Immunotherapy in in Ovarian Cancer: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Hyunho Yoon
,
Ayoung Kim
,
Hoon Jang

Ovarian cancer (OC) is gynecological cancer, and diagnosis and treatment are continuously advancing. Next-generation sequencing (NGS)-based diagnoses have emerged as novel methods for identifying molecules and pathways in cancer research. The NGS-based applications have expanded in OC research for early detection and identification of aberrant genes and dysregulation pathways, demonstrating comprehensive views of the entire transcriptome, such as fusion genes, genetic mutations, and gene expression profiling. Coinciding with advances in NGS-based diagnosis, treatment strategies for OC, such as molecular targeted therapy and immunotherapy, have also advanced. Immunotherapy is effective against many other cancers, and its efficacy against OC has also been demonstrated at the clinical phase.

  • next-generation sequencing
  • ovarian cancer
  • immunotherapy

1. Introduction

Gynecological cancer is a type of cancer that occurs in female reproductive organs, such as the vulva, vagina, cervix, uterus, fallopian tubes, and ovaries, that is related to the secretion of sex hormones [1]. Ovarian cancer (OC) is the eighth most common cancer in women, with a 5-year survival rate of approximately 45% [2][3]. The incidence of OC is approximately 10% that of breast cancer. OC can be classified into several histological types, characterized by cancer risk factors, clinical features, and molecular expression [4], and they include high-grade serous carcinoma (HGSC), endometrioid carcinoma of the ovary (ECO), clear cell carcinoma (CCC), mucinous carcinoma (MC), and low-grade serous carcinoma (LGSC) [5]. LGSC is associated with serous borderline tumor mutations in KRAS and BRAF. In contrast, HGSCs are not associated with serous borderline tumor mutations and have TP53 and BRCA mutations [6][7]. As these OC types are distinct diseases, diagnosis or treatment requires methodological approaches, suggesting that histopathological diagnosis of reproducible tumor cell types is critical for the successful treatment of OC.
In general, OC that has progressed to the advanced stage of a malignant tumor shows intractability, relapse, and drug resistance, resulting in poor prognosis with conventional treatment. The first-line standard care of patients with OC is surgery with platinum-based agent-based chemotherapy [8]. The combination of taxane compounds, such as paclitaxel, and platinum-based agents, such as carboplatin, is mainly adopted as first-line chemotherapy in OC [9]. However, in most patients who receive first-line treatment, OC relapses within several years [10][11]. More than 25% of patients with relapse have a poor prognosis due to a platinum-resistant or platinum-refractory disease [12][13]. Although outcomes and response rates are low, platinum-resistant patients are treated with non-platinum agents, such as liposomal doxorubicin, melphalan, paclitaxel, gemcitabine, and topotecan [1][14][15]. With an increasing understanding of cancer progression mechanisms, targeted therapies are emerging as innovative and promising therapeutic strategies. Therefore, antiangiogenic molecules, immune checkpoint inhibitors, poly ADP-ribose polymerase (PARP) inhibitors, estrogen receptor inhibitors, and various inhibitors of intrinsic tumor signaling pathways are being used as potential therapeutic agents for OC patients [1].
In particular, PARP inhibitors, such as olaparib or niraparib, have been mainly used in OC patients with BRCA mutations [16][17][18][19], and new chemotherapy, that induces drug combinations, is constantly being developed. PARP inhibitors play a key role in the maintenance of therapy for recurrent OC and primary HGSC [20]. A study has demonstrated that PARP inhibitors remarkably extend progression-free survival (PFS) after response to platinum-based chemotherapy [21]. However, relapse after first-line treatment and toxicity of chemotherapeutic agents are still high, so it is necessary to find an effective and safe treatment method that reduces side effects.
Recent studies have shown that next-generation sequencing (NGS)-based approaches provide a rationale for sequence-matching therapies to improve the overall drug response and survival rates in cancer patients [22]. The genetic landscape of cancer patients, including mutational status and gene expression patterns, may provide new druggable targets and pathways, leading to a clinical advantage for cancer patients [23][24][25]. Thus, a variety of NGS-based applications, such as whole transcriptome sequencing (RNA-seq) and assays for transposase-accessible chromatin sequencing (scATAC-seq), have been used to investigate the detailed genetic landscape of OC. These efforts not only provide detailed information for the understanding of the genetic variation of OC but also form the basis for immunotherapy, a new therapeutic strategy for the treatment of OC.

2. Immunotherapy in OC

In cancer research, immunotherapy enhances the immune response such that the patient’s immune cells can kill cancer cells. It is effective against several tumors and has innovative therapeutic potential to replace chemotherapy as the next-generation treatment for gynecological cancers [26]. Immunotherapy can be categorized into active and passive types. Active immunotherapy directly targets specific cancer antigens, and this involves treatment with immunostimulatory vaccines, genetically modified to recognize target antigens or chimeric antigen receptor T cells (CAR-T). Passive immunotherapy involves treatment with cytokines or checkpoint inhibitors, which indirectly activate a patient’s immune response [27]. These treatments are innovative, but according to the results of clinical trials, only some cancers can be treated, and side effects, such as cytokine syndrome and decreased immune function, can occur [26][28].

2.1. Immune-Stimulating Peptide Vaccines

Vaccine-mediated immunostimulatory therapy involves the use of a specific antigenic vaccine of the tumor, which is an immunotherapeutic agent that suppresses tumor growth or cancer recurrence by inducing an immune response [29][30]. Peptide vaccines consist of DNA vectors expressing dendritic cells, recognized by autologous tumor-specific antigens or tumor-specific peptides that induce immune activation, and the activity of which can be enhanced by various immune modulators [31][32].

