Barriers to Immunotherapy in Ovarian Cancer: Metabolic, Genomic, and Immune Perturbations in the Tumour Microenvironment

A lack of explicit early clinical signs and effective screening measures mean that ovarian cancer (OC) often presents as advanced, incurable disease. While conventional treatment combines maximal cytoreductive surgery and platinum-based chemotherapy, patients frequently develop chemoresistance and disease recurrence. The clinical application of immune checkpoint blockade (ICB) aims to restore anti-cancer T-cell function in the tumour microenvironment (TME). Disappointingly, even though tumour infiltrating lymphocytes are associated with superior survival in OC, ICB has offered limited therapeutic benefits. Herein, we discuss specific TME features that prevent ICB from reaching its full potential, focussing in particular on the challenges created by immune, genomic and metabolic alterations. We explore both recent and current therapeutic strategies aiming to overcome these hurdles, including the synergistic effect of combination treatments with immune-based strategies and review the status quo of current clinical trials aiming to maximise the success of immunotherapy in OC.

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Strengthening the AntiTumor NK Cell Function for the Treatment of Ovarian Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20040890 ◽

2019 ◽

Vol 20 (4) ◽

pp. 890 ◽

Cited By ~ 12

Author(s):

Marco Greppi ◽

Giovanna Tabellini ◽

Ornella Patrizi ◽

Simona Candiani ◽

Andrea Decensi ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Cells ◽

Cell Function ◽

Nk Cell ◽

Immune Surveillance ◽

Therapy Resistance ◽

Disease Recurrence ◽

Host Cells ◽

Platinum Based Chemotherapy ◽

Immunosuppressive Tumor Microenvironment

The crosstalk between cancer cells and host cells is a crucial prerequisite for tumor growth and progression. The cells from both the innate and adaptive immune systems enter into a perverse relationship with tumor cells to create a tumor-promoting and immunosuppressive tumor microenvironment (TME). Epithelial ovarian cancer (EOC), the most lethal of all gynecological malignancies, is characterized by a unique TME that paves the way to the formation of metastasis and mediates therapy resistance through the deregulation of immune surveillance. A characteristic feature of the ovarian cancer TME is the ascites/peritoneal fluid, a malignancy-associated effusion occurring at more advanced stages, which enables the peritoneal dissemination of tumor cells and the formation of metastasis. The standard therapy for EOC involves a combination of debulking surgery and platinum-based chemotherapy. However, most patients experience disease recurrence. New therapeutic strategies are needed to improve the prognosis of patients with advanced EOC. Harnessing the body’s natural immune defenses against cancer in the form of immunotherapy is emerging as an innovative treatment strategy. NK cells have attracted attention as a promising cancer immunotherapeutic target due to their ability to kill malignant cells and avoid healthy cells. Here, we will discuss the recent advances in the clinical application of NK cell immunotherapy in EOC.

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Adoptive Cell Immunotherapy for Epithelial Ovarian Cancer

10.1093/med/9780190248208.003.0005 ◽

2018 ◽

Author(s):

Samir A. Farghaly

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Residual Disease ◽

Adoptive Cell Therapy ◽

Human Leukocyte ◽

Progression Free Survival ◽

Tumor Infiltrating Lymphocytes ◽

Residual Tumor ◽

Disease Recurrence ◽

Platinum Based Chemotherapy

The standard management for epithelial ovarian cancer (EOC) is a combination of aggressive debulking surgery with residual tumor of less than 1 cm and platinum-based chemotherapy. However, a high percentage of patients experience disease recurrence. Extensive efforts to find new therapeutic options have been made, albeit cancer cells develop drug resistance and malignant progression occurs. Novel therapeutic strategies are needed to enhance progression-free survival and overall survival of patients with advanced EOC. Several preclinical and clinical studies investigated feasibility and efficacy of adoptive cell therapy (ACT) in EOC. The aim of this chapter is to present an overview of ACT in EOC, focusing on Human Leukocyte Antigen (HLA)-restricted tumor infiltrating lymphocytes and MHC-independent immune effectors such as natural killer and cytokine-induced killer. The available data suggest that ACT may provide the best outcome in patients with low tumor burden, minimal residual disease, or maintenance therapy. Further preclinical studies and clinical trials are needed.

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OPSALIN: A phase II placebo-controlled randomized study of ombrabulin in patients with platinum-sensitive recurrent ovarian cancer treated with carboplatin (Cb) and paclitaxel (P).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.tps5112 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. TPS5112-TPS5112

Author(s):

Eric Pujade-Lauraine ◽

Ignace B. Vergote ◽

Aurore Allard ◽

Augustin A. Rey ◽

Cristiana Sessa ◽

...

