Advances in precision treatment of ovarian cancer

Xiao-Dong Wang, Jin-Feng LiuZhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 33010, China. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.

#Xiao-Dong Wang and Jin-Feng Liu are the co-first authors of this paper.

Abstract Ovarian cancer is one of the most common malignant tumors in female reproductive organs. Due to the lack of effective screening and early diagnosis methods, the vast majority of patients with ovarian cancer are in advanced stages once diagnosed. Precision therapy mainly includes immunotherapy, targeted therapy, biological therapy, and gene therapy. At present, precision therapy is increasingly used in the clinical treatment of ovarian cancer due to its advantages, such as fewer side effects and a high degree of killing. This article summarizes the recent advances in the precise treatment of ovarian cancer.

Keywords: Ovarian cancer, Precision therapy, Immunotherapy, Targeted therapy, Biological therapy, Gene therapy

Background

Ovarian cancer is one of the three major malignant tumors in gynecology, and its incidence is third only after cervical cancer and uterine cancer [1]. Although the five-year survival rate of early-stage ovarian cancer is as high as 90%, nearly 75% of clinically diagnosed ovarian cancer patients are already in stage III or IV [2,3]. The current treatment for ovarian cancer is mainly surgery and chemotherapy. Despite continuous improvements in surgical methods and chemotherapy,90% of patients with ovarian cancer will still relapse[4]. Precision treatment is a new medical concept and the medical model proposed in recent years. Precision medicine is based on, but different from individualized medicine. Precision medicine is based on the foundation of big data to establish more rapid and accurate genetic testing methods and propose targeted treatment plans [5]. In recent years, in the precise treatment of ovarian cancer, immunotherapy,biological therapy, targeted therapy, and gene therapy have developed rapidly, and they are more and more used in clinical practice. This article summarizes the recent advances in the precision treatment of ovarian cancer and provides new ideas for the precision of clinical therapy.

Active immunotherapy

Active immunotherapy refers to a method of stimulating the host's immune system by using an anti-cancer vaccine against whole tumor cells or tumor peptides/nucleic acids. Active immunotherapy has long-lasting effects and potential resistant memory induction advantages [6]. At present, active immunotherapy mainly includes dendritic cell (DC)vaccine, autologous tumor vaccine, recombinant tumor vaccine, and molecular vaccine.

Dendritic cell vaccine

DC is a classic antigen-presenting cell. Immature DCs have a strong phagocytosis ability, and mature DCs can produce a large number of cytokines and have strong immunoregulatory functions. DC is currently the most commonly used cellular vaccine for ovarian cancer.DCs were co-cultured with stimulating factors such as granulocyte-macrophage colony-stimulating factor(GM-CSF) and interleukin (IL) 4. At the same time,tumor cells, tumor-specific antigen, a tumor-associated antigen (TAA), and tumor anti-idiotype antibody are incorporated into DCs to obtain mature DCs expressing tumor antigenicity [7].

Studies have shown that in vitro sensitization of DCs with acid-washed peptides from ovarian cancer cells or injection of blood monocyte-derived DCs through human epidermal growth factor receptor 2(HER2) and mucin 1 (MUC-1) peptides are injected into Patients with ovarian cancer. Both of these methods can cause specific cytotoxic T lymphocyte(CTL) to kill tumors against autologous tumor cells [8].In ovarian cancer, MUC-1 is a glycosylated type 1 transmembrane protein that is overexpressed in a large number of diseases. By co-culturing MUC-1 with DC in vitro, the progression-free survival (PFS) and overall survival (OS) of ovarian cancer patients can be increased [9]. Mature DCs in peripheral blood can significantly enhance the proliferation and toxicity of T lymphocytes under the continuous stimulation of heat-shock protein (HSP). In a preliminary clinical trial,the MSLN-Hsp70 protein binds scFv to mesothelin(MSLN). Because the fusion protein localizes DC activation to cancer cells that express MSLN, it can immediately recognize tumor antigens and increase tumor-specific CD8+T cell responses [10].

Autologous tumor vaccine

Autologous tumor vaccine refers to the injection of an inactivated but immunogenic cancer tissue mixed with an adjuvant and then induces a specific immune response mainly composed of CLTs. Inactivated autologous tumor cells are made into autologous tumor cell vaccine, and then mixed with GM-CSF secreting cells for subcutaneous injection can increase the number of CD8+and CTL in peripheral blood and reduce CD4+and CD25+regulatory T cells [11].

Recombinant virus vaccine

Recombinant virus vaccines use genetically modified viruses as vectors to direct DNA encoded by TAA into cells. Since most viruses elicit an immune response,the virus can serve as an antigen delivery system. The immunogenicity of the virus induces the aggregation of immune cells, which is recognized by antigen-presenting cells and induces tumor-specific humoral or cellular immune responses.