2.1.1. P53 Peptide Vaccine

The most common mutant gene in human cancers is p53, with nearly 50% of OCs having p53 mutations [33]. Because p53 mutations mainly increase the expression and stability of the p53 protein, the amount of p53 in cancer cells is higher than that in normal cells [34]. Therefore, a p53 peptide vaccine could be a targeted therapeutic strategy for various cancer cells. It has been reported that p53-synthetic long peptide (p53-SLP) vaccine treatment in OC patients significantly induced p53-SLP-specific T-cell responses [35]. In addition, low-dose cyclophosphamide pre-treatment in patients with recurrent OC improved the immunogenicity of the p53-SLP vaccine, by enhancing the activity of regulatory T cells [36]. In a clinical study on platinum-resistant OC, p53 vaccine and gemcitabine significantly increased the reactivity of T cells, leading to better survival [37]. Recently, studies on the combination of various immunomodulators and p53 vaccines have been conducted to improve biochemical sensitivity and immune responses [38][39].

2.1.2. Wilms’ Tumor 1 (WT1) Peptide Vaccine

WT1 is often detected in various cancers, including leukemia, lung cancer, breast cancer, thyroid cancer, melanoma cancer, and OC [40]. Mouse and human WT1 genes have high homology, and hence, a murine model was used for WT1 vaccine development [40]. After confirming that the WT1 vaccine inhibited the growth of cancer cells by inducing a strong immune response, a WT1 vaccine using serum from cancer patients was evaluated for the first time [40]. HLA-A*24:02-restricted WT1-targeting vaccine promoted peptide-specific humoral immunity in refractory OC patients; therefore, WT1 levels can be used as a potential prognostic marker [41].

2.1.3. New York Esophageal Squamous Cell Carcinoma-1 (NYESO-1) Peptide Vaccine

NYESO-1 is a marker expressed in various cancer cells, including OC, and it is a significant target for vaccines [42]. Vaccine-mediated CD4+ and CD8+ T-cell responses, and the application of NY-ESO-1+ lymphocytes, have been reported [43]. The modified NY-ESO-1 vaccine rapidly induced a consistent and safe immune response in most vaccinated OC patients [44]. A recent study reported that the NYESO1 vaccine linked to the secretin-penetratin peptide induced a stronger and more specific T-cell immune response in a mouse animal model [45].

2.1.4. Glypican-3 (GPC3)-Derived Peptide Vaccine

GPC3, a heparan sulfate proteoglycan bound to the cell membrane by glycosylphosphatidylinositol, is specifically expressed in liver cancer, OC, lung cancer, and melanoma [46][47]. A recent report showed that the GPC3 vaccine improved the survival rate of chemoresistant OCs after chemotherapy [48]. In addition, it has been reported that adjuvant miRNA enhances the effect of GPC3 vaccine, and that the combination of miR-375, 193a, and 1128 can be used as predictive biomarkers [49]. The GPC3 vaccine was used in combination with CAR-T therapy, to significantly enhance the therapeutic effect against OC, suggesting that the GPC3 vaccine could be used in combination with several cancer treatments in the future [50].

2.1.5. Dendritic Cell (DC)-Based Peptide Vaccine

DCs are antigen-presenting cells of the immune system and are widely recognized as important cell types that can initiate antitumor responses [51]. DC-based vaccines are a novel strategy for effectively treating cancer patients, and hence, various clinical studies have been conducted using DC-related responses in cancer patients. Correll et al. reported that a DC vaccine could inhibit the activity of regulatory T cells in the blood of melanoma patients, and subsequently restore T-cell activity [52]. As a result of these observations, DC vaccines were evaluated in several carcinomas. Autologous DC-based vaccines with tumor lysates after chemotherapy in OC patients have also been reported to successfully reduce the rate of cancer progression and improve survival [53]. In addition, DC vaccines related to neoantigen peptides are being developed as clinical candidates for immune enhancement [54]. DC-based vaccines have great potential to improve the treatment of OC patients, and the advantage of using the immune system to induce a more sustained response, compared with that during cytotoxic chemotherapy [55]. However, further clinical studies of a cohort of patients with OC using DC vaccines are needed to confirm its safety and efficacy.

2.2. Blockade of Checkpoint

Checkpoint inhibitors are widely used to treat refractory tumors, including OC. Immune checkpoints are generally regulated by negative feedback inhibition, and they protect the host from autoimmunity and maintain self-tolerance by regulating the responses of various immune cells [56][57]. When activated T-cells recognize and bind to specific markers of tumor cells, immune checkpoints rapidly regulate the immune response through the T-cell receptor (TCR) signaling pathway [58].

2.2.1. Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) Inhibitor

CTLA-4 inhibitors are widely used as immune checkpoint blockers to induce an immune response. PHI-101, a checkpoint kinase 2 inhibitor, showed a tumor-reducing effect on platinum-resistant, recurrent OC [59]. PHI-101 therapy was assessed in a phase IA clinical trial, and a phase II clinical trial has been recommended for the same. Ipilimumab, under the trade name Yervoy, is a CTLA-4 antibody generally used in the treatment of various cancers [60]. However, the anti-CTLA-4 antibodies need improvement, because immunotoxicity has often been reported in the liver, gastrointestinal tract, and endocrine system within the first few weeks of treatment [61].