Keyword(s):

Ovarian Cancer ◽

Phase Ii ◽

Randomized Study ◽

Recurrent Ovarian Cancer ◽

Disease Recurrence ◽

Prior History ◽

Vascular Disrupting Agent ◽

Platinum Sensitive ◽

Platinum Based Chemotherapy

TPS5112 Background: Most women with ovarian cancer have disease recurrence after responding to their first treatment with platinum-based chemotherapy and are considered to have platinum-sensitive disease if the relapse-free period is more than 6 months. Although CbP is standard first-line chemotherapy for ovarian cancer, patients with platinum-sensitive recurrent disease are often retreated with CbP. Ombrabulin (AVE8062) is a vascular disrupting agent and analogue of combretastatin A4 that damages established tumor vasculature causing tumor necrosis and has synergistic antitumor activity with platinum agents in tumor models in vivo (Cancer Sci. 2003;94:200). A phase I study showed that treatment with vivo ombrabulin plus CbP is feasible in patients with advanced solid tumors (NCI-AACR-EORTC 2010;Abs 386). We initiated OPSALIN, a phase II randomized trial, to evaluate whether the addition of ombrabulin to CbP improves outcomes in patients with platinum-sensitive recurrent ovarian cancer (NCT01332656; EFC10260). Methods: Eligibility criteria include age of at least 18 years, ECOG PS 0–2, measurable carcinoma of the ovarian epithelium, fallopian tube, or primary peritoneum that is platinum sensitive, and completion of only one previous line of platinum-based chemotherapy. Exclusion criteria include uncontrolled brain metastases, peripheral neuropathy >grade 1, and a prior history of cardiovascular disease. Patients are being randomized (1:1) to receive either ombrabulin 35mg/m2 or placebo plus CbP every 3 weeks. Assigned treatment will continue until disease progression or death, unacceptable toxicity, or consent withdrawal. The primary endpoint is progression-free survival stratified by the time of first disease recurrence (6–12 months or >12 months). Secondary endpoints include safety, response rate, overall survival, pharmacokinetics, and analysis of predictive/prognostic biomarkers. Planned randomization is a total of 150 patients at approximately 45 sites globally. Sixty-five patients have been randomized as of January 2012.

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A randomized trial in ovarian cancer (OC) of early treatment of relapse based on CA125 level alone versus delayed treatment based on conventional clinical indicators (MRC OV05/EORTC 55955 trials)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.18_suppl.1 ◽

2009 ◽

Vol 27 (18_suppl) ◽

pp. 1-1 ◽

Cited By ~ 40

Author(s):

G. J. Rustin ◽

M. E. van der Burg

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Early Treatment ◽

Clinical Signs ◽

Figo Stage ◽

Primary Outcome Measure ◽

Serum Marker ◽

Significance Level ◽

Platinum Based Chemotherapy

1 Background: Serum CA125 often rises several months before women with OC have symptoms or clinical signs of relapse. OV05/55955 was designed to determine whether there were benefits from early treatment based on a confirmed elevation of CA125 levels versus delaying treatment until clinically indicated. Methods: Women with OC in clinical complete remission after first-line platinum-based chemotherapy and a normal CA125 were registered. CA125 was measured every 3 months but patients and investigators were blinded to the results, which were only monitored by the trials units. If CA125 levels exceeded twice the upper limit of normal, patients were randomized to either immediate treatment or to remain having blinded CA125 measurements with treatment commencing when clinical or symptomatic recurrence appeared. Patients in both arms were treated according to standard local practice. The primary outcome measure was overall survival. The study was designed to detect a 10% improvement in 2-year overall survival in the immediate treatment arm with at least 85% power and 5% significance level (2-sided). Results: 1,442 patients were registered from 59 sites in 10 countries between 1996 and 2005. Randomization closed on March 31, 2008 with 527 patients (264 immediate and 263 delayed) randomized and when the targeted number of events (deaths) were reached. 915 patients have not been randomized due to: no CA125 rise and no relapse (48%); relapse with or without CA125 rise (30%); death (6%); patient withdrawal (14%); or other reasons (2%). For randomized patients baseline characteristics were well balanced between the groups. Median age at registration was 61 years; 81% were FIGO stage III/IV. Second-line chemotherapy started a median of 5 months earlier in the immediate arm. With a median follow-up of 49 months from randomization and a total of 351 deaths, there was no evidence of a difference in overall survival between the immediate and delayed arms, hazard ratio 1.01, 95% CI 0.82–1.25, p = 0.91. Conclusions: There is no survival benefit from early treatment based on a raised serum marker level alone, and therefore no value in the routine measurement of CA125 in the follow-up of ovarian cancer patients. No significant financial relationships to disclose.

