Ovarian Cancer Immunotherapy and Personalized Medicine.
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ABSTRACT:
SUBMITTER: Morand S
PROVIDER: S-EPMC8234871 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Treating cancer according to its molecular alterations (i.e., targeted treatment, TT) is the goal of precision medicine tumor boards (PTBs). Their clinical applicability has been evaluated for ovarian cancer patients in this analysis. METHODS:All consecutive ovarian cancer patients discussed in a PTB at the Medical University of Vienna, Austria, from April 2015 to April 2019 were included (n = 44). RESULTS:In 38/44 (86%) cases, at least one mutation, deletion or amplification was detected. The most frequently altered genes were p53 (64%), PI3K pathway (18%), KRAS (14%), BRCA1 (11%) and BRCA2 (2%). In 31 patients (70%) a TT was recommended. A total of 12/31 patients (39%) received the recommended therapy. Median time from indication for PTB to TT start was 65 days (15-216). Median time to treatment failure was 2.7 months (0.2-13.2). Clinical benefit rate (CBR) was 42%. Reasons for treatment discontinuation were disease progression (42%), poor performance status (PS > 2; 25%), death (17%) or treatment related side effects (8%). In 61% the TT was not administered-mainly due to PS > 2. CONCLUSION:Even though a TT recommendation can be derived frequently, clinical applicability remains limited due to poor patients' general condition after exploitation of standard treatment. However, we observed antitumor activity in a substantial number of heavily pretreated patients.
| S-EPMC7139570 | biostudies-literature
Project description:BackgroundHigh grade serous ovarian cancer (HGSOC) is among the deadliest human cancers and its prognosis remains extremely poor. Tumor heterogeneity and rapid acquisition of resistance to conventional chemotherapeutic approaches strongly contribute to poor outcome of patients. The clinical landscape of HGSOC has been radically transformed since the advent of targeted therapies in the last decade. Nevertheless, the lack of predictive biomarkers informing on the differential clinical benefit in select subgroups, and allowing patient-centric approaches, currently limits the efficacy of these novel therapies. Thus, rational selection of the best possible treatment for each patient represents a clinical priority in order to improve outcome, while limiting undesirable effects.Main bodyIn this review, we describe the state of the art and the unmet needs in HGSOC management, illustrate the treatment options that are available and the biomarkers that are currently employed to orient clinical decisions. We also describe the ongoing clinical trials that are testing new therapeutic approaches for HGSOC. Next, we introduce the organoid technology as a promising, expanding strategy to study cancer and to develop personalized therapeutic approaches. In particular, we discuss recent studies that have characterized the translational potential of Patient's Derived Organoids (PDOs) to inform on drug sensitivity of HGSOC patients.ConclusionsPDOs can predict the response of patients to treatments and may therefore guide therapeutic decisions. Although preliminary results appear encouraging, organoids still need to be generated and expanded efficiently to enable drug screening in a clinically meaningful time window. A new generation of clinical trials based on the organoid technology should guarantee tailored approaches to ovarian cancer management, as it is now clear that the one-size-fits-all approach cannot lead to efficient and meaningful therapeutic advancements.
| S-EPMC8011220 | biostudies-literature
Project description:Over the past decade, patients with advanced non-small-cell lung cancer (NSCLC) have witnessed substantial advances in regards to therapeutic alternatives. Among newly developed agents, angiogenesis inhibitors were extensively tested in different settings and have produced some favorable outcomes despite several shortcomings. Bevacizumab is the most examined agent in this context and has demonstrated significant survival benefits when combined with standard chemotherapy in eligible patients. Preliminary results on the addition of bevacizumab to erlotinib in patients with EGFR-mutated NSCLC seem promising. Other antiangiogenic agents were also tested, but ramucirumab and nintedanib are the only agents with a positive impact on survival. More recently, immune checkpoint inhibitors (ICIs) have had considerable success due to their prolonged durations of response, yet response rates are still deemed suboptimal, and various combination therapies are being tested in an effort to improve efficacy. Preclinical evidence suggests an immunosuppressive effect of pro-angiogenic factors, which sets up a plausible rationale for combining ICIs and antiangiogenic agents. Herein, we review the landmark data supporting the success of angiogenesis inhibitors, and we discuss the potential for combination with immunotherapy and targeted agents.