2.2.2. Programed Cell Death Protein 1 (PD-1) and Programed Cell Death-Ligand 1 (PD-L1) Inhibitors

PD-1, a co-inhibitory receptor, inhibits T-cell activation, suggesting that it is a target for immunotherapy in cancer cells. PD-1 has two types of potential ligands: PD-L1 and PD-L2. PD-L1 is mainly expressed in most hematopoietic cells and vascular endothelial cells, whereas PD-L2 is expressed in some macrophages and dendritic cells [62]. PD-L1 is generally found in various malignancies, including OC [63][64]. PD-1–PD-L1 interaction normally inhibits the survival, proliferation, and functions of T cells [65]. Blocking the interaction of PD-1 with PD-L1 is widely used clinically for the treatment of tumors, and this strategy is less toxic than the use of CTLA-4 inhibitors, such as ipilimumab [66].
Pembrolizumab, also known as Keytruda, is a PD-1 inhibitor, and it has been effective in patients with recurrent OC [67][68]. A recent study showed that the combination of pembrolizumab and PEGylated liposomal doxorubicin has a potential therapeutic effect on platinum-resistant OC [69]. The combination of pembrolizumab with bevacizumab dramatically decreased the serum CA-125 level and regression of recurrent masses, with no marked side effects [70].
Nivolumab, under the trade name Opdivo, is a human monoclonal antibody approved for the treatment of several malignancies; it enhanced the anticancer activity of T cells by blocking the PD-1 and PD-L1/L2 pathways [63][71][72]. Monotherapy with nivolumab exhibited low tumor specificity and response in platinum-resistant OC [71]. Co-administration of nivolumab with various adjuvants has shown optimistic trends in the treatment of various cancers, including OC. In addition, the combination of nivolumab with the anti-CTLA4 antibody, ipilimumab, has been reported to improve the overall response to OC [73].
Atezolizumab (tecentriq; MPDL3280A) is an immunoglobulin mAb, that selectively interacts with PD-L1 in cancer cells, in the tumor microenvironment, and reactivates suppressed T cells to kill malignant tumors [74]. As PD-L1 expression is highly detectable in OC specimens, atezolizumab has been attracting attention as a potential immunotherapeutic agent. In addition, a combination of atezolizumab and other immunotherapeutic agents showed preliminary clinical activity in patients with OC [75]. For example, the combination of atezolizumab and bevacizumab induces a sustained response in some patients with platinum-resistant OC [76].
Abelumab, a monoclonal antibody capable of mediating antibody-dependent cytotoxicity, is a checkpoint inhibitor that interacts with PD-L1, especially when administered in combination with chemotherapeutic agents [77][78]. Several clinical studies have shown that avelumab monotherapy is effective in Merkel cell carcinoma (MCC) and urothelial cancer [79]. In addition, it has been reported that combination therapy with avelumab and axitinib increased the survival rate of urothelial cancer patients and showed significant activity when combined with docetaxel [79]. Several combination strategies have recently been evaluated, and further studies are underway to improve the response rate of avelumab in patients with OC [80][81][82].

2.3. Chimeric Antigen Receptor T (CAR-T) Cells

CAR-T cells are genetically modified patient-derived immune cells designed to activate the immune response by recognizing specific surface antigens on cancer cells. The inhibition of histone deacetylase (HDAC) activity plays an important role in CAR-T cell immune recognition. Co-treatment with sodium valproate (VPA), a representative HDAC inhibitor, and CAR-T enhanced the immune recognition of CAR-T cells in OC [83]. The identification of specific antigens overexpressed in cancer cells is an important strategy in CAR-T therapy. The most common target antigens for CAR-T in OC are mesothelin, mucin 16 (MUC16), folate receptor α, and human epidermal growth factor receptor 2 (HER2) [84].
Mesothelin is a new antigen that can be a target of CAR-T and is overexpressed in various cancers, including OC. However, it is also expressed in some normal tissues and has the disadvantage of causing off-target effects [85]. Mouse studies have shown that treatment with mesothelin-induced CAR-T cells is a potential therapy for OC. It was able to significantly prolong the survival of mice with OC [86].
Mucine 16 (MUC16), a glycoprotein of the mucin family, is expressed in various tumor cells and is involved in the proliferation and metastasis of cancer cells [87]. MUC16 is strongly expressed in most OCs and known well as a tumor marker (CA125), because it is cleaved and released from peripheral blood, suggesting that MUC16 is an ideal antigenic target for CAR-T. It has been reported that PD1-anti-MUC16 CAR-T cells have more potent anticancer activity than single MUC16-CAR-T cells in OC animal models [88][89]. The clinical application of MUC16 is still lacking due to several limitations, but immunotherapeutic studies using CAR-T cell construction are ongoing [90].
Folate receptor-α (FRα) protein is expressed at low levels in normal cells, specifically in OC [91]. T-cell activation using CAR targeting with FRα has been evaluated for use in OC treatment [92]. Recently, CAR-modified, cytokine-induced killer cells with FRα, enhanced anticancer immunity against OC [93].
Human epidermal growth factor receptor 2 (HER-2) is overexpressed in breast cancer and OC [94]. One study reported that radiolabeled pertuzumab for HER2 imaging enables rapid and unambiguous delineation of OCs overexpressing HER2 [95]. The suppression of HER2 using shHER2-RNA treatment with cisplatin also enhanced the anticancer effect of OC [96]. The study of HER2-interact synthetic Notch CAR cells has been investigated in a mouse model, and it is expected that clinical therapeutics for HER2-CAR-T cells will also be developed in the near future [97] (Table 2 and Figure 2).
Cimb 45 00081 g002 550
Figure 2. Overview of immunotherapy in OC. Schematic showing the types and mechanisms of T-cell-mediated immunotherapy currently used in clinical practice. WT1, Wilms’ tumor 1; NYESO-1, New York esophageal squamous cell carcinoma-1; GPC3, Glypican-3; DC, Dendritic cell; CAR-T, Chimeric Antigen Receptor T; CTLA-4, Cytotoxic T-lymphocyte antigen 4; PD-1, Programed cell death protein 1; PD-L1, Programed cell death-ligand 1; MUC16, Mucin 16; FRα, Folate receptor-α; HER2, human epidermal growth factor receptor 2.
Table 2. Immunotherapies for OC.
Type of Mechanism Agents FDA
Approval		 Combination with Ref.
Peptide vaccines        
P53 P53-SLP vaccine no Cyclophosphamide; Gemcitabine [35][36][37]
WT1 WT1 vaccine no   [40][41]
NYESO-1 NYESO-1 vaccine no Secretin-penetratin [42][43][44][45]
GPC3 GPC3 vaccine no miR-375, miR-93a, miR-1128; CAR-T cell [48][49][50]
DC DC protein vaccine yes   [52]
DC Neoantigen vaccine no   [53]
Checkpoint inhibitor        
CTLA-4 PHI-101 yes   [59]
CTLA-4 Ipilimumab yes   [60]
PD-1 Pembrolizumab yes Doxorubicin; Bevacizumab [67][68][69][70]
PD-1 Nivolumab yes Ipilimumab [71][73]
PD-L1 Atezolizumab yes Bevacizumab [75][76]
PD-L1 Avelumab yes Axitinib; Docetaxel; Doxolubicin [79][80][81]
PD-L1 Avelumab yes Carboplatin + Paclitaxel [82]
CAR-T        
Mesothelin MSTL-CAR-T no   [86]
MUC16 PD1-MUC16-CAR-T no   [89]
FRα FRα-CAR-T no   [92]
FRα FRα-CAR-T no Cytokine-inducing killer cell [93]
HER2 HER2-CAR-T no Pertuzumab [95]
HER2 HER2-CAR-T no Synthetic Notch [97]
p53-SLP, p53-synthetic long peptide; WT1, Wilms’ tumor 1; NYESO-1, New York esophageal squamous cell carcinoma-1; GPC3, Glypican-3; DC, dendritic cell; CAR-T, chimeric antigen receptor T; CTLA-4, cytotoxic T-lymphocyte antigen 4; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1; MUC16, mucin 16; FRα, folate receptor-α; HER2, human epidermal growth factor receptor 2.

