7 months (95% CI, 4.1, 9.0). The safety profile of the pooled population was consistent with that previously reported (ASCO Annual Meeting, 2016) with the most common AEs being diarrhea, fatigue, nausea, and blurred vision; these were low grade and readily managed. Conclusions: IMGN853 continues to be characterized by favorable tolerability and encouraging activity in pts with platinum-resistant EOC. In particular, both the ORR (46%) and PFS (6.7 months) achieved in this group of pts are superior to outcomes typically seen with established single-agent chemotherapy within the setting of primary platinum resistance. Overall, these analyses provide continued, robust support for the patient eligibility strategy employed in the phase III evaluation of IMGN853. Clinical trial information: NCT01609556.

[18F] Fluciclatide PET as a biomarker of clinical response to combination therapy of pazopanib and paclitaxel in patients with platinum-resistant or platinum-refractory advanced ovarian cancer: Results of a phase Ib study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3070-3070
Author(s):  
Rohini Sharma ◽  
Pablo Oriol Valls ◽  
Marianna Inglese ◽  
Suraiya Rahim Dubash ◽  
Michelle Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Combination Therapy ◽  
Kinetic Modelling ◽  
Single Agent ◽  
Advanced Ovarian Cancer ◽  
Platinum Resistance ◽  
Phase Ib ◽  
Resistant Refractory ◽  
Platinum Resistant ◽  
Pet Tracer

3070 Background: Angiogenesis has been shown to be a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum resistant/refractory ovarian cancer. Integrins αvβ3 and αvβ5 are both up-regulated in tumour-associated vasculature. [18F]Fluciclatide is a novel PET tracer that has high affinity for integrins αvβ3/5, and was used to assess the anti-angiogenic effect of pazopanib. Methods: We conducted an open-label, phase Ib study in patients with platinum resistant/refractory ovarian cancer. Patients received 1 week of single agent pazopanib (800mg daily) followed by combination therapy with weekly paclitaxel 80mg/m2. Following completion of 18 weeks of therapy, patients continued with single agent pazopanib until disease progression. Dynamic [18F]Fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. Results: Fourteen patients were included in the intention-to-treat analysis. Complete and partial response was seen in 7 patients (54%). Median progression free survival (PFS) was 7.97 months, and overall survival (OS) was 18.5 months. A reduction in [18F]fluciclatide uptake was observed following 1 week of pazopanib, and the reduction in uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and FGF were predictive of greater reduction in SUV60,mean following pazopanib. Kinetic modelling indicated a reduction in K1 and Ki following pazopanib indicating reduced radiotracer delivery and retention. Conclusions: Combination therapy followed by maintenance pazopanib is effective and tolerable in patients with platinum resistant/refractory ovarian cancer. We have shown that [18F]fluciclatide-PET uptake parameters alter with pazopanib therapy indicating an anti-angiogenic response. Clinical trial information: NCT01608009.

scholarly journals Immune Checkpoint Inhibitors in Esophageal Cancers: Are We Finally Finding the Right Path in the Mist?

2020 ◽  
Vol 21 (5) ◽  
pp. 1658
Author(s):  
Caterina Vivaldi ◽  
Silvia Catanese ◽  
Valentina Massa ◽  
Irene Pecora ◽  
Francesca Salani ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Single Agent ◽  
Predictive Biomarkers ◽  
Combination Strategies ◽  
Cancer Review ◽  
The Right

Esophageal cancer remains a challenging disease due to limited treatment options and poor prognosis. In recent years, immune checkpoint inhibitors (ICI) have been proven to be safe and effective in the treatment of highly lethal malignancies, such as non-small cell lung cancer and melanoma. Recent clinical trials also showed promising activity in immune checkpoint inhibitors in pretreated advanced esophageal carcinoma and a potentially significant impact on the outcome of selected patients, independently of histology. Combination studies evaluating immunotherapy and chemotherapy and, in localized disease, radiotherapy are in progress and will hopefully confirm their promises in the near future. However, reliable predictive biomarkers are still lacking. Indeed, at present, the role of programmed cell death ligand 1 expression and other factors (such as microsatellite instability and tumor mutational burden) as predictive biomarkers of benefit to immune checkpoint inhibitors is still controversial. Our aim was to explore the rationale of ICIs in esophageal cancer, review the results already available in multiple settings, and investigate future perspectives with single-agent and combination strategies.