| S-EPMC5372785 | biostudies-literature
Project description:Cancer immunotherapy has emerged as a novel and effective treatment strategy for several types of cancer. Immune checkpoint inhibitors (ICIs) have recently demonstrated impressive clinical benefit in some advanced cancers. Nonetheless, in the majority of patients, the successful use of ICIs is limited by a low response rate, high treatment cost, and treatment-related toxicity. Therefore, it is necessary to identify predictive and prognostic biomarkers to select the patients who are most likely to benefit from, and respond well to, these therapies. In this review, we summarize the evidence for candidate biomarkers of response to cancer immunotherapy.
| S-EPMC6770350 | biostudies-literature
Project description:Colorectal cancer (CRC) is a very heterogeneous disease that is caused by the interaction of genetic and environmental factors. CRC develops through a gradual accumulation of genetic and epigenetic changes, leading to the transformation of normal colonic mucosa into invasive cancer. CRC is one of the most prevalent and incident cancers worldwide, as well as one of the most deadly. Approximately 1235108 people are diagnosed annually with CRC, and 609051 die from CRC annually. The World Health Organization estimates an increase of 77% in the number of newly diagnosed cases of CRC and an increase of 80% in deaths from CRC by 2030. The incidence of CRC can benefit from different strategies depending on its stage: health promotion through health education campaigns (when the disease is not yet present), the implementation of screening programs (for detection of the disease in its early stages), and the development of nearly personalized treatments according to both patient characteristics (age, sex) and the cancer itself (gene expression). Although there are different strategies for screening and although the number of such strategies is increasing due to the potential of emerging technologies in molecular marker application, not all strategies meet the criteria required for screening tests in population programs; the three most accepted tests are the fecal occult blood test (FOBT), colonoscopy and sigmoidoscopy. FOBT is the most used method for CRC screening worldwide and is also the primary choice in most population-based screening programs in Europe. Due to its non-invasive nature and low cost, it is one of the most accepted techniques by population. CRC is a very heterogeneous disease, and with a few exceptions (APC, p53, KRAS), most of the genes involved in CRC are observed in a small percentage of cases. The design of genetic and epigenetic marker panels that are able to provide maximum coverage in the diagnosis of colorectal neoplasia seems a reasonable strategy. In recent years, the use of DNA, RNA and protein markers in different biological samples has been explored as strategies for CRC diagnosis. Although there is not yet sufficient evidence to recommend the analysis of biomarkers such as DNA, RNA or proteins in the blood or stool, it is likely that given the quick progression of technology tools in molecular biology, increasingly sensitive and less expensive, these tools will gradually be employed in clinical practice and will likely be developed in mass.
| S-EPMC4051918 | biostudies-other
Project description:Ovarian cancer is the most deadly gynecologic malignancy, with more than 15,000 deaths anticipated in 2012. While approximately 80% of patients will respond to frontline chemotherapy, more than 60% of patients will experience disease recurrence and only 44% will be alive at 5 y. Host anti-tumor immune responses are associated with a significant improvement in overall survival for women with ovarian cancer. By bolstering these responses, it may therefore be possible to significantly influence the prognosis of women with this lethal disease. In this review, we will focus on innovative immune-based strategies which are currently being investigated in the treatment of ovarian cancer.