This entry is adapted from the peer-reviewed paper 10.3390/cimb45020081

References

  1. Wang, Q.; Peng, H.; Qi, X.; Wu, M.; Zhao, X. Targeted therapies in gynecological cancers: A comprehensive review of clinical evidence. Signal Transduct. Target. Ther. 2020, 5, 137.
  2. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249.
  3. Webb, P.M.; Jordan, S.J. Epidemiology of epithelial ovarian cancer. Best Pract. Res. Clin. Obstet. Gynaecol. 2017, 41, 3–14.
  4. Matulonis, U.; Sood, A.; Fallowfield, L.; Howitt, B.; Sehouli, J.; Karlan, B. Ovarian cancer. Nat. Rev. Dis. Prim. 2016, 2, 16061.
  5. Prat, J. Ovarian carcinomas: Five distinct diseases with different origins, genetic alterations, and clinicopathological features. Virchows Arch. 2012, 460, 237–249.
  6. Singer, G.; Oldt, R., 3rd; Cohen, Y.; Wang, B.G.; Sidransky, D.; Kurman, R.J.; Shih Ie, M. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J. Natl. Cancer Inst. 2003, 95, 484–486.
  7. Singer, G.; Stohr, R.; Cope, L.; Dehari, R.; Hartmann, A.; Cao, D.F.; Wang, T.L.; Kurman, R.J.; Shih Ie, M. Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: A mutational analysis with immunohistochemical correlation. Am. J. Surg. Pathol. 2005, 29, 218–224.
  8. Reid, B.M.; Permuth, J.B.; Sellers, T.A. Epidemiology of ovarian cancer: A review. Cancer Biol. Med. 2017, 14, 9–32.
  9. Katsumata, N.; Yasuda, M.; Isonishi, S.; Takahashi, F.; Michimae, H.; Kimura, E.; Aoki, D.; Jobo, T.; Kodama, S.; Terauchi, F.; et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): A randomised, controlled, open-label trial. Lancet Oncol. 2013, 14, 1020–1026.
  10. Colombo, N.; Peiretti, M.; Parma, G.; Lapresa, M.; Mancari, R.; Carinelli, S.; Sessa, C.; Castiglione, M.; Group, E.G.W. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2010, 21, v23–v30.
  11. Ledermann, J.A.; Raja, F.A.; Fotopoulou, C.; Gonzalez-Martin, A.; Colombo, N.; Sessa, C.; Group, E.G.W. Corrections to “Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up”. Ann. Oncol. 2018, 29, iv259.
  12. Christie, E.L.; Bowtell, D.D.L. Acquired chemotherapy resistance in ovarian cancer. Ann. Oncol. 2017, 28, viii13–viii15.
  13. Pignata, S.; Pisano, C.; Di Napoli, M.; Cecere, S.C.; Tambaro, R.; Attademo, L. Treatment of recurrent epithelial ovarian cancer. Cancer 2019, 125, 4609–4615.
  14. Conteduca, V.; Scarpi, E.; Farolfi, A.; Brighi, N.; Rossi, L.; Gurioli, G.; Lolli, C.; Schepisi, G.; Bleve, S.; Gianni, C.; et al. Melphalan as a Promising Treatment for BRCA-Related Ovarian Carcinoma. Front. Oncol. 2021, 11, 716467.
  15. Kaern, J.; Baekelandt, M.; Trope, C.G. A phase II study of weekly paclitaxel in platinum and paclitaxel-resistant ovarian cancer patients. Eur. J. Gynaecol. Oncol. 2002, 23, 383–389.
  16. Ledermann, J.; Harter, P.; Gourley, C.; Friedlander, M.; Vergote, I.; Rustin, G.; Scott, C.L.; Meier, W.; Shapira-Frommer, R.; Safra, T.; et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: A preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014, 15, 852–861.
  17. Moore, K.; Colombo, N.; Scambia, G.; Kim, B.G.; Oaknin, A.; Friedlander, M.; Lisyanskaya, A.; Floquet, A.; Leary, A.; Sonke, G.S.; et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N. Engl. J.Med. 2018, 379, 2495–2505.
  18. Gonzalez-Martin, A.; Pothuri, B.; Vergote, I.; DePont Christensen, R.; Graybill, W.; Mirza, M.R.; McCormick, C.; Lorusso, D.; Hoskins, P.; Freyer, G.; et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N. Engl. J. Med. 2019, 381, 2391–2402.
  19. Lau, C.H.; Seow, K.M.; Chen, K.H. The Molecular Mechanisms of Actions, Effects, and Clinical Implications of PARP Inhibitors in Epithelial Ovarian Cancers: A Systematic Review. Int. J. Mol. Sci. 2022, 23, 8125.
  20. McMullen, M.; Karakasis, K.; Madariaga, A.; Oza, A.M. Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer. Cancers 2020, 12, 1607.
  21. Klotz, D.M.; Wimberger, P. Overcoming PARP inhibitor resistance in ovarian cancer: What are the most promising strategies? Arch. Gynecol. Obstet. 2020, 302, 1087–1102.
  22. Malone, E.R.; Oliva, M.; Sabatini, P.J.B.; Stockley, T.L.; Siu, L.L. Molecular profiling for precision cancer therapies. Genome. Med. 2020, 12, 8.
  23. Garofalo, A.; Sholl, L.; Reardon, B.; Taylor-Weiner, A.; Amin-Mansour, A.; Miao, D.; Liu, D.; Oliver, N.; MacConaill, L.; Ducar, M.; et al. The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine. Genome. Med. 2016, 8, 79.