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.

Gemcitabine reverses platinum resistance in platinum-resistant ovarian and peritoneal carcinoma

2005 ◽  
Vol 15 (Suppl 1) ◽  
pp. 18-22 ◽  
Author(s):  
P. G. Rose
Keyword(s):  
Ovarian Cancer ◽  
Excision Repair ◽  
Ovarian Cancer Cell Line ◽  
Single Agent ◽  
Cancer Cell Line ◽  
Platinum Resistance ◽  
Synergistic Activity ◽  
Primary Therapy ◽  
Platinum Sensitive ◽  
Platinum Resistant

Platinum compounds are the key components of chemotherapy for ovarian cancer. Preclinical models in an ovarian cancer cell line (A2780) have demonstrated synergistic activity when gemcitabine is added to cisplatin compared with either single agent alone. Furthermore, the combination leads to increased platinum-adduct retention as a result of decreased DNA repair compared with cisplatin alone. Inhibition of specific exonucleases, such as excision repair cross-complementation group 1 (ERCC1), is integral to the platinum–gemcitabine synergy. In platinum-sensitive recurrent ovarian cancer patients (defined as those patients whose cancer recurs after >6 months following primary therapy), platinum and gemcitabine have demonstrated an improvement in progression-free survival compared with platinum alone. This is also true for the patients who are only moderately platinum sensitive (defined as those patients who have cancer recurring 6–12 months after primary therapy). Increasing numbers of phase II experiences have demonstrated the activity of the platinum–gemcitabine combination in patients defined as platinum resistant (those with disease progression on therapy or whose disease recurs within 6 months of a platinum-based regimen).

scholarly journals Cancer Vaccines for Genitourinary Tumors: Recent Progresses and Future Possibilities

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 623
Author(s):  
Brigida Anna Maiorano ◽  
Giovanni Schinzari ◽  
Davide Ciardiello ◽  
Maria Grazia Rodriquenz ◽  
Antonio Cisternino ◽  
...  
Keyword(s):  
Cancer Vaccines ◽  
Viral Vectors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Tumor Development ◽  
Resistance Mechanisms ◽  
High Morbidity ◽  
Therapeutic Vaccines ◽  
Combination Strategies ◽  
New Treatment

Background: In the last years, many new treatment options have widened the therapeutic scenario of genitourinary malignancies. Immunotherapy has shown efficacy, especially in the urothelial and renal cell carcinomas, with no particular relevance in prostate cancer. However, despite the use of immune checkpoint inhibitors, there is still high morbidity and mortality among these neoplasms. Cancer vaccines represent another way to activate the immune system. We sought to summarize the most recent advances in vaccine therapy for genitourinary malignancies with this review. Methods: We searched PubMed, Embase and Cochrane Database for clinical trials conducted in the last ten years, focusing on cancer vaccines in the prostate, urothelial and renal cancer. Results: Various therapeutic vaccines, including DNA-based, RNA-based, peptide-based, dendritic cells, viral vectors and modified tumor cells, have been demonstrated to induce specific immune responses in a variable percentage of patients. However, these responses rarely corresponded to significant survival improvements. Conclusions: Further preclinical and clinical studies will improve the knowledge about cancer vaccines in genitourinary malignancies to optimize dosage, select targets with a driver role for tumor development and growth, and finally overcome resistance mechanisms. Combination strategies represent possibly more effective and long-lasting treatments.