| S-EPMC3579897 | biostudies-literature
Project description:All work referenced herein relates to treatment of epithelial ovarian carcinomas, as their treatment differs from ovarian germ cell cancers and other rare ovarian cancers, the treatments of which are addressed elsewhere. Fallopian tube cancers and primary peritoneal adenocarcinomatosis are also generally treated as epithelial ovarian cancers. The standard of care initial treatment of advanced stage epithelial ovarian cancer is optimal debulking surgery as feasible plus chemotherapy with a platinum plus a taxane agent. If this front-line approach fails, as it too often the case, several FDA-approved agents are available for salvage therapy. However, because no second-line therapy for advanced-stage epithelial ovarian cancer is typically curative, we prefer referral to clinical trials as logistically feasible, even if it means referring patients outside our system. Immune therapy has a sound theoretical basis for treating carcinomas generally, and for treating ovarian cancer in particular. Advances in understanding the immunopathogenic basis of ovarian cancer, and the immunopathologic basis for prior failures of immunotherapy for it and other carcinomas promises to afford novel treatment approaches with potential for significant efficacy, and reduced toxicities compared with cytotoxic agents. Thus, referral to early phase immunotherapy trials for ovarian cancer patients that fail conventional treatment merits consideration.
| S-EPMC4355232 | biostudies-literature
Project description:Immunological destruction of tumors is a multistep, coordinated process that can be modulated or targeted at several critical points to elicit tumor rejection. These steps in the cancer immunity cycle include: (i) generation of sufficient numbers of effector T cells with high avidity recognition of tumor antigens in vivo; (ii) trafficking and infiltration into the tumor; (iii) overcoming inhibitory networks in the tumor microenvironment; (iv) direct recognition of tumor antigens and generation of an effector anti-tumor response; and (v) persistence of the anti-tumor T cells. In an effort to understand whether the immune system plays a role in controlling ovarian cancer, our group and others demonstrated that the presence of tumor infiltrating lymphocytes (TILs) is associated with improved clinical outcome in ovarian cancer patients. Recently, we hypothesized that the quality of infiltrating T cells could also be a critical determinant of outcome in ovarian cancer patients. In the past decade, several immune-based interventions have gained regulatory approval in many solid tumors and hematologic malignancies. These interventions include immune checkpoint blockade, cancer vaccines, and adoptive cell therapy. There are currently no approved immune therapies for ovarian cancer. Immunotherapy in ovarian cancer will have to consider the immune suppressive networks within the ovarian tumor microenvironment; therefore, a major direction is to develop biomarkers that would predict responsiveness to different types of immunotherapies, and allow for treatment selection based on the results. Moreover, such biomarkers would allow rational combination of immunotherapies, while minimizing toxicities. In this review, the current understanding of the host immune response in ovarian cancer patients will be briefly reviewed, progress in immune therapies, and future directions for exploiting immune based strategies for long lasting durable cure.
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Project description:Despite the tremendous potential of peptide-based cancer vaccines, their efficacy has been limited in humans. Recent innovations in tumour exome sequencing have signalled the new era of personalized immunotherapy with patient-specific neoantigens, but a general methodology for stimulating strong CD8α+ cytotoxic T-lymphocyte (CTL) responses remains lacking. Here we demonstrate that high-density lipoprotein-mimicking nanodiscs coupled with antigen (Ag) peptides and adjuvants can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cells. Strikingly, nanodiscs elicited up to 47-fold greater frequencies of neoantigen-specific CTLs than soluble vaccines and even 31-fold greater than perhaps the strongest adjuvant in clinical trials (that is, CpG in Montanide). Moreover, multi-epitope vaccination generated broad-spectrum T-cell responses that potently inhibited tumour growth. Nanodiscs eliminated established MC-38 and B16F10 tumours when combined with anti-PD-1 and anti-CTLA-4 therapy. These findings represent a new powerful approach for cancer immunotherapy and suggest a general strategy for personalized nanomedicine.
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Project description:Despite advances in surgery and chemotherapy, the overall outcomes for patients with advanced ovarian cancer remain poor. Although initial response rates to platinum-based chemotherapy is about 60-80%, most patients will have recurrence and succumb to the disease. However, a DNA repair-directed precision medicine strategy has recently generated real hope in improving survival. The clinical development of PARP inhibitors has transformed lives for many patients with BRCA germline-deficient and/or platinum-sensitive epithelial ovarian cancers. Antiangiogenic agents and intraperitoneal chemotherapy approaches may also improve outcomes in patients. Moreover, evolving immunotherapeutic opportunities could also positively impact patient outcomes. Here we review the current clinical state of PARP inhibitors and other clinically viable targeted approaches in ovarian cancer.
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