  24. Shyr, D.; Liu, Q. Next generation sequencing in cancer research and clinical application. Biol. Proced. Online 2013, 15, 4.
  25. Morash, M.; Mitchell, H.; Beltran, H.; Elemento, O.; Pathak, J. The Role of Next-Generation Sequencing in Precision Medicine: A Review of Outcomes in Oncology. J. Pers. Med. 2018, 8, 30.
  26. Levinson, K.; Dorigo, O.; Rubin, K.; Moore, K. Immunotherapy in Gynecologic Cancers: What We Know Now and Where We Are Headed. Am. Soc. Clin. Oncol. Educ. Book 2019, 39, e126–e140.
  27. Lobenwein, D.; Kocher, F.; Dobner, S.; Gollmann-Tepekoylu, C.; Holfeld, J. Cardiotoxic mechanisms of cancer immunotherapy—A systematic review. Int. J. Cardiol. 2021, 323, 179–187.
  28. Palaia, I.; Tomao, F.; Sassu, C.M.; Musacchio, L.; Benedetti Panici, P. Immunotherapy For Ovarian Cancer: Recent Advances And Combination Therapeutic Approaches. Onco. Targets Ther. 2020, 13, 6109–6129.
  29. Seledtsov, V.I.; von Delwig, A. Clinically feasible and prospective immunotherapeutic interventions in multidirectional comprehensive treatment of cancer. Expert Opin. Biol. Ther. 2021, 21, 323–342.
  30. Wang, Y.; Zhang, L.; Xu, Z.; Miao, L.; Huang, L. mRNA Vaccine with Antigen-Specific Checkpoint Blockade Induces an Enhanced Immune Response against Established Melanoma. Mol. Ther. 2018, 26, 420–434.
  31. Yang, X.; Fan, J.; Wu, Y.; Ma, Z.; Huang, J.; Zhang, Y.; Zhou, Z.; Mo, F.; Liu, X.; Yuan, H.; et al. Synthetic multiepitope neoantigen DNA vaccine for personalized cancer immunotherapy. Nanomedicine 2021, 37, 102443.
  32. Zamani, P.; Teymouri, M.; Nikpoor, A.R.; Navashenaq, J.G.; Gholizadeh, Z.; Darban, S.A.; Jaafari, M.R. Nanoliposomal vaccine containing long multi-epitope peptide E75-AE36 pulsed PADRE-induced effective immune response in mice TUBO model of breast cancer. Eur. J. Cancer 2020, 129, 80–96.
  33. Marks, J.R.; Davidoff, A.M.; Kerns, B.J.; Humphrey, P.A.; Pence, J.C.; Dodge, R.K.; Clarke-Pearson, D.L.; Iglehart, J.D.; Bast, R.C., Jr.; Berchuck, A. Overexpression and mutation of p53 in epithelial ovarian cancer. Cancer Res. 1991, 51, 2979–2984.
  34. Havrilesky, L.; Darcy, K.M.; Hamdan, H.; Priore, R.L.; Leon, J.; Bell, J.; Berchuck, A.; Gynecologic Oncology Group, S. Prognostic significance of p53 mutation and p53 overexpression in advanced epithelial ovarian cancer: A Gynecologic Oncology Group Study. J. Clin. Oncol. 2003, 21, 3814–3825.
  35. Leffers, N.; Lambeck, A.J.; Gooden, M.J.; Hoogeboom, B.N.; Wolf, R.; Hamming, I.E.; Hepkema, B.G.; Willemse, P.H.; Molmans, B.H.; Hollema, H.; et al. Immunization with a P53 synthetic long peptide vaccine induces P53-specific immune responses in ovarian cancer patients, a phase II trial. Int. J. Cancer 2009, 125, 2104–2113.
  36. Vermeij, R.; Leffers, N.; Hoogeboom, B.N.; Hamming, I.L.; Wolf, R.; Reyners, A.K.; Molmans, B.H.; Hollema, H.; Bart, J.; Drijfhout, J.W.; et al. Potentiation of a p53-SLP vaccine by cyclophosphamide in ovarian cancer: A single-arm phase II study. Int. J. Cancer 2012, 131, E670–E680.
  37. Hardwick, N.R.; Frankel, P.; Ruel, C.; Kilpatrick, J.; Tsai, W.; Kos, F.; Kaltcheva, T.; Leong, L.; Morgan, R.; Chung, V.; et al. p53-Reactive T Cells Are Associated with Clinical Benefit in Patients with Platinum-Resistant Epithelial Ovarian Cancer After Treatment with a p53 Vaccine and Gemcitabine Chemotherapy. Clin. Cancer Res. 2018, 24, 1315–1325.
  38. Davodabadi, F.; Sarhadi, M.; Arabpour, J.; Sargazi, S.; Rahdar, A.; Diez-Pascual, A.M. Breast cancer vaccines: New insights into immunomodulatory and nano-therapeutic approaches. J. Control Release 2022, 349, 844–875.
  39. Advani, S.; Kopetz, S. Ongoing and future directions in the management of metastatic colorectal cancer: Update on clinical trials. J. Surg. Oncol. 2019, 119, 642–652.
  40. Gaiger, A.; Reese, V.; Disis, M.L.; Cheever, M.A. Immunity to WT1 in the animal model and in patients with acute myeloid leukemia. Blood 2000, 96, 1480–1489.
  41. Nishida, S.; Morimoto, S.; Oji, Y.; Morita, S.; Shirakata, T.; Enomoto, T.; Tsuboi, A.; Ueda, Y.; Yoshino, K.; Shouq, A.; et al. Cellular and Humoral Immune Responses Induced by an HLA Class I-restricted Peptide Cancer Vaccine Targeting WT1 Are Associated With Favorable Clinical Outcomes in Advanced Ovarian Cancer. J. Immunother. 2022, 45, 56–66.