scholarly journals SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Jing Li ◽  
Ruiqin Wu ◽  
Mingo M. H. Yung ◽  
Jing Sun ◽  
Zhuqing Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Kinase Activity ◽  
Regulatory Mechanism ◽  
Platinum Resistance ◽  
Platinum Drug ◽  
Clinical Prognosis ◽  
Platinum Resistant ◽  
Poor Clinical Prognosis ◽  
Stat Pathway

AbstractThe JAK2/STAT pathway is hyperactivated in many cancers, and such hyperactivation is associated with a poor clinical prognosis and drug resistance. The mechanism regulating JAK2 activity is complex. Although translocation of JAK2 between nucleus and cytoplasm is an important regulatory mechanism, how JAK2 translocation is regulated and what is the physiological function of this translocation remain largely unknown. Here, we found that protease SENP1 directly interacts with and deSUMOylates JAK2, and the deSUMOylation of JAK2 leads to its accumulation at cytoplasm, where JAK2 is activated. Significantly, this novel SENP1/JAK2 axis is activated in platinum-resistant ovarian cancer in a manner dependent on a transcription factor RUNX2 and activated RUNX2/SENP1/JAK2 is critical for platinum-resistance in ovarian cancer. To explore the application of anti-SENP1/JAK2 for treatment of platinum-resistant ovarian cancer, we found SENP1 deficiency or treatment by SENP1 inhibitor Momordin Ic significantly overcomes platinum-resistance of ovarian cancer. Thus, this study not only identifies a novel mechanism regulating JAK2 activity, but also provides with a potential approach to treat platinum-resistant ovarian cancer by targeting SENP1/JAK2 pathway.

scholarly journals Hypermethylation of mismatch repair gene hMSH2 associates with platinum-resistant disease in epithelial ovarian cancer

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Hua Tian ◽  
Li Yan ◽  
Li Xiao-fei ◽  
Sun Hai-yan ◽  
Chen Juan ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Ovarian Cancer ◽  
Dna Methylation ◽  
Epithelial Ovarian Cancer ◽  
Upstream Region ◽  
Platinum Resistance ◽  
Maldi Tof Mass Spectrometry ◽  
Platinum Resistant ◽  
Aberrant Dna Methylation ◽  
Low Expression

Abstract Purpose One major reason of the high mortality of epithelial ovarian cancer (EOC) is due to platinum-based chemotherapy resistance. Aberrant DNA methylation may be a potential mechanism underlying the development of platinum resistance in EOC. The purpose of this study is to discover potential aberrant DNA methylation that contributes to drug resistance. Methods By initially screening of 16 platinum-sensitive/resistant samples from EOC patients with reduced representation bisulfite sequencing (RRBS), the upstream region of the hMSH2 gene was discovered hypermethylated in the platinum-resistant group. The effect of hMSH2 methylation on the cellular response to cisplatin was explored by demethylation and knockdown assays in ovarian cancer cell line A2780. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry was employed to examine the methylation levels of hMSH2 upstream region in additional 40 EOC patient samples. RT-qPCR and IHC assay was used to detect the hMSH2 mRNA and protein expression in extended 150 patients. Results RRBS assay discovered an upstream region from − 1193 to − 1125 of hMSH2 was significant hypermethylated in resistant EOC patients (P = 1.06 × 10−14). In vitro analysis demonstrated that global demethylation increased cisplatin sensitivity along with a higher expression of the hMSH2 mRNA and protein. Knockdown hMSH2 reduced the cell sensitivity to cisplatin. MALDI-TOF mass spectrometry assay validated the strong association of hypermethylation of hMSH2 upstream region with platinum resistance. Spearman’s correlation analysis revealed a significantly negative connection between methylation level of hMSH2 upstream region and its expression. The Kaplan-Meier analyses showed the high methylation of hMSH2 promoter region, and its low expressions are associated with worse survival. In multivariable models, hMSH2 low expression was an independent factor predicting poor outcome (P = 0.03, HR = 1.91, 95%CI = 1.85–2.31). Conclusion The hypermethylation of hMSH2 upstream region is associated with platinum resistant in EOC, and low expression of hMSH2 may be an index for the poor prognosis.

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