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Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model

Cancers ◽

10.3390/cancers12061645 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1645

Author(s):

Brittney S. Harrington ◽

Michelle K. Ozaki ◽

Michael W. Caminear ◽

Lidia F. Hernandez ◽

Elizabeth Jordan ◽

...

Keyword(s):

Oxidative Stress ◽

Ovarian Cancer ◽

Drug Metabolism ◽

Disease Recurrence ◽

Adherent Cells ◽

Sequencing Analysis ◽

Post Surgery ◽

Platinum Based Chemotherapy

Disease recurrence is the major cause of morbidity and mortality of ovarian cancer (OC). In terms of maintenance therapies after platinum-based chemotherapy, PARP inhibitors significantly improve the overall survival of patients with BRCA mutations but is of little benefit to patients without homologous recombination deficiency (HRD). The stem-like tumor-initiating cell (TIC) population within OC tumors are thought to contribute to disease recurrence and chemoresistance. Therefore, there is a need to identify drugs that target TICs to prevent relapse in OC without HRD. RNA sequencing analysis of OC cells grown in TIC conditions revealed a strong enrichment of genes involved in drug metabolism, oxidative phosphorylation and reactive oxygen species (ROS) pathways. Concurrently, a high-throughput drug screen identified drugs that showed efficacy against OC cells grown as TICs compared to adherent cells. Four drugs were chosen that affected drug metabolism and ROS response: disulfiram, bardoxolone methyl, elesclomol and salinomycin. The drugs were tested in vitro for effects on viability, sphere formation and markers of stemness CD133 and ALDH in TICs compared to adherent cells. The compounds promoted ROS accumulation and oxidative stress and disulfiram, elesclomol and salinomycin increased cell death following carboplatin treatment compared to carboplatin alone. Disulfiram and salinomycin were effective in a post-surgery, post-chemotherapy OC relapse model in vivo, demonstrating that enhancing oxidative stress in TICs can prevent OC recurrence.

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Treatment Strategies for ARID1A-Deficient Ovarian Clear Cell Carcinoma

Cancers ◽

10.3390/cancers13081769 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1769

Author(s):

Kazuaki Takahashi ◽

Masataka Takenaka ◽

Aikou Okamoto ◽

David D. L. Bowtell ◽

Takashi Kohno

Keyword(s):

Ovarian Cancer ◽

Cell Carcinoma ◽

Clear Cell ◽

Clear Cell Carcinoma ◽

Immune Checkpoint Blockade ◽

Serous Carcinoma ◽

Histological Subtype ◽

Ovarian Clear Cell Carcinoma ◽

Chemotherapeutic Regimen ◽

Platinum Based Chemotherapy

Ovarian clear cell carcinoma (OCCC) is a histological subtype of ovarian cancer that is more frequent in Asian countries (~25% of ovarian cancers) than in US/European countries (less than 10%). OCCC is refractory to conventional platinum-based chemotherapy, which is effective against high-grade serous carcinoma (HGSC), a major histological subtype of ovarian cancer. Notably, deleterious mutations in SWI/SNF chromatin remodeling genes, such as ARID1A, are common in OCCC but rare in HGSC. Because this complex regulates multiple cellular processes, including transcription and DNA repair, molecularly targeted therapies that exploit the consequences of SWI/SNF deficiency may have clinical efficacy against OCCC. Three such strategies have been proposed to date: prioritizing a gemcitabine-based chemotherapeutic regimen, synthetic lethal therapy targeting vulnerabilities conferred by SWI/SNF deficiency, and immune checkpoint blockade therapy that exploits the high mutational burden of ARID1A-deficient tumor. Thus, ARID1A deficiency has potential as a biomarker for precision medicine of ovarian cancer.

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Understanding the Effects of Radiotherapy on the Tumour Immune Microenvironment to Identify Potential Prognostic and Predictive Biomarkers of Radiotherapy Response

Cancers ◽

10.3390/cancers12102835 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2835

Author(s):

Shuhui Cheng ◽

Eleanor J. Cheadle ◽

Timothy M. Illidge

Keyword(s):

Clinical Decision Making ◽

Single Agent ◽

Predictive Biomarkers ◽

Clinical Decision ◽

Tumour Microenvironment ◽

Immune Checkpoint Blockade ◽

Rational Approach ◽

Immunomodulatory Effects ◽

Combination Treatments ◽

Immunological Effects

Radiotherapy (RT) is a highly effective anti-cancer treatment. Immunotherapy using immune checkpoint blockade (ICI) has emerged as a new and robust pillar in cancer therapy; however, the response rate to single agent ICI is low whilst toxicity remains. Radiotherapy has been shown to have local and systemic immunomodulatory effects. Therefore, combining RT and immunotherapy is a rational approach to enhance anti-tumour immune responses. However, the immunomodulatory effects of RT can be both immunostimulatory or immunosuppressive and may be different across different tumour types and patients. Therefore, there is an urgent medical need to establish biomarkers to guide clinical decision making in predicting responses or in patient selection for RT-based combination treatments. In this review, we summarize the immunological effects of RT on the tumour microenvironment and emerging biomarkers to help better understand the implications of these immunological changes, and we provide new insights into the potential for combination therapies with RT and immunotherapy.

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Does Time-to-Chemotherapy Impact the Outcomes of Resected Ovarian Cancer? Meta-analysis of Randomized and Observational Data

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000923 ◽

2017 ◽

Vol 27 (2) ◽

pp. 274-280 ◽

Cited By ~ 6

Author(s):

Pedro Luiz Serrano Usón ◽

Diogo Diniz Gomes Bugano ◽

Monique Sedlmaier França ◽

Yuri Philippe Pimentel Vieira Antunes ◽

Patricia Taranto ◽

...

Keyword(s):

Ovarian Cancer ◽

Confidence Interval ◽

Odds Ratio ◽

Meta Analysis ◽

Disease Recurrence ◽

Curative Intent ◽

Platinum Based Chemotherapy ◽

Definition Of ◽

Optimal Debulking ◽

The Impact

ObjectivesThis study is a meta-analysis of prior publications evaluating the impact of time-to-chemotherapy (TTC) on disease recurrence and survival 3 years after the original surgery.MethodsWe performed a meta-analysis of studies published in PubMed (1950–2016) as of April 2016. Inclusion criteria were as follows: randomized controlled trials and prospective or retrospective cohorts that included patients with ovarian cancer who had undergone surgery with curative intent and use of adjuvant chemotherapy. We compared rates of disease recurrence and death according to the TTC (“early” vs “delayed”) using a random-effects model and performed a metaregression to evaluate the impact of covariates on these outcomes.ResultsOf 239 abstracts in the original search, 12 were considered eligible. The cutoffs used for TTC were between 20 and 40 days. All studies used a platinum-based chemotherapy, and the rates of patients with suboptimal resection varied from 33% to 70%. A longer TTC was not associated with higher rates of disease recurrence (odds ratio, 0.89; 95% confidence interval, 0.63–1.24) or death at 3 years (odds ratio, 1.06; 95% confidence interval, 0.9–1.24). There was no evidence of significant publication bias (Egger test P = 0.472), but data were heterogeneous (I2 = 64.3%). Metaregression showed that the percentage of patients with suboptimal surgery and values used as cutoff to define “delayed” chemotherapy combined were a significant source of bias (residual I2 = 0%).ConclusionsIn our analysis, TTC after surgery for ovarian cancer with curative intent was not associated with higher risk of disease recurrence or death. However, this association was influenced by the rate of optimal debulking and definition of “late” initiation of chemotherapy, so we must be careful when applying these data to patients with complete resection.

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The future of immune checkpoint combinations with tumor-targeted small molecule drugs

Emerging Topics in Life Sciences ◽

10.1042/etls20210064 ◽

2021 ◽

Author(s):

Jaclyn Sceneay ◽

Charles Sinclair

Keyword(s):

Signaling Pathways ◽

Immune Checkpoint ◽

Cell Function ◽

Immune Cell ◽

Immune Escape ◽

Acquired Resistance ◽

Immune Checkpoint Blockade ◽

Tumor Evolution ◽

Full Potential ◽

Precision Oncology

Immune-checkpoint blockade (ICB) has transformed the landscape of cancer treatment. However, there is much to understand around refractory or acquired resistance in patients in order to utilize ICB therapy to its full potential. In this perspective article, we discuss the opportunities and challenges that are emerging as our understanding of immuno-oncology resistance matures. Firstly, there has been remarkable progress made to understand the exquisite overlap between oncogenic and immune signaling pathways. Several cancer-signaling pathways are constitutively active in oncogenic settings and also play physiological roles in immune cell function. A growing number of precision oncology tumor-targeted drugs show remarkable immunogenic properties that might be harnessed with rational combination strategies. Secondly, we now understand that the immune system confers a strong selective pressure on tumors. Whilst this pressure can lead to novel tumor evolution and immune escape, there is a growing recognition of tumor-intrinsic dependencies that arise in immune pressured environments. Such dependencies provide a roadmap for novel tumor-intrinsic drug targets to alleviate ICB resistance. We anticipate that rational combinations with existing oncology drugs and a next wave of tumor-intrinsic drugs that specifically target immunological resistance will represent the next frontier of therapeutic opportunity.

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