  42. Odunsi, K.; Jungbluth, A.A.; Stockert, E.; Qian, F.; Gnjatic, S.; Tammela, J.; Intengan, M.; Beck, A.; Keitz, B.; Santiago, D.; et al. NY-ESO-1 and LAGE-1 cancer-testis antigens are potential targets for immunotherapy in epithelial ovarian cancer. Cancer Res. 2003, 63, 6076–6083.
  43. Odunsi, K.; Qian, F.; Matsuzaki, J.; Mhawech-Fauceglia, P.; Andrews, C.; Hoffman, E.W.; Pan, L.; Ritter, G.; Villella, J.; Thomas, B.; et al. Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer. Proc. Natl. Acad. Sci. USA 2007, 104, 12837–12842.
  44. Odunsi, K.; Matsuzaki, J.; Karbach, J.; Neumann, A.; Mhawech-Fauceglia, P.; Miller, A.; Beck, A.; Morrison, C.D.; Ritter, G.; Godoy, H.; et al. Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients. Proc. Natl. Acad. Sci. USA 2012, 109, 5797–5802.
  45. Yang, Y.; Guo, X.; Hu, B.; He, P.; Jiang, X.; Wang, Z.; Zhu, H.; Hu, L.; Yu, M.; Feng, M. Generated SecPen_NY-ESO-1_ubiquitin-pulsed dendritic cell cancer vaccine elicits stronger and specific T cell immune responses. Acta. Pharm. Sin. B 2021, 11, 476–487.
  46. Yu, S.; Yi, M.; Qin, S.; Wu, K. Next generation chimeric antigen receptor T cells: Safety strategies to overcome toxicity. Mol. Cancer 2019, 18, 125.
  47. Nakatsura, T.; Nishimura, Y. Usefulness of the novel oncofetal antigen glypican-3 for diagnosis of hepatocellular carcinoma and melanoma. BioDrugs 2005, 19, 71–77.
  48. Suzuki, S.; Sakata, J.; Utsumi, F.; Sekiya, R.; Kajiyama, H.; Shibata, K.; Kikkawa, F.; Nakatsura, T. Efficacy of glypican-3-derived peptide vaccine therapy on the survival of patients with refractory ovarian clear cell carcinoma. Oncoimmunology 2016, 5, e1238542.
  49. Ukai, M.; Yokoi, A.; Yoshida, K.; Suzuki, S.; Shibata, K.; Kikkawa, F.; Nakatsura, T.; Kajiyama, H. Extracellular miRNAs as Predictive Biomarkers for Glypican-3-Derived Peptide Vaccine Therapy Response in Ovarian Clear Cell Carcinoma. Cancers 2021, 13, 550.
  50. Pang, N.; Shi, J.; Qin, L.; Chen, A.; Tang, Y.; Yang, H.; Huang, Y.; Wu, Q.; Li, X.; He, B.; et al. IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin. J. Hematol. Oncol. 2021, 14, 118.
  51. Hubbe, M.L.; Jaehger, D.E.; Andresen, T.L.; Andersen, M.H. Leveraging Endogenous Dendritic Cells to Enhance the Therapeutic Efficacy of Adoptive T-Cell Therapy and Checkpoint Blockade. Front. Immunol. 2020, 11, 578349.
  52. Correll, A.; Tuettenberg, A.; Becker, C.; Jonuleit, H. Increased regulatory T-cell frequencies in patients with advanced melanoma correlate with a generally impaired T-cell responsiveness and are restored after dendritic cell-based vaccination. Exp. Dermatol. 2010, 19, e213–e221.
  53. Tanyi, J.L.; Bobisse, S.; Ophir, E.; Tuyaerts, S.; Roberti, A.; Genolet, R.; Baumgartner, P.; Stevenson, B.J.; Iseli, C.; Dangaj, D.; et al. Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer. Sci. Transl. Med 2018, 10, eaao5931.
  54. Morisaki, T.; Hikichi, T.; Onishi, H.; Morisaki, T.; Kubo, M.; Hirano, T.; Yoshimura, S.; Kiyotani, K.; Nakamura, Y. Intranodal Administration of Neoantigen Peptide-loaded Dendritic Cell Vaccine Elicits Epitope-specific T Cell Responses and Clinical Effects in a Patient with Chemorefractory Ovarian Cancer with Malignant Ascites. Immunol. Investig. 2021, 50, 562–579.
  55. Caro, A.A.; Deschoemaeker, S.; Allonsius, L.; Coosemans, A.; Laoui, D. Dendritic Cell Vaccines: A Promising Approach in the Fight against Ovarian Cancer. Cancers 2022, 14, 4037.
  56. Fares, C.M.; Van Allen, E.M.; Drake, C.G.; Allison, J.P.; Hu-Lieskovan, S. Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for All Patients? Am. Soc. Clin. Oncol. Educ. Book 2019, 39, 147–164.
  57. Gonzalez, N.L.; Puwanant, A.; Lu, A.; Marks, S.M.; Zivkovic, S.A. Myasthenia triggered by immune checkpoint inhibitors: New case and literature review. Neuromuscul. Disord. 2017, 27, 266–268.
  58. Kreileder, M.; Barrett, I.; Bendtsen, C.; Brennan, D.; Kolch, W. Signaling Dynamics Regulating Crosstalks between T-Cell Activation and Immune Checkpoints. Trends Cell Biol. 2021, 31, 224–235.
  59. Park, S.J.; Chang, S.J.; Suh, D.H.; Kong, T.W.; Song, H.; Kim, T.H.; Kim, J.W.; Kim, H.S.; Lee, S.J. A phase IA dose-escalation study of PHI-101, a new checkpoint kinase 2 inhibitor, for platinum-resistant recurrent ovarian cancer. BMC Cancer 2022, 22, 28.
  60. Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010, 363, 711–723.