PANVAC uses the poxvirus as the carrier, which contains the tumor-associated antigen MUC-1, the transgene of carcinoembryonic antigen, and three human T cell transgenic co-stimulatory molecules(B7-1, intracellular adhesion molecule-1, and leukocyte function related antigen-3) [12]. Cancer testis antigen NY-ESO-1 is a widely recognized target for immunotherapy of ovarian cancer and has been the focus of many cancer vaccine research. Odunsi et al.[13] used vaccinia and fowlpox virus as vectors to inoculate NY-ESO-1 antigen in patients with ovarian cancer, which improved the clinical efficacy. Besides,the ovarian cancer virus vaccine ADVEXIN, also known as Adp53, is a p53-based and MVA-based vaccine [14] and is currently being used in patients with ovarian cancer who are treated with gemcitabine chemotherapy.

Molecular vaccine

Molecular vaccines rely primarily on immune-derived stimuli inoculated into peptides to generate an immune response. Autoantigens such as phosphoprotein,testicular cancer antigen NY-ESO-1, HER2/neu peptide, and Mesothelin can be expressed in large quantities in patients with ovarian cancer [15]. Some of these antigens can prolong T-cell responses as synthetic peptides [16].

A good example is the long overlapping peptide(OLP) derived from NY-ESO-1. When OLP was combined with Montanide and Poly-ICLC as adjuvants,it was administered as a molecular vaccine in 82 ovarian cancer patients. 91% of patients showed both NY-ESO-1 specific CD8+T cells and NY-ESO-specific antibody responses. However, when OLP was inoculated alone, NY-ESO-1-specific CD8+T cells and NY-ESO-1-specific antibody responses were not detected [17]. In addition, when the wild-type p53 epitope peptide with high affinity to HLA-A2.1 becomes an immunogen, the immunogen can specifically anti-tumor curative effect, which can significantly improve the survival time of patients [18].

Passive immunotherapy

Passive immunotherapy is to give the body specific synthetic immune components to induce or enhance the anti-tumor response.

Tumor-associated monoclonal antibody

Unlike normal cells, tumor cells can express or overexpress certain related molecules or receptors.Such molecules or receptors are TAAs. TAAs are involved in the activation of signal transduction pathways that promote the growth or division of cancer cells, stimulate tumor cell growth, and inhibit apoptosis [19]. Therefore, TAAs can be used as a target for monoclonal antibodies in the treatment of ovarian cancer, and promote the targeted killing of ovarian cancer cells by immune cells.

Catumaxomab is a bispecific trifunctional antibody against epithelial adhesion molecules and T cell antigen CD3. This antibody is mainly used to treat patients with chemotherapy-resistant ovarian cancer.And the study found that the quality of life of patients was greatly improved after receiving treatment [20].Farletuzumab is a FRa-specific humanized IgG1 antibody. A clinical study showed that the combination of farletuzumab with carboplatin and paclitaxel increased the objective response rate of patients with platinum-sensitive recurrent ovarian cancer [21].Abagovomab is an anti-idiotype monoclonal antibody that functionally mimics the tumor antigen CA-125 and induces a specific immune response against CA-125, thereby breaking immune tolerance.Unfortunately, although Abagovomab can safely and effectively generate a strong immune response, it does not prolong the PFS or OS [22, 23].

Vascular-associated monoclonal antibody

Tumor microvessel formation is closely related to vascular endothelial growth factor (VEGF). Studies have shown that the binding of VEGF to vascular endothelial growth factor receptor (VEGFR) activates downstream signals of the pathway to promote cell proliferation, division, and the formation of tumor neovascularization [24].

Bevacizumab inhibits epidermal cell proliferation and angiogenesis through binding to vascular endothelial growth factor receptors to achieve anti-tumor effects [25]. Several studies have shown that bevacizumab alone or in combination with chemotherapy drugs for the treatment of ovarian cancer can effectively improve the OS of patients[26-29]. Sorafenib is a non-selective multikinase inhibitor. Sorafenib can not only inhibit tumor neovascularization but also block cell-mediated RAF/MEK/ERK signaling pathways [30]. Sorafenib can inhibit the activity of RAF-1, RAF-2, and serine/tyrosine kinases. At the same time, sorafenib can inhibit VEGFR-2 and VEGFR-3 on the cell membrane surface, as well as platelet-derived growth factor receptor (PDGFR) beta and FMS-like tyrosine kinase 3[31, 32]. Trebananib can target the inhibition of the angiopoietin-Tie-2 complex, and clinical experiments have proven that trebananib can effectively prolong the PFS of patients [33]. Both nintedanib and cediranib can target VEGFR1, VEGFR2, and VEGFR3. Also,nintedanib can also inhibit fibroblast growth factor receptor 1, fibroblast growth factor receptor 2,fibroblast growth factor receptor 3, PDGFRα,PDGFRβ. Both can effectively play a therapeutic role in ovarian cancer [34-36].

Epidermal growth factor receptor inhibitor

Epidermal growth factor receptor (EGFR) is widely distributed in many normal and malignant epithelial cells, and overexpression and self-activation may be related to the occurrence and development of many tumors. At present, more researches focus on two targets, EGFR (HER1/ErbB1) and HER2.

EGFR is overexpressed in 35% to 70% of ovarian cancers. Erlotinib and gefitinib are both anti-EGFR small-molecule tyrosine kinase inhibitors. In addition to inhibiting the intracellular domain of HER and blocking signal transmission, tyrosine kinase inhibitors can also inhibit tumor cell proliferation and promote its apoptosis, as well as increase the efficacy of chemotherapy and radiotherapy. Several studies have shown that these two drugs can increase PFS and OS in patients and relieve platinum resistance in patients with ovarian cancer [37-39]. Pertuzumab is a class of HER2-specific monoclonal antibodies. Adding pertuzumab during treatment can effectively improve patient survival [40].

Polyadenosine diphosphate ribosepolymerase inhibitor

Poly adenosine diphosphate ribose polymerase (PAPR)can make a patient's DNA single-strand break damage impossible to repair, thereby causing DNA double-strand break and losing self-repairing function.Eventually, PARP causes cells to become toxic and die[41, 42]. Currently, PARP inhibitors include olaparib,rucaparib, and niraparib. Lheureux et al. [43] showed that maintenance treatment with olaparib improved PFS in patients with high-grade serous ovarian cancer,especially those with a BRCA1/2 mutation. Coleman et al. [44] found that rucaparib significantly improved the PFS of patients with platinum-sensitive ovarian cancer. Besides, Mirza et al. [45] found that the PFS of patients receiving niraparib was significantly longer than that of patients receiving a placebo.

Gene therapy

Gene therapy refers to inserting a specific gene fragment, nucleic acid substance, or cloned gene into a patient's tumor cells, thereby suppressing, inducing,and killing the tumor cells.

Suicide gene therapy

Suicide gene therapy refers to the introduction of a gene encoding a specific enzyme in tumor cells to cause the tumor to express a specific enzyme locally.This enzyme converts non-toxic prodrugs into highly toxic drugs, and finally kills tumor cells that have introduced the gene and surrounding tumor cells that have not been transfected.

Ganciclovir is a non-toxic nucleoside analog with an antiviral effect. The herpes simplex virus type I thymidine kinase (HSV-TK) gene can block the replication and synthesis of DNA by triphosphorylating ganciclovir. This HSV-TK-mediated effect causes the death of ovarian cancer cells [46, 47]. In addition, researchers have found that HSV-TK gene-mediated cell-killing effects also include bystander effects [48].

Error-correcting gene therapy

Error-correcting gene therapy refers to the way of introducing specific genes into tumor cells to correct the genetic defects of tumor cells and stop their cell cycle. At the same time, it can promote the programmed cell death of tumor cells or be sensitive to radiotherapy and chemotherapy, thereby destroying tumor cells. It mainly includes restorative gene therapy and inactivated gene therapy. Studies have confirmed that IL-1, IL-6, GM-CSF, and tumor necrosis factor-alpha can stimulate the growth of ovarian cancer cells. When ovarian cancer cell lines OC436, CAOV3,and OVCAR3 are implanted with antisense oligonucleotides, tumor cells reduce the secretion of IL-6 and stop proliferating [49].

Immunoenhancement gene therapy

Immunoenhancement gene therapy refers to increasing the level of various cytokines in patients by introducing specific genes into tumor cells, thereby enhancing patients' ability to resist tumors. Cytokines such as IL-2, tumor necrosis factor 2, IL-12,interferon-gamma, and GM-CSF all have effective anti-tumor capabilities. IL-12 can inhibit tumor development by inhibiting tumor angiogenesis and its immune mechanism. Related studies [50] have shown that injecting IL-12 gene-transfected fibroblasts into a mouse model of ovarian cancer by intraperitoneal injection has significantly reduced tumor burden in mice.

Summary

At present, tumor treatment methods are mainly surgical treatment, chemotherapy, and radiotherapy.The side effects and adverse reactions brought about by these treatments are more harmful. Therefore, the current surgical procedure is more inclined to precise treatment with less trauma and high efficiency. At the same time, immunotherapy, biological therapy,targeted therapy, and gene therapy not only bring new hope to tumor treatment but also contribute to the development of precision medicine. Precise treatment reduces the toxic and side effects of the drug on the normal tissues and also increases the drug's stronger lethality to tumor tissues.

In summary, precision therapy is playing an increasingly important role in the treatment of ovarian cancer. Due to the uniqueness of its treatment and its sound effects, it has received attention from various quarters in recent years. If the treatment method is to be applied to clinical practice, continuous research and demonstration are needed.