  61. Chang, H.W.; Frey, G.; Liu, H.; Xing, C.; Steinman, L.; Boyle, W.J.; Short, J.M. Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches. Proc. Natl. Acad. Sci. USA 2021, 118, e2020606118.
  62. Loke, P.; Allison, J.P. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc. Natl. Acad. Sci. USA 2003, 100, 5336–5341.
  63. Hamanishi, J.; Mandai, M.; Iwasaki, M.; Okazaki, T.; Tanaka, Y.; Yamaguchi, K.; Higuchi, T.; Yagi, H.; Takakura, K.; Minato, N.; et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl. Acad. Sci. USA 2007, 104, 3360–3365.
  64. Hino, R.; Kabashima, K.; Kato, Y.; Yagi, H.; Nakamura, M.; Honjo, T.; Okazaki, T.; Tokura, Y. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 2010, 116, 1757–1766.
  65. Tseng, S.Y.; Otsuji, M.; Gorski, K.; Huang, X.; Slansky, J.E.; Pai, S.I.; Shalabi, A.; Shin, T.; Pardoll, D.M.; Tsuchiya, H. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J. Exp. Med. 2001, 193, 839–846.
  66. Fecher, L.A.; Agarwala, S.S.; Hodi, F.S.; Weber, J.S. Ipilimumab and its toxicities: A multidisciplinary approach. Oncologist 2013, 18, 733–743.
  67. Matulonis, U.A.; Shapira-Frommer, R.; Santin, A.D.; Lisyanskaya, A.S.; Pignata, S.; Vergote, I.; Raspagliesi, F.; Sonke, G.S.; Birrer, M.; Provencher, D.M.; et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: Results from the phase II KEYNOTE-100 study. Ann. Oncol. 2019, 30, 1080–1087.
  68. Mehnert, J.M.; Varga, A.; Brose, M.S.; Aggarwal, R.R.; Lin, C.C.; Prawira, A.; de Braud, F.; Tamura, K.; Doi, T.; Piha-Paul, S.A.; et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced, PD-L1-positive papillary or follicular thyroid cancer. BMC Cancer 2019, 19, 196.
  69. Lee, E.K.; Xiong, N.; Cheng, S.C.; Barry, W.T.; Penson, R.T.; Konstantinopoulos, P.A.; Hoffman, M.A.; Horowitz, N.; Dizon, D.S.; Stover, E.H.; et al. Combined pembrolizumab and pegylated liposomal doxorubicin in platinum resistant ovarian cancer: A phase 2 clinical trial. Gynecol. Oncol. 2020, 159, 72–78.
  70. Lin, Y.C.; Wen, K.C.; Sung, P.L.; Chou, Y.T.; Liew, P.L.; Chen, L.Y.; Huang, R.L.; Lai, H.C.; Chang, L.T. Complete remission of heavily treated ovarian clear cell carcinoma with ARID1A mutations after pembrolizumab and bevacizumab combination therapy: A case report. J. Ovarian. Res. 2020, 13, 143.
  71. Hamanishi, J.; Mandai, M.; Ikeda, T.; Minami, M.; Kawaguchi, A.; Murayama, T.; Kanai, M.; Mori, Y.; Matsumoto, S.; Chikuma, S.; et al. Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. J. Clin. Oncol. 2015, 33, 4015–4022.
  72. Iwai, Y.; Ishida, M.; Tanaka, Y.; Okazaki, T.; Honjo, T.; Minato, N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl. Acad. Sci. USA 2002, 99, 12293–12297.
  73. Zamarin, D.; Burger, R.A.; Sill, M.W.; Powell, D.J., Jr.; Lankes, H.A.; Feldman, M.D.; Zivanovic, O.; Gunderson, C.; Ko, E.; Mathews, C.; et al. Randomized Phase II Trial of Nivolumab Versus Nivolumab and Ipilimumab for Recurrent or Persistent Ovarian Cancer: An NRG Oncology Study. J. Clin. Oncol. 2020, 38, 1814–1823.
  74. Herbst, R.S.; Soria, J.C.; Kowanetz, M.; Fine, G.D.; Hamid, O.; Gordon, M.S.; Sosman, J.A.; McDermott, D.F.; Powderly, J.D.; Gettinger, S.N.; et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014, 515, 563–567.
  75. Liu, J.F.; Gordon, M.; Veneris, J.; Braiteh, F.; Balmanoukian, A.; Eder, J.P.; Oaknin, A.; Hamilton, E.; Wang, Y.; Sarkar, I.; et al. Safety, clinical activity and biomarker assessments of atezolizumab from a Phase I study in advanced/recurrent ovarian and uterine cancers. Gynecol. Oncol. 2019, 154, 314–322.
  76. Moroney, J.W.; Powderly, J.; Lieu, C.H.; Bendell, J.C.; Eckhardt, S.G.; Chang, C.W.; Molinero, L.; Spahn, J.; Williams, P.; Lin, Y.G.; et al. Safety and Clinical Activity of Atezolizumab Plus Bevacizumab in Patients with Ovarian Cancer: A Phase Ib Study. Clin. Cancer Res. 2020, 26, 5631–5637.
  77. Boyerinas, B.; Jochems, C.; Fantini, M.; Heery, C.R.; Gulley, J.L.; Tsang, K.Y.; Schlom, J. Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells. Cancer Immunol. Res. 2015, 3, 1148–1157.
  78. Kaufman, H.L.; Russell, J.; Hamid, O.; Bhatia, S.; Terheyden, P.; D’Angelo, S.P.; Shih, K.C.; Lebbe, C.; Linette, G.P.; Milella, M.; et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: A multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016, 17, 1374–1385.
  79. Hamilton, G. Avelumab: Search for combinations of immune checkpoint inhibition with chemotherapy. Expert Opin. Biol. Ther. 2021, 21, 311–322.
  80. Disis, M.L.; Taylor, M.H.; Kelly, K.; Beck, J.T.; Gordon, M.; Moore, K.M.; Patel, M.R.; Chaves, J.; Park, H.; Mita, A.C.; et al. Efficacy and Safety of Avelumab for Patients With Recurrent or Refractory Ovarian Cancer: Phase 1b Results From the JAVELIN Solid Tumor Trial. JAMA Oncol. 2019, 5, 393–401.
  81. Pujade-Lauraine, E.; Fujiwara, K.; Ledermann, J.A.; Oza, A.M.; Kristeleit, R.; Ray-Coquard, I.L.; Richardson, G.E.; Sessa, C.; Yonemori, K.; Banerjee, S.; et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): An open-label, three-arm, randomised, phase 3 study. Lancet Oncol. 2021, 22, 1034–1046.
  82. Monk, B.J.; Colombo, N.; Oza, A.M.; Fujiwara, K.; Birrer, M.J.; Randall, L.; Poddubskaya, E.V.; Scambia, G.; Shparyk, Y.V.; Lim, M.C.; et al. Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100): An open-label, randomised, phase 3 trial. Lancet Oncol. 2021, 22, 1275–1289.
  83. Song, D.G.; Ye, Q.; Santoro, S.; Fang, C.; Best, A.; Powell, D.J., Jr. Chimeric NKG2D CAR-expressing T cell-mediated attack of human ovarian cancer is enhanced by histone deacetylase inhibition. Hum. Gene Ther. 2013, 24, 295–305.
  84. Yan, W.; Hu, H.; Tang, B. Advances Of Chimeric Antigen Receptor T Cell Therapy In Ovarian Cancer. Onco. Targets Ther. 2019, 12, 8015–8022.
  85. Morello, A.; Sadelain, M.; Adusumilli, P.S. Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors. Cancer Discov. 2016, 6, 133–146.
  86. Schoutrop, E.; El-Serafi, I.; Poiret, T.; Zhao, Y.; Gultekin, O.; He, R.; Moyano-Galceran, L.; Carlson, J.W.; Lehti, K.; Hassan, M.; et al. Mesothelin-Specific CAR T Cells Target Ovarian Cancer. Cancer Res. 2021, 81, 3022–3035.
  87. Felder, M.; Kapur, A.; Gonzalez-Bosquet, J.; Horibata, S.; Heintz, J.; Albrecht, R.; Fass, L.; Kaur, J.; Hu, K.; Shojaei, H.; et al. MUC16 (CA125): Tumor biomarker to cancer therapy, a work in progress. Mol. Cancer 2014, 13, 129.
  88. Liu, Q.; Cheng, Z.; Luo, L.; Yang, Y.; Zhang, Z.; Ma, H.; Chen, T.; Huang, X.; Lin, S.Y.; Jin, M.; et al. C-terminus of MUC16 activates Wnt signaling pathway through its interaction with beta-catenin to promote tumorigenesis and metastasis. Oncotarget 2016, 7, 36800–36813.
  89. Li, T.; Wang, J. Therapeutic effect of dual CAR-T targeting PDL1 and MUC16 antigens on ovarian cancer cells in mice. BMC Cancer 2020, 20, 678.
  90. Coelho, R.; Marcos-Silva, L.; Ricardo, S.; Ponte, F.; Costa, A.; Lopes, J.M.; David, L. Peritoneal dissemination of ovarian cancer: Role of MUC16-mesothelin interaction and implications for treatment. Expert. Rev. Anticancer Ther. 2018, 18, 177–186.
  91. Coney, L.R.; Tomassetti, A.; Carayannopoulos, L.; Frasca, V.; Kamen, B.A.; Colnaghi, M.I.; Zurawski, V.R., Jr. Cloning of a tumor-associated antigen: MOv18 and MOv19 antibodies recognize a folate-binding protein. Cancer Res. 1991, 51, 6125–6132.
  92. Kandalaft, L.E.; Powell, D.J., Jr.; Coukos, G. A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer. J. Transl. Med. 2012, 10, 157.
  93. Zuo, S.; Wen, Y.; Panha, H.; Dai, G.; Wang, L.; Ren, X.; Fu, K. Modification of cytokine-induced killer cells with folate receptor alpha (FRalpha)-specific chimeric antigen receptors enhances their antitumor immunity toward FRalpha-positive ovarian cancers. Mol. Immunol. 2017, 85, 293–304.
  94. Berchuck, A.; Kamel, A.; Whitaker, R.; Kerns, B.; Olt, G.; Kinney, R.; Soper, J.T.; Dodge, R.; Clarke-Pearson, D.L.; Marks, P.; et al. Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res. 1990, 50, 4087–4091.
  95. Jiang, D.; Im, H.J.; Sun, H.; Valdovinos, H.F.; England, C.G.; Ehlerding, E.B.; Nickles, R.J.; Lee, D.S.; Cho, S.Y.; Huang, P.; et al. Radiolabeled pertuzumab for imaging of human epidermal growth factor receptor 2 expression in ovarian cancer. Eur. J. Nucl. Med. Mol. Imaging 2017, 44, 1296–1305.
  96. Song, X.; Sun, K.; Hu, J.; Zhou, J. Suppression of human epidermal growth factor receptor 2 via interference increases the chemosensitivity of ovarian carcinoma. Oncol. Lett. 2016, 11, 3028–3032.
  97. Hyrenius-Wittsten, A.; Su, Y.; Park, M.; Garcia, J.M.; Alavi, J.; Perry, N.; Montgomery, G.; Liu, B.; Roybal, K.T. SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models. Sci. Transl. Med. 2021, 13, 591.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback