Keywords

1 Introduction

Management of advanced and/or recurrent gynecological malignancies has been a challenge, because conventional therapy is often of limited and transient benefit [1,2,3]. In the search for more effective alternatives, attention has shifted more towards targeted and immune therapies. Recent immunotherapy trials have demonstrated significantly improved response rates in non-gynecologic cancers that were historically seen to be difficult to treat, such as metastatic melanoma and non-small cell lung carcinoma [4, 5]. Essential to protect the human body against foreign pathogens, the immune system also plays an integral role in eliminating cancerous cells through the process of immune surveillance [6]. Malignant cells may evade the immune system by several mechanisms which include activation of immune checkpoint pathways involving programmed cell death protein-1 (PD-1)/programmed cell death ligand (PD-L1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and various immunosuppressive cytokines. These mechanisms serve to suppress T-cell activity, thus promoting tumor tolerance and growth [7]. Treatment modalities in immunotherapy serve to augment the host’s antitumor immune response and/or inhibit the immunosuppressive signals in the tumor microenvironment [6]. We will begin this chapter with a brief review of various immunotherapy approaches in use and under investigation for the treatment of gynecologic cancers including immune checkpoint inhibitors, cancer vaccines, and adoptive cell transfer (ACT) [8]. We will then summarize some of the major findings detailing outcomes of immunotherapy and ongoing clinical trials targeting different gynecologic cancers.

1.1 Immune Checkpoint Inhibitors

Regulated by a balance of co-stimulatory and inhibitory signals, immune checkpoints help the human immune system respond effectively to foreign pathogens while preventing over-activation that could result in autoimmunity or collateral tissue destruction [7]. At the initial antigen recognition by the T-cell receptor (TCR), CTLA-4 mitigates the amplitude of TCR-mediated signaling in cytotoxic T lymphocytes (CTLs) via counteracting CD28 co-stimulatory activity. Specifically, CTLA-4 sequesters CD80 and CD86 from binding to CD28 in CTLs while enhancing the immune-suppressive activity of regulatory T cells. While CTLA-4 primarily acts on newly activated T cells, PD-1 receptor activation via PD-L1 and PD-L2 functions to limit activation of CD-8+ effector T cells mainly in peripheral tissue (due to the wide expression pattern of PD-1 ligands on a variety of normal and malignant cell types) to prevent collateral tissue damage. Tumor cells may overexpress PD-L1 either in response to inflammatory signals in the tumor microenvironment (adaptive immune resistance) or via upregulation through oncogenic signaling (innate immune resistance). In either situation, PD-1 downregulates effector T-cell response, and with chronic antigen exposure from tumor cells, this can result in T-cell anergy and self-tolerance.

Thus, immune checkpoint blockade via anti-CTLA-4 antibodies (e.g., ipilimumab, tremelimumab, etc.), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab, dostarlimab, etc.), and/or anti-PD-L1 antibodies (e.g., durvalumab, avelumab, atezolizumab, etc.) serves as potential therapeutic options to augment the antitumor activity of adaptive immunity.

1.2 Cancer Vaccines

The general principle of cancer vaccines is to elicit the host’s adaptive immune response to target malignant cells and can be given either in the prophylactic or therapeutic setting [9, 10]. For prophylactic vaccines, these are typically given prior to exposure to the neoplastic-inducing antigen to prevent premalignant and malignant cellular transformation. One classic example is administration of the human papilloma virus (HPV) – vaccine series containing L1 virus-like particles specific high-risk carcinogenic HPV types (e.g., 16 and 18) to teenagers and adults in order to reduce HPV infection rates in order to lessen the incidence of cervical dysplasia or cervical cancer. In contrast, therapeutic vaccines consisting of tumor-specific antigens (as peptides or antigen-activated dendritic cells) are administered in patients with cancer in order to enhance the host’s antitumor immune response [9]. As well, whole tumor antigen vaccine prepared via several approaches (including but not limited to free-thaw lysates, tumor cells treated with ultraviolet irradiation, RNA electroporation, or hypochlorous oxidation) is a novel technique that can potentially allow for a broad and stronger immune response given a higher number of tumor-associated antigens as opposed to a single antigen [11].

1.3 Adoptive Cell Transfer

In adoptive cell transfer (ACT), autologous T cells are extracted (either from tumor tissue itself or from the peripheral blood) and are subsequently expanded ex vivo, with or without genetic modification, and then re-infused back into circulation [12, 13]. Clinically used categories of ACT include tumor-infiltrating lymphocytes (TIL), genetically engineered T-cell receptors (TCR), and chimeric antigen receptor (CAR) T-cell therapies [12, 13]. TIL therapy consists of several steps including surgical extraction of tumor tissue to gain access to a heterogeneous population of T lymphocytes that presumably recognize tumor-specific antigens [13, 14]. Isolation of TIL is subsequently followed by ex vivo cellular expansion, preconditioning lymphodepletion, TIL infusion, and adjuvant IL-2 to aid with in vivo TIL expansion and maintenance [14, 15]. Lymphodepletion is thought to be critical and improve the therapeutic responses to TIL immunotherapy through the elimination of both the endogenous T lymphocytes that may compete with TIL for stimulatory cytokines/IL-2 and the regulatory T cells that serve to inhibit the T-cell activity [13, 16]. In contrast to TIL (which are naturally occurring group of polyclonal T-lymphocytes with varying recognition of and affinities toward tumor associated antigens), genetically engineered TCR and CAR T cells are T-lymphocyte populations modified with the same high-affinity tumor recognition moiety that is obtained from the peripheral blood [12, 13]. Following leukopheresis, the peripheral blood-derived T lymphocytes are genetically modified (frequently via the use of retroviral vectors), to render specificity against a tumor-specific antigen, and then subsequently expanded and re-infused back into the patient [12, 13]. These genetically modified T-cell approaches also frequently involve preconditioning using lymphodepleting chemotherapy. Important distinctions between CAR and TCR engineered T-cell therapies include the fact that TCR-modified T cells recognize tumor-specific antigens in the context of a specific major histocompatibility complex (MHC) – 1 [12, 13]. Therefore, one of the limitations of TCR T cells is their utility is limited to patients with common HLA types (typically HLA-A*0201) used in engineering the TCR. Another limitation is the possibility of tumors downregulating MHC protein expression and thereby decreasing tumor recognition. CAR T cells address this limitation as these cells are genetically modified with an antigen recognition moiety fused to intracellular T-cell signaling domains. This allows tumor antigen recognition by CAR T-cells to be independent of MHC proteins [17]. However, the major limitation of the CAR T-cell approach is the need for tumor antigen to be present on the cell surface.

In an era of precision medicine, immunotherapy represents one of the promising therapies that may be used to improve oncologic outcomes in gynecologic cancers. The following text will review the published, ongoing, and upcoming clinical trials in endometrial, ovarian, and cervical cancer.

2 Endometrial Cancer

Following the published results by the Cancer Genome Atlas Research Network, contemporary classification of endometrial cancer has shifted away from the traditional two histologic types (endometrioid vs. non-endometrioid; sometimes referred to as type I and type II cancers) and towards four types based on genomic sequencing: DNA polymerase epsilon (POLE) ultramutated, microsatellite instability hypermutated (MSI-H), and copy-number low and copy-number high [18]. Microsatellites are repeated sequences of DNA that become sites of DNA replication errors with “microsatellite instability” occurring in the setting of defects in the DNA mismatch repair (MMR) pathway. Defect of MMR function results in MSI in approximately 20–30% of endometrial tumors [18, 19]. Loss of MMR function is typically due to sporadic hypermethylation of the MLH1 promotor and less frequently due to germline mutations (i.e., hereditary non-polyposis colon cancer (HNPCC) syndrome, also known as Lynch syndrome) [18, 20]. MMR-deficient and POLE-mutant endometrial tumors display a high number of tumor-infiltrating lymphocytes as well as a high neoantigen load (due to high somatic tumor DNA mutational burden) giving the potential to elicit a strong antitumor immune response [18, 21,22,23].

2.1 Immune Checkpoint Inhibitors in Endometrial Cancer

2.1.1 MSI-H Tumors

There has been growing interest in the use of immune checkpoint inhibitors in MSI-H endometrial tumors since the landmark publication by Le and colleagues [24]. In this phase 2 study of MMR-deficient (dMMR) colorectal cancers and non-colorectal solid tumors and MMR-proficient (pMMR) colorectal cancers treated with pembrolizumab (anti-PD-1 antibody), patients with MMR-deficient cancers had clinically significant objective response rates (ORR) of 30–70% and an improved progression-free survival (PFS). Among the colorectal cancer patients, those with pMMR tumors demonstrated no responses [24]. Although this cohort predominantly consisted of colorectal cancer patients, there were two dMMR endometrial cancers that demonstrated favorable responses (one had a partial response and the other a complete response) [24]. In another study, Le and colleagues expanded their evaluation of pembrolizumab (10 mg/kg every 2 weeks) by examining the response in a cohort of 86 patients with 12 different dMMR cancer types who had progressive disease on at least one prior treatment (Table 1) [25]. Among the 15 endometrial cancer patients, there was a 53% ORR (three complete and five partial responses) with a 73% disease control rate (DCR) (20% had stable disease) [25]. MSI-H tumors display a higher expression of PD-L1 compared to microsatellite stable (MSS) tumors, and this expression appears to be correlated with improved response to PD-1 and PD-L1 inhibitors [23, 26]. In a phase II basket trial of MSI-H/dMMR tumors, KEYNOTE-158 reported a 57.1% ORR (28 of 49; 8 complete and 20 partial responses) in advanced MSI-H endometrial cancer patients who failed prior systemic therapy. Additionally, the median duration of response that was not reached (NR) (95% CI 2.9 to 27.0+ months) [27]. Pembrolizumab had an impressive, favorable impact on survival outcomes. The median PFS was 25.7 months (95% CI 4.9 to NR), and the median overall survival (OS) was NR (95% CI 27.2 to NR). Given its clinical efficacy, pembrolizumab was awarded United States Food and Drug Association (FDA) – accelerated approval for the use in treatment of MSI-H/dMMR solid tumors following recurrence or progression on standard therapy in May 2017.

Table 1 Reported immune checkpoint inhibitors trials in endometrial cancer
Full size table

Another PD-1 inhibitor under investigation is nivolumab. In a Japanese, phase II multicenter study, nivolumab (240 mg IV every 2 weeks) was administered to mixed cohort of patients including advanced uterine cancer patients (clinical trial JapicCTI-163,212) [28]. Tamura and colleagues found an overall ORR of 23% in 23 uterine cancer patients with acceptable drug safety profile. ORR was similar regardless of the presence or absence of PD-L1 expression (25% vs. 21.4%, respectively) [28]. MSI testing was performed in 8 patients, and the ORRs for MSI-H and MSI-L tumors were 100% (2 of 2 had partial responses) and 0% (0 of 6), respectively. In the NCI-MATCH trial, patients with relapsed or refractory non-colorectal tumors were screened for MMR-deficiency by immunohistochemistry and administered IV nivolumab for the primary endpoint of ORR [29]. For the evaluable patients in the endometrial tumor cohort (n = 14), the ORR was 42.9% (4 partial and 2 complete responses) with a disease control rate of 64.3% (9 of 14) [29].

Dostarlimab is another PD-1 inhibitor that has been investigated in endometrial cancer and was evaluated in the GARNET study. In this phase 1b/II trial, the investigators administered dostarlimab at 500 mg IV every 3 weeks for the first 4 cycles and then 1000 mg IV every 6 weeks across multiple tumor types, including dMMR endometrial cancer (n = 104) [30]. Among the evaluable dMMR recurrent/advanced endometrial cancer patients, the ORR was 42.3% (30 of 71) with 21 partial (29.6%) and 9 (12.7%) complete responses; the median duration of response (DOR) was NR [30]. The most frequent treatment-related adverse events (TRAEs) were asthenia, diarrhea, fatigue, and nausea. The TRAE rate for grade 3 or higher was 11.5% with anemia being most commonly reported (2.9%) [30].

PD-L1 inhibitors have also demonstrated favorable activity in dMMR/MSI-H endometrial tumors. In the preliminary results of a phase II PHAEDRA trial, the investigators administered durvalumab 1500 mg IV every 4 weeks to advanced endometrial cancer patients that progressed on prior systemic therapy (n = 71) [31]. Among the dMMR endometrial cancer patients, the ORR was 40% (14/35) with 10 partial and 4 complete responses with favorable safety profile [31]. In another PD-L1 inhibitor trial, Konstantinopoulos et al. administered avelumab 10 mg/kg IV every 2 weeks to two cohort endometrial cancers stratified by mutational profile: 1) hypermutated (dMMR/polymerase ε (POLE) mutant (n = 15)) and 2) hypomutated (non-dMMR (n = 16)) [32]. In the 12 evaluable patients in the hypermutated cohort, there were no POLE mutations, and the ORR was 33.3% (3 partial and 1 complete response). Furthermore, the 6-month PFS rate was 40% with responders having negative PD-L1 expression and ongoing response by the data cutoff date [32]. In contrast, avelumab was observed to have poor activity in the non-dMMR cohort with an ORR of 7.1% and a 6-month PFS rate of 6.3% [32].

2.1.2 TMB-H Tumors

Similar to MSI status, tumor mutational burden (TMB) demonstrates potential as a biomarker of response for PD-1 inhibitors [33,34,35]. TMB is defined as the total number of somatic mutations per coding area in the tumor genome with high TMB (TMB-H) generally defined as tumors with ≥10 mutations/megabase [33, 35]. Compared to tumors with low TMB (TMB-L), tumors with TMB-H are postulated to produce greater numbers of neoantigens and thereby generate a stronger response to immune checkpoint inhibitors across a diverse number of tumor types [33,34,35]. In a prospective exploratory analysis of the KEYNOTE-158 trial, endometrial cancer patients with TMB-H (n = 15) had improved response to pembrolizumab compared to those with TMB-L (n = 67) (ORR 46.7% vs. 6%, respectively) [33]. It should be noted that 10 of the 15 endometrial tumors with TMB-H also were MSI-H, while there were no MSI-H tumors in the TMB-L cohort [33]. In a retrospective study performed at the Memorial Sloan Kettering Cancer Center, Valero et al. correlated TMB with response to immune checkpoint inhibitors in patients with MSS solid tumors and who received treatment with PD-1/PD-L1 monotherapy or combination therapy [34]. In the endometrial cohort, the TMB-H and TMB-L tumors had an ORR of 66.7% (2 of 3) and 20.5% (9 of 44), respectively [34]. In June 2020, the FDA granted accelerated approval to pembrolizumab in the treatment of unresectable or metastatic TMB-H solid tumors that have progressed on prior therapy.

2.1.3 MSS Tumors

For MSS tumors, monotherapy immune checkpoint has shown more limited benefit. As an ongoing, open-label phase Ib trial, KEYNOTE-028 is evaluating the safety and efficacy of pembrolizumab on PD-L1-positive advanced solid tumors [36]. In this study, a cohort of 24 patients with advanced endometrial cancer and PD-L1 positivity were treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24 months (or until progression or unacceptable toxicity) after failing 2 prior lines of therapy [36]. The ORR was 12.5% (n = 3; all partial responses) with a DCR of 25% (n = 6) [36]. Progressive disease occurred in 54.2% (n = 13), and 20.8% (n = 5) could not be assessed. Of note, 19 of the 24 tumor samples were evaluable for MSI-H status, and they were predominantly MSS; the sole patient with an MSI-H tumor had progressive disease [36]. One of the three patients with a partial response was found to have a POLE mutant tumor [36]. The high expression of a large set of immune-related genes and increased neoantigen load may explain the favorable response to immune checkpoint inhibitors in POLE-mutated tumors [18, 37]. Additionally, POLE-mutated tumors demonstrate a higher expression of PD-L1/PD-L2 proteins as well as a higher extent of T lymphocytic infiltration than MSI-H and MSS endometrioid tumors [18, 22, 23, 37]. Other PD-1/PD-L1 trials have demonstrated similar ORRs among MSS tumors. In a trial by Tamura et al., nivolumab had an ORR of 0% (0 of 6) among MSS tumors [28]. Avelumab, durvalumab (PD-L1 inhibitor), and dostarlimab have shown ORRs of 7.1%, 3%, and 13.4%, respectively, among pMMR tumors [31, 32, 38]. In a phase I study by Liu et al., atezolizumab (PD-L1 inhibitor) demonstrated an overall ORR of 13.3% in a predominantly MSS uterine cancer population 2 partial responses, each in a MSI-H and MSS patient [39].

Although immune checkpoint inhibitor monotherapy has been limited in MSS tumors, the combination of immune checkpoint inhibitors and multi-tyrosine kinase inhibitors has been reported to result in substantially higher response rates. In a phase Ib/II study (KEYNOTE-146/Study 111), lenvatinib (20 mg po daily) (inhibitor of vascular endothelial growth factor 1–3, fibroblast growth factor receptor 1–4, and other kinases) and pembrolizumab (200 mg IV every 3 weeks) were administered in advanced endometrial cancer patients with predominantly MSS tumors (85%) [40]. Among 108 evaluable patients, the overall ORR was 38.9% (8 complete responses and 34 partial responses) and DCR was 84.3% [40]. Remarkably, this regimen had efficacy in serous histologies as well with an ORR of 42.4% [40]. Based on efficacy results, pembrolizumab and lenvatinib therapy was given accelerated FDA approval for use in non-MSI-H/dMMR advanced endometrial cancer that failed at least 1 prior line of systemic therapy in September 2019. Although impressive tumor responses were seen, toxicity was significant with a grade 3–4 TRAE rate of 66.9% (most common being hypertension, fatigue, and diarrhea) [40]. There were two deaths related to TRAE (sepsis and intracranial hemorrhage) [40]. There were 17.7% of patients who discontinued treatment due to toxicity (mainly related to lenvatinib), and the majority of patients had lenvatinib-dose interruptions (70.2%) [40]. Despite the combination regimen receiving accelerated FDA approval with lenvatinib dosing at 20 mg/daily, the majority of patients had lenvatinib dose reductions (62.9%), and the mean lenvatinib dose intensity was 14.4 mg/daily [40]. The combination of pembrolizumab and lenvatinib provides a promising alternative for treatment of recurrent endometrial cancer, but it remains to be seen the tolerability and feasibility of this regimen in clinical practice. Currently, a phase 3 trial investigating lenvatinib/pembrolizumab vs. physician’s choice is underway (NCT03517449).

At the 2019 American Society of Clinical Oncologists Meeting, the preliminary results of a phase II trial of durvalumab with or without tremelimumab (CTLA-4 inhibitor) in persistent/recurrent endometrial cancer were presented (NCT03015129) [41]. Twenty-eight patients were enrolled in each treatment arm. The durvalumab monotherapy group had an ORR of 14.8% (1 complete response and 3 partial responses) with PFS of 13.3% at 24 weeks [41]. The combination group had an ORR of 11.1% (2 complete responses and 1 partial response) with a PFS of 18.5% at 24 weeks [41]. Grade 3 and 4 TRAE were 7% and 4% in the monotherapy group and 32% and 11% in the combination group, respectively [41].

There are numerous ongoing clinical trials of combination therapy with immune checkpoint inhibitors, and these include but are not limited to the following:

  • KEYNOTE-775 (NCT03517449): phase III trial of pembrolizumab and lenvatinib vs. physician’s choice

  • LEAP-001 (NCT03884101): phase III trial of pembrolizumab and lenvatinib vs. carboplatin and paclitaxel

  • RUBY (NCT03981796): phase III trial of carboplatin, paclitaxel, and dostarlimab vs. carboplatin, paclitaxel, and placebo

  • AtTEnd (NCT03603184): phase III trial of carboplatin, paclitaxel, and atezolizumab vs. carboplatin, paclitaxel, and placebo

  • NRG-GY018 (NCT02549209): phase II trial of carboplatin/paclitaxel plus pembrolizumab

  • DOMEC (NCT03951415): phase II trial of durvalumab plus olaparib

  • EndoBARR (NCT03694262): phase II trial of rucaparib, bevacizumab, and atezolizumab

2.2 Vaccines in Endometrial Cancer

One of the identified tumor-associated antigens that has been utilized, as a target for therapeutic vaccinations, is a product of the Wilm’s tumor gene: WT1 [42, 43]. Classically categorized as a tumor-suppressor gene, WT1 may instead perform oncogenic functions in many malignancies and is highly expressed in multiple cancers including gynecologic malignancies [43]. In a phase II clinical trial, Ohno et al. utilized a WT1 peptide vaccine on 12 patients with HLA-A*2402-positive gynecologic cancers resistant to standard therapy (Table 2) [43]. Two of endometrial cancer patients (carcinosarcoma and endometrioid adenocarcinoma histologic subtypes) both had progressive disease after 3 months, but the treatment was otherwise well tolerated [43]. In another phase I/II study, a mixed cohort of end-stage serous endometrial carcinoma (n = 3) and leiomyosarcoma (n = 3) patients received 4 weekly vaccines of autologous dendritic cells electroporated with WT1 mRNA [44]. Although all three serous endometrial carcinoma patients (two HLA-A2 positive and one HLA-A2 negative) demonstrated disease progression, some immunological activity was present in the HLA-A2-positive patients as noted by an increase in WT1-specific T cells and NK cells [44]. However, the two HLA-A2-positive leiomyosarcomas demonstrated some disease control (one with stable disease but eventually progressed and another had a mixed response prior to progression) [44].

Table 2 Reported vaccine therapy trials in endometrial cancer
Full size table

Another targeted epitope is associated with NY-ESO-1, which is classified as a “cancer-germ line antigen” (an antigen expressed in the germ cells and multiple different types of malignancies). In a series of 36 patients with various stage III/IV NY-ESO-1 expressing malignancies, the patients were administered a recombinant vaccinia/fowlpox-NY-ESO-1 vaccine series [45]. In the only endometrial cancer patient, the vaccine mounted both humoral and cellular responses indicated by NY-ESO-1-specific antibody production and CD4/CD8 response although the patient ultimately had progressive disease [45].

Human epidermal growth factor-2, HER2, is overexpressed in many epithelial-derived cancers (often with breast cancers) and has been the target for vaccination in other malignancies [46]. In a phase I clinical study, patients with various metastatic cancers received combination vaccines of a mixture of two B-cell epitopes of HER2 fused to a T-cell epitope [46]. Of the 24 patients enrolled, two endometrial cancer patients had received the vaccines after 2 failed chemotherapy treatments with one of the patients demonstrating high antibody production and partial response [46].

Folate binding protein (FBP) is another immunogenic protein overexpressed in endometrial (as well as ovarian) cancer [47]. In a phase I/IIa trial by Brown and colleagues, a very heterogeneous cohort of 51 patients with endometrial or ovarian cancer who all had no evidence of disease in either the frontline or recurrent setting who received an HLA-A2-restricted, FBP-derived E39 peptide vaccine +/− booster inoculations to prevent recurrence [48]. Overall, the vaccine was well tolerated, and the disease-free survival (DFS) was improved in the higher dosage vaccine group (1000 mcg) compared to the lower dosage vaccine (<1000 mcg) or control group (77.9% vs 31.2% vs 40%; p = 0.013) [48]. Other factors associated with decreased risk of recurrence included use of booster inoculations, vaccination in frontline setting, and low FBP expression in tumors [48].

2.3 ACT in Endometrial Cancer

There are few reported studies discussing TIL, TCR-T, or CAR-T therapy in endometrial cancer. In a phase I trial by Qiao et al., the investigators administered several therapeutic options (hyperthermia + ACT +/− pembrolizumab +/− chemotherapy) to a heterogeneous group of solid tumors that failed prior therapy [49]. With the ACT, mononuclear cells were collected from the peripheral blood, and the cultured cytokine-induced mix of T and natural killer immune effector cells was infused back into the patient [49]. In the endometrial cohort (n = 5), there was 1 patient with a partial response and 2 patients with stable disease [49]. Overall, the majority of toxicities were associated with grade 1 or 2 and chemotherapy [49]. Another ACT therapeutic option involves lymphokine-activated killer (LAK) cells. This process involves collection of peripheral blood containing mononuclear cells that are stimulated in vitro with IL-2 to become LAK cells [50]. These LAK cells are re-infused into the patient and are capable of lysing tumor cells without MHC restriction while sparing normal tissue [50]. In study by Steis et al., they selected patients with various cancers that had metastatic disease restricted to the peritoneal cavity [51]. These patients received IL-2 (100,000 U/kg IV every 8 h) for 3 days, followed by leukapheresis for 5 days [51]. LAK cells were expanded in vitro by incubating the peripheral blood mononuclear cells in IL-2 for 7 days and then administered IP for 5 days with IL-2 (25,000 U/kg IP every 8 h) [51]. In the cohort, there was only one endometrial cancer patient, but that patient failed to respond to therapy with the therapy overall having multiple side effects including intraperitoneal fibrosis [51]. In another study, Santin et al. observed stable disease in a patient with endometrial cancer with unresectable, chemoresistant liver metastases who was treated with infusion of peripheral T cells stimulated with tumor lysate-pulsed autologous dendritic cells [52].

3 Cervical Cancer

The carcinogenesis of cervical cancer evokes great interest in immunotherapeutic options. Chronic HPV infection is attributed as the etiologic agent for the development of cervical cancer in nearly all cases. Although the majority of HPV-infected people do not develop cervical cancer (due to HPV clearance by a competent immune system), chronic HPV infections result in the expression of oncoproteins E6 and E7 that bind and inactivate the TP53 and Rb tumor suppressor gene product, respectively. Immunotherapeutic options for cervical cancer will be reviewed.

3.1 Immune Checkpoint Inhibitors in Cervical Cancer

Several studies have demonstrated relatively high PD-1/PD-L1 expression on cervical tumors (as high as 95% in cervical intraepithelial neoplasia and 80% of squamous cell carcinomas), and thus these cancers are potential targets for immune checkpoint inhibitors [53,54,55]. In KEYNOTE-028, the cervical cancer subgroup consisted of 24 patients with advanced disease and PD-L1-positive tumors that had progressed on prior standard therapy [56]. Following the administration of pembrolizumab (10 mg/kg every 2 weeks up to 24 months), the subgroup had an ORR of 17% (4 patients with partial response) with a DCR of 17% (Table 3) [56]. In an interim analysis in the KEYNOTE-158 phase 2, open-label trial, 98 cervical cancer patients received pembrolizumab (200 mg every 3 weeks), including 83.7% of patients who had PD-L1-expression (defined as combined positive score (CPS) ≥1) in their tumors and 78.6% who had prior lines of chemotherapy for recurrent or advanced disease (NCT02628067) [57]. Among these patients, the ORR was 12.2% (nine had a partial response and three had a complete response) with responders all having PD-L1-positive tumors (including one patient with adenocarcinoma). The DCR was 30.6% including 15 of the 18 (83.3%) patients with stable disease who had PD-L1-positive tumors [57]. Furthermore, the median duration of response was NR, and 91% of patients had a response duration of at least 6 months [57]. Since June 2018, the FDA has approved pembrolizumab in advanced cervical cancer expressing PD-L1 (CPS ≥1) with disease progression during or after chemotherapy.

Table 3 Reported immune checkpoint inhibitors trials in cervical cancer
Full size table

Another PD-1 inhibitor reported in the cervical cancer literature is nivolumab and has demonstrated promising results. For neuroendocrine cervical cancer known to be an aggressive cervical cancer subtype, two case reports have demonstrated complete response to nivolumab monotherapy (despite being PD-L1 negative) and a near complete response (95% resolution of target lesions) when nivolumab was combined with stereotactic body radiation [58, 59]. In a larger study, nivolumab (240 mg every 2 weeks) was tested in five HPV-associated malignancies including cervical, vulvar, and vaginal cancers that previously had up to two failed prior systemic therapies (CheckMate358; NCT02488759) [60]. In the preliminary results of this ongoing phase I/II multicohort study, the majority of the cohort consisted of cervical cancer patients (19 of 24) with the rest having vaginal or vulvar cancer. The overall ORR was 20.8% with a DCR of 70.8% (15 of 24) and was well-tolerated [60]. Response to therapy was only noted in the cervical cancer patients (ORR 26.3%) with one complete and four partial responses, regardless of PD-L1 status [60]. In the phase II results of another trial with nivolumab (NRG-GY002), the agent was demonstrated to have poor response rate (despite PD-L1 positivity in 77.3% of tumors) with an ORR of 4% (1 partial response) with a DCR 36% in a cohort of 25 cervical cancer patients with persistent or recurrent disease who failed at least 1 prior line of systemic therapy [61]. In a phase II study by Friedman et al., atezolizumab (1200 mg IV every 3 weeks) and bevacizumab (15 mg/kg IV every 3 weeks) were administered to patients with recurrent, persistent, or metastatic cervical cancer (NCT02921269) [62]. There were 10 evaluable patients with no confirmed responses and a DCR of 50% [62]. The median PFS was 2.9 months, and overall survival was 9 months with 23% of patients having grade 3 TRAE [62]. In a phase I study, Rischin et al. reported the safety and antitumor activity results of cemiplimab (PD-L1 inhibitor) with or without hypofractionated radiation therapy evaluated in recurrent or metastatic cervical cancer patients [63]. The ORR was 10% in both the monotherapy and combination therapy group with a duration of response of 11.2 and 6.4 months, respectively [63].

Another immune checkpoint inhibitor under investigation in patients with cervical cancer is ipilimumab (CTLA-4 inhibitor). In the phase I study (GOG 9929), ipilimumab was administered after chemoradiation for patients with stage IB2–IIB or IIIB–IVA cervical cancer with node-positive disease (NCT01711515). Preliminary results in the 19 evaluable subjects demonstrate a 1-year disease-free survival of 74% with tolerable side effects [64]. In another phase I/II clinical trial, 42 patients with metastatic cervical cancer (squamous cell or adenocarcinoma) with progression on at least one line of platinum chemotherapy received ipilimumab [65]. Among the 34 evaluable patients, the ORR was 2.9% (1 partial response) with DCR of 32.4% and a median PFS and OS of 2.5 months and 8.5 months, respectively [65]. Expression of CD3, CD4, CD8, FoxP3, indoleamin 2,3-dioxygenase, and PD-L1 did not predict benefit [65]. More recently, at the 2019 European Society of Medical Oncology Congress, the investigators of CheckMate-358 (NCT02488759) presented their preliminary results of an ongoing phase I/II study evaluating two dosing regimens of ipilimumab and nivolumab in patients with advanced/recurrent cervical cancer [66]. Of note, this study was stratified based on whether patients had received prior systemic chemotherapy [66]. Both regimens [low-dose ipilimumab (1 mg/kg) and high-dose nivolumab (3 mg/kg) vs. high-dose ipilimumab (3 mg/kg) and low-dose nivolumab (1 mg/kg) followed by maintenance nivolumab (1 mg/kg)] demonstrated impressive objective response rates that were higher in subjects who had received no prior systemic therapy (31.6% and 45.8%, respectively) [66]. The clinical benefit rate of mirroring responses was also impressive for both regimens and higher in subjects who had received no prior systemic therapy (63.2% versus 70.8%, respectively). Furthermore, responses were noted regardless of PD-L1 status [66]. Although there were no safety concerns, 28.9% and 37% of patients in the low-dose ipilimumab and high-dose ipilimumab regimens, respectively, had grade 3–4 treatment-related adverse events [66].

There are numerous ongoing clinical trials of combination therapy with immune checkpoint inhibitors, and these include but are not limited to the following:

  • KEYNOTE-826 (NCT03635567): phase III trial of pembrolizumab and investigator’s choice of chemotherapy vs. placebo and investigator’s choice chemotherapy

  • BEATcc (NCT03556839): phase III trial of platinum chemotherapy, paclitaxel, bevacizumab, and atezolizumab vs. platinum chemotherapy, paclitaxel, and bevacizumab

  • NCT03614949: phase II trial of stereotactic body radiation therapy and atezolizumab

  • NCT03508570: phase Ib trial of intraperitoneal nivolumab +/− ipilimumab

  • KEYNOTE-A18/ENGOT-cx11 (NCT04221945): phase III trial of chemoradiation with or without pembrolizumab in locally advanced cervical cancer

  • CALLA (NCT03830866): phase III trial of chemoradiation with or without durvalumab in locally advanced cervical cancer

  • NCT03894215: phase II study of balstilimab with or without zalifrelimab in second-line treatment of cervix cancer

3.2 Vaccines in Cervical Cancer

Given the role of chronic HPV infection in the carcinogenesis of cervical cancer and the success of prophylactic HPV vaccines for prevention of dysplasia and cervical cancer, there is great interest in development of therapeutic HPV vaccines that typically target the E6 and E7 oncoproteins. In phase I vaccine trial, Hasan et al. administered MEDI0457, DNA-based vaccine targeting E6 and E7 of HPV-16/18 that is coinjected with an IL-12 plasmid followed by electroporation with the CELLECTRA 5P device in cervical cancer patients following chemoradiation in the primary and recurrent setting [67]. In this small 10-patient study, they observed detectable cellular or humoral immune responses in 8 of 10 patients with 6 of 10 generating anti-HPV antibody and IFN-gamma producing T-cell responses [67]. The vaccine demonstrated tolerable safety profile [67]. In a phase II study, amalimogene filolisbac (ADXS11-001) (live, attenuated Listeria monocytogenes (Lm) vaccine containing the HPV-16 E7 oncoprotein) was administered by random assignment with or without cisplatin to 109 recurrent or treatment-refractory cervical cancer patients in India. The response rate was similar between both groups (17.1% vs. 14.7%) with comparable survival rates, but the combination group experienced more adverse events that were not related to the study drug [68]. ADXS11–001 was also examined in the GOG/NRG0265 phase II study (NCT01266460) (Table 4) [69]. In the preliminary results of the trial, ADXS11–001 was administered as monotherapy to 50 patients with persistent or recurrent metastatic cervical cancer who progressed on at least one prior line of systemic chemotherapy [69]. The 12-month OS was 38% with an ORR of 2% (1 complete response) and DCR of 32% [69]. TRAE occurred in 96% of patients with the most frequent being fatigue, chills, anemia, and nausea; grade 3 and 4 TRAE were present in 39% and 4% of patients, respectively [69]. Another phase I/II study examined the safety and efficacy of durvalumab (anti-PD-1 inhibitor) with or without ADSX11-001 in previously treated recurrent or metastatic cervical cancer and other HPV-related squamous cell carcinomas of the head and neck (NCT02291055) [70]. In the phase I portion of the trial, combination therapy was examined with eight cervical cancer patients treated [70]. Among the five evaluable patients, the ORR and DCR were 40% (1 partial and 1 complete response) with TRAE present in 91% of patients and grade 3 and 4 TRAE present in 27% and 9%, respectively. The most frequent TRAE were chills/rigors, fever, nausea, hypotension, diarrhea, fatigue, tachycardia, and headache.

Table 4 Reported vaccine therapy and adoptive cell therapy trials in cervical cancer
Full size table

In the interim results of another trial combining immune checkpoint inhibitors and vaccine therapy, Youn et al. administer pembrolizumab and GX-18E (therapeutic HPV DNA vaccine that encodes for HPV-16 and HPV-18 E6 and E7) to inoperable recurrent or advanced HPV-16 or 18 positive cervical cancer (n = 36) [71]. In the 26 evaluable patients, the ORR was 42% (7 partial and 4 complete responses) and tolerable safety profile [71]. Of note, the responses were mainly seen among those with PD-L1-positive tumors: ORR 50% (10 of 20) in PD-L1-positive tumors and 17% (1 of 6) in PD-L1-negative tumors [71].

3.3 ACT in Cervical Cancer

In their phase II study, Stevanovic and colleagues administered a single infusion of E6 and E7 reactive TIL following lymphodepletion chemotherapy in patients with metastatic HPV-associated cancers following at least one prior standard chemotherapy or chemoradiotherapy regimen [72, 73]. In the cervical cancer subcohort, the ORR and DCR were 28% (5 out of 18) including two patients who had complete responses after 22 and 15 months of treatment with no evidence of disease after 67 and 53 months, respectively (Table 4) [72, 73]. The proportion of HPV-reactive T cells in peripheral blood post-infusion was positively correlated with improved clinical response [72]. Interestingly, analysis of the tumor antigens targeted by the TIL administered in patients who had complete objective responses demonstrated persistence of TIL that recognized neoantigens and cancer germline antigens in addition to the expected HPV viral antigens [74]. Given these promising results, there is another ongoing phase II, multicenter study to evaluate TIL therapy in patients with recurrent, metastatic, or recurrent cervical cancer (NCT03108495). The preliminary results of this trial presented at 2019 annual American Society of Clinical Oncology Meeting showed an ORR of 44% (1 complete and 11 partial responses) with a DCR of 89%, but with a short follow-up period (median follow-up of 3.5 months) [75].

Using ACT with genetically modified T cells, Lu and colleagues administered dose-escalating autologous purified CD4+ T-cell therapy using an MHC class II-restricted TCR that recognizes the cancer germline antigen, melanoma-associated antigen-A3 (MAGE-A3) to a cohort of 17 patients with various cancers [76]. In the preliminary results, although two of the three cervical cancer patients did not demonstrate a response to therapy, one of the patients who received 2.7 × 109 cells had a complete objective response at 29 months [76].

4 Ovarian Cancer

Immunotherapy represents a potentially promising alternative therapy in ovarian cancer for several reasons. PD-L1 expression appears to be highly prevalent in ovarian cancer compared to other malignancies with high expression associated with worse survival [77]. Furthermore, with a high prevalence of TIL and select groups with high neoantigen load, ovarian tumors are potential targets for therapeutic vaccines and ACT as well [78, 79].

4.1 Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer

In a multicenter phase 1 trial, Brahmer et al. administered an anti-PD-L1 antibody, a heterogeneous cohort of advanced cancers, including 17 ovarian cancer patients [80]. In the ovarian cancer cohort, the ORR was 6% (1 partial response) with a DCR of 23.5% (Table 5) [80]. In an open-label, phase II trial, Hamanishi and colleagues administered up to 6 cycles of nivolumab to advanced or recurrent, platinum-resistant ovarian cancer [81]. In a cohort of 20 patients, nivolumab demonstrated an ORR of 15% (1 partial and 2 complete responses) and DCR of 45%. The median PFS was 3.5 months and median OS was 20 months [81]. In KEYNOTE-028, 26 patients with PD-L1-positive advanced, metastatic ovarian cancer received pembrolizumab with the majority of patients having at least three prior lines of systemic therapy [82]. The ORR was 11.5% (2 partial and 1 response) with a DCR of 38.5% and acceptable side effect profile [82]. In KEYNOTE-100 study, 376 patients with advanced, recurrent ovarian cancer were administered pembrolizumab and divided into two cohorts (A, n = 285 or B, n = 91) based on the history of number of prior lines of systemic therapy and treatment-free interval [83]. The ORR in cohort A was 7.4% (16 partial and 5 complete responses), while in cohort B it was 9.9% (7 partial and 2 complete responses), while the DCR was 37.2% and 37.4%, respectively. Higher PD-L1 expression (as measured as combined positivity score (CPS) ≥ 10) appeared to be correlated with higher clinical response (ORR 17.1% vs. 5.2% vs. 5.0% for CPS ≥ 10, 1–10, <1, respectively) [83].

Table 5 Reported immune checkpoint inhibitors trials in epithelial ovarian cancer
Full size table

The JAVELIN trials have investigated the use of avelumab in epithelial ovarian cancer. In the phase 1B JAVELIN Solid Tumor study, avelumab was administered to 125 patients with advanced, recurrent, or refractory ovarian cancer [84]. The ORR was 9.6% (including 1 complete and 11 partial responses) and DCR of 52% [84]. The 1-year PFS rate was 10.2% with a median OS of 11.2 months and acceptable side effect profile [84]. The study authors did not find an association between PD-L1 nor BRCA status and treatment response [84]. In JAVELIN Ovarian 200, 566 platinum-resistant/refractory ovarian cancer patients were randomized to one of three treatment arms: avelumab alone, pegylated liposomal doxorubicin alone, or both (NCT02580058) [85]. Preliminary results demonstrated that avelumab monotherapy resulted in the worst PFS, and there was no additional benefit with the combination of avelumab to pegylated liposomal doxorubicin (1.9 vs. 3.5 vs. 3.7 months, respectively). Similar results were seen with OS (11.8 vs. 13 vs. 15.7 months) [85]. However, subgroup analyses demonstrated that PD-L1 positivity was associated with slight clinical benefit with combination therapy in terms improved PFS (3.7 vs. 3.0 months; HR 0.65, 95% CI 0.46–0.92) with a trend toward improved OS (17.7 vs. 13.1 months; HR 0.72, 95% CI 0.48–1.08) [85]. Grade 3 TRAEvwere highest in the combination arm (42.9%) followed by PLD alone (31.6%) and avelumab alone (16.0%) [85].

In a phase I study by Infante and colleagues, atezolizumab was administered to 12 patients with advanced ovarian cancer with the majority having at least 2 prior lines of therapy [86]. In preliminary results of the nine patients with an evaluable response, there was a 22% ORR and DCR (two patients with partial response) [86].

4.1.1 Combination Therapy: IO + Chemotherapy

Given the strength immunosuppressive tumor microenvironment and modest response to single-agent immune checkpoint inhibitor therapies, interest has grown to utilize combination therapy in ovarian cancer. Wenham and colleagues presented their preliminary findings at the 2018 International Gynecologic Cancer Society Meeting where platinum-resistant recurrent ovarian cancer patients were treated with weekly paclitaxel and pembrolizumab (NCT02440425) [87]. In the 37 evaluable patients, the ORR was 51.4% (all partial responses) with DCR of 86.5%. The 6-month PFS rate was 64.5% and median PFS 7.6 months with a median OS of 13.4 months [87]. In another phase II nonrandomized clinical trial, Zsiros et al. evaluated pembrolizumab, bevacizumab, and oral cyclophosphamide in a mixed cohort of platinum-sensitive and platinum-resistant ovarian cancer (n = 40) [88]. In the platinum-resistant cohort (n = 30), there were 10 partial and 3 complete responses, making an ORR of 43.3% [88]. The median duration of response was 5.5 months, median PFS 7.6 months, and the disease control rate 93.3% [88]. This regimen was well tolerated and represents a potential therapeutic option for platinum-resistant ovarian cancer that should be investigated in larger studies.

The interim results of two phase III trials combining chemotherapy and immune checkpoint inhibitors in the frontline setting have not demonstrated improved efficacy over chemotherapy alone. In JAVELIN 100, stage III–IV advanced ovarian cancer patients (n = 998) undergoing frontline therapy (with primary cytoreduction or candidates for neoadjuvant chemotherapy and interval cytoreduction) were randomized 1:1:1 to (1) 6 cycles of chemotherapy (carboplatin/paclitaxel) followed by avelumab maintenance, (2) chemotherapy with avelumab followed by avelumab maintenance, and (3) chemotherapy followed by observation [89]. The response rates were similar across all cohorts (ORR 30.4% vs 36% vs 30.4%, respectively) [89]. The hazards ratios for PFS were not statistically significant when comparing the avelumab arms versus the control arm: 1.43 (95% CI 1.1–1.9) for arm 1 versus 3 and 1.14 (95% CI 0.8–1.6) for arm 2 versus 3 [89]. In the IMagyn050/GOG 3015/ENGOT-OV39 trial, stage III/V ovarian cancer patients (n = 1301) undergoing frontline therapy (primary cytoreductive surgery with gross residual disease or candidates for neoadjuvant chemotherapy and interval cytoreduction) were randomized 1:1 to receive 6 cycles of chemotherapy (carboplatin/paclitaxel/bevacizumab) with atezolizumab followed by atezolizumab maintenance or chemotherapy with placebo followed by placebo maintenance [90]. There was no statistically significant improvement in PFS with the atezolizumab arm (median PFS 19.5 months vs. 18.4 months, respectively; HR 0.92 (95% CI 0.70–1.07)) [90]. Furthermore, PD-L1 status did not significantly improve PFS [90].

4.1.2 Combination Therapy: IO + Targeted Therapy

In a phase 1 study by Lee and colleagues, durvalumab was administered with either olaparib (poly-ADP-Ribose inhibitor) or cediranib (vascular endothelial growth factor receptor 1–3 inhibitor) to 26 patients with various cancers, the majority of which was ovarian (73%) [91]. In the 10 evaluable recurrent ovarian cancer patients who received durvalumab and olaparib, the ORR was 20% (two partial responses) with a DCR of 90% [91]. Durable responses in this treatment group were not explained by homologous recombination DNA repair pathway defects, and none of the patients had germline BRCA mutations (two patients who had somatic BRCA mutations had stable disease). For the six evaluable patients who received durvalumab and intermittent cediranib and were assessed for response, the ORR was 50% (all partial responses) and had a DCR of 83% [91]. Although the doublets overall had an acceptable safety profile, daily dosing cediranib treatment was not tolerated due to recurrent grade 2 and non-dose-limiting toxicity grade 3 and 4 TRAE [91]. A biomarker analysis of a subset of the tumors demonstrated some clinical benefit correlated with tumoral PD-L1 expression [92]. In a larger cohort of recurrent, platinum-resistant ovarian cancer patients (majority consisting of BRCA wild types), Lee and colleagues found that durvalumab and olaparib had an ORR of 14.7% (five partial responses, two with germline BRCA mutated, and three with BRCA wild type) and DCR of 52.9% (NCT02484404) [93]. In another durvalumab/olaparib study, Drew et al. administered olaparib followed by maintenance olaparib and durvalumab therapy in platinum-sensitive ovarian cancer patients with germline BRCA-mutations (MEDIOLA study; NCT02734004) [94]. In the 32 patients, there was an ORR of 63% (14 partial and 6 complete responses) with a DCR of 81% at 12 weeks and tolerable safe profile [94]. In TOPACIO/KEYNOTE-162, the investigators examined another PARPi/immune checkpoint inhibitor combination in a different patient population consisting of recurrent, platinum-resistant ovarian cancer patients with enrollment regardless of BRCA mutational status [95]. In this phase I/II study, niraparib and pembrolizumab were given to a cohort of 67 patients with ovarian or triple-negative breast cancer [95]. In the 60 evaluable ovarian cancer patients, the ORR was 18% (eight partial and three complete responses), and the DCR was 65% (three with acceptable treatment side effect profile) [95]. The ORRs were seen to be consistent regardless of platinum-based chemotherapy sensitivity, previous bevacizumab, somatic BRCA tumor mutation, or homologous recombination defect biomarker status [95].

In another combination doublet study, Liu and colleagues tested nivolumab plus bevacizumab in a mixed cohort of platinum-sensitive and platinum-resistant ovarian cancer patients [96]. In the preliminary analyses of 38 patients, there was an ORR of 26.3% (10 partial responses with the majority in platinum-sensitive patients) with a DCR of 34.2% and tolerable side effect profile (NCT02873962) [96].

4.1.3 Combination Therapy: IO Combinations

In the phase II NRG-GY003 trial, 100 recurrent ovarian cancer patients with a platinum-free interval < 12 months were randomized to either nivolumab alone (n = 49) or nivolumab/ipilimumab (n = 51) followed by maintenance nivolumab [97]. The ORR at 6 months was higher in the combination group than the monotherapy group (31.4% vs. 12.2%, respectively; OR 3.28, p = 0.034) [97]. Furthermore, median PFS was slightly better in the combination group (3.9 vs 2 months, respectively; HR 0.53 (95% CI 0.34–0.82). Interestingly, clear cell histologies had fivefold odds of response with combination therapy compared to other histologies (p = 0.0498) [97]. Grade ≥ 3 adverse events were higher in the combination group than the monotherapy group (49% vs 33%, respectively) but were overall well tolerated [97].

There is a plethora of ongoing clinical trials of combination therapy with immune checkpoint inhibitors, and these include but are not limited to the following:

  • NCT02839707: phase II/III trial of atezolizumab and pegylated liposomal doxorubicin vs atezolizumab, pegylated liposomal doxorubicin, and bevacizumab vs pegylated liposomal doxorubicin and bevacizumab

  • ATLANTE (NCT02891824): phase III trial of physician’s choice platinum chemotherapy, bevacizumab, and atezolizumab vs platinum chemotherapy, bevacizumab, and placebo

  • FIRST (NCT03602859): standard of care chemotherapy with niraparib vs standard of care chemotherapy with dostarlimab vs standard of care chemo with placebo

  • MK-7339-001/KEYLYNK-001/ENGOT-ov43/GOG-3036 (NCT03740165): phase III trial of standard of care chemotherapy with niraparib and pembrolizumab vs standard of care chemotherapy with niraparib-placebo and pembrolizumab vs standard of care chemotherapy with niraparib and pembrolizumab-placebo

  • DUO-O (NCT03737643): phase III trial of standard of care chemotherapy with olaparib, durvalumab, and bevacizumab vs standard of care chemotherapy with olaparib-placebo, durvalumab, and bevacizumab vs standard of care chemotherapy with olaparib, durvalumab-placebo, and bevacizumab

  • ATHENA (NCT03522246): phase III trial of maintenance rucaparib with or without nivolumab following frontline chemotherapy

  • NCT02608684: phase II trial of pembrolizumab, gemcitabine, and cisplatin

4.2 Vaccines in Epithelial Ovarian Cancer

Vaccines have been a point of interest in ovarian cancer to target tumor-associated antigens. NY-ESO-1 is expressed in >40% of advanced epithelial ovarian cancers and is one of the tumor-associated antigens of interest for vaccine therapy [98] (Table 6). In a study by Diefenbach et al., high-risk ovarian cancer patients with HLA-A*0201 positivity had the administration of NY-ESO-1b peptide and Montanide vaccination series following primary debulking and chemotherapy [99]. In the nine patients evaluated, the vaccine series was overall well-tolerated and appeared to mount a T-cell immunity response regardless of tumor expression of NY-ESO-1 and three patients with NY-ESO-1-negative tumors having clinical remission at 25, 38, and 52 months [99]. In another phase I study, the addition of NY-ESO-1 vaccine and decitabine (DNA methylation inhibitor) following doxorubicin chemotherapy for 10 patients with recurrent epithelial ovarian cancer demonstrated increased antibody production and T-cell responses with an ORR of 10% (1 partial response) and DCR of 60% [100]. A phase I trial by Sabbatini et al. demonstrated that vaccine adjuvants to NY-ESO-1 such as Montanide-ISA-51 preparation and toll-like receptor ligand poly-ICLS (polyinosinic-polycytidylic acid-stablized by lysine and carboxymethylcellulose) can generate a stronger immune response in terms of antibody and CD8+ activity [101].

Table 6 Reported vaccine therapy trials in epithelial ovarian cancer
Full size table

Dendritic cell vaccines have also been used in several trials. In a phase I/II trial, 11 ovarian cancer patients in their first or second clinical remission received monocyte-derived dendritic (DC) loaded with Her2/neu (highly expressed in ovarian cancers), human telomerase reverse transcriptase, and pan-DR peptide antigens with or without cyclophosphamide chemotherapy prior to administration [102]. Overall 3-year survival was 90% with a trend toward survival in those who received cyclophosphamide therapy prior to vaccination [102]. In a phase I/II study, Baek et al. administered autologous dendritic-cell vaccination with IL-2 consolidation following debulking and chemotherapy and demonstrated good tolerability in 10 patients [103]. Three patients had maintenance of complete remission after vaccination for 83, 80.9, and 38.2 months, and one patient had complete response for 50.8 months [103]. Increased immune response and reduced immune-suppressive factor secretion were also evident [103]. Another study compared autologous dendritic cell vaccine with chemotherapy to chemotherapy alone for recurrent platinum-sensitive ovarian cancers and demonstrated a trend toward improved ORR (87.5% vs. 62.5%, respectively) for the vaccine cohort (NCT02107950) [104]. A European multicenter, phase II study found that sequential administration of dendritic vaccines following primary cytoreductive surgery and chemotherapy had a trend of improved PFS compared with concomitant administration with adjuvant chemotherapy (24.3 vs. 18.3 months, p = 0.05) (NCT02107937) [105].

Kuwano et al. investigated the use of personalized vaccination based on HLA-type and preexisting host immunity (by IGG response levels to tumor-associated antigens) and have demonstrated some disease stabilization with good tolerability [106]. Personalized vaccine generated by autologous dendritic cells pulsed with oxidized autologous whole-tumor cell lysate also demonstrated broad antitumor immune response activity [107].

In the DeCidE trial, DPX-Survivac (vaccine containing mix of HLA class I peptides against survivin antigen), low-dose cyclophosphamide, and epacadostat (selective inhibitor of indoleamine 2,3-dioxygenase 1) were administered to stage IIC–IV recurrent ovarian cancer patients (NCT02785250) [108]. Preliminary results in the 10 evaluable patients demonstrated an ORR of 30% (3 partial responses) and DCR of 60% with good treatment tolerability [108].

In the VITAL study, the investigators utilized an autologous tumor cell vaccine (gemogenovatucel-T) in stage III/IV high-grade serous, endometrioid, or clear cell ovarian cancer that had a complete response to carboplatin/paclitaxel frontline therapy [109]. Gemogenovatucel-T is an autologous tumor cell vaccine generated from harvested tumor and transfected ex vivo with a plasmid encoding the GMCSF gene and a bifunctional short-hairpin RNA that ultimately reduces expression of immunosuppressive TGF-β1 and TGF-β2 [109]. In this phase IIb trial, 91patients were randomized to gemogenovatucel-T (n = 47) or placebo (n = 44) [109]. The recurrence-free survival (RFS) was similar between the treatment and placebo groups (11.5 months vs. 8.4 months, respectively; p = 0.078) [109]. However, in a post-hoc analysis among patients with BRCA wild-type tumors, RFS was improved in the treatment group, compared to the placebo group (HR 0.50, 90% CI 0.30–0.88; p = 0.02) [109]. The 1-year and 2-year RFS rates were improved in the treatment group compared to the placebo group (51% vs 28%, respectively, p = 0.036; 33% vs. 14%, respectively, p = 0.048) [109]. The vaccine was observed to safe with no grade 3–4 TRAEs [109].

A trial by O’Cearbhaill et al. sought to investigate the safety and efficacy of a polyvalent vaccine-Keyhole limpet hemocyanin (KLH) conjugate with the adjuvant OPT-821 compared to OPT-821 alone [110]. The investigators randomized, in 1:1 fashion, 171 ovarian cancer patients in their second or third clinical remission to vaccine and adjuvant (n = 86) vs. adjuvant alone (n = 85). Despite being tolerable, the combination therapy was modestly immunogenic and did not improve PFS or OS [110].

4.3 ACT in Epithelial Ovarian Cancer

Multiple trials have examined ACT in ovarian cancer. The first trial that was by a 1991 study by Aoki et al. examined TIL therapy without IL-2 infusion in advanced or recurrent ovarian cancer with or without cisplatin-containing combination chemotherapy [111]. In the TIL group without chemotherapy, there was an ORR of 71.4% (one complete and four partial responses), while the group with both TIL and chemotherapy had a 90% ORR (seven with complete response and two with partial responses) which 4 of the 7 patients with complete responses did not have recurrence for >15 months of follow-up (Table 7) [111]. Another study by Ikarashi et al. demonstrated that TIL therapy may also induce increased cytotoxic T-cell and natural killer cell activity [112]. Another study by Fujita and colleagues compared patients with EOC following primary debulking and chemotherapy who were treated with TIL therapy without IL-2 infusion compared to controls. In their small study, they found that those who received TIL therapy had a better 3-year overall survival (100% vs. 65.5%) and PFS (82.1% vs. 54.5% respectively) rate compared with the control group [113]. In contrast to the above previous three studies, Pedersen et al. utilized an IL-2 infusion following TIL therapy in six patients with progressive platinum-resistant disease [114]. The DCR was 100% with five patients who had a reduction in size of target lesions (but did not meet partial response criteria) and antitumor reactivity seen in the TIL infusion products [114]. However, they noted that the lack of better therapeutic response may be due to high expression of lymphocyte-activation gene 3 (LAG-3) and PD-1, which are both involved in immune inhibitory signaling when interacting with MHCII and PD-L1, respectively [114]. In another study by the previous group, Kverneland et al. treated six patients with advanced-stage metastatic high-grade serous ovarian cancer with ipilimumab followed by TIL extraction and re-infusion with expanded TILs with low-dose IL-2 and nivolumab [115]. In their results, there was one partial response with the remaining five having stable disease for up to 12 months [115]. Most of the grade 3–4 toxicity was related to the conditioning chemotherapy prior to TIL infusion [115]. Another study by Freedman et al. examined the administration of intraperitoneal TIL therapy with IL-2 in 11 patients and found clinical activity in 4 patients: ascites regression (2 patients), tumor and Ca-125 reduction (1 patient), and stable tumor and CA-125 levels in 1 patient [116].

Table 7 Reported trials in adoptive cell therapy in epithelial ovarian cancer
Full size table

5 Other Gynecologic Malignancies

There are few immunotherapy studies in other gynecologic malignancies. Quéreux and colleagues examined patients with metastatic or unresectable vulvar and vaginal melanomas who received immune checkpoint inhibitors in a retrospective review [117]. In the six patients that received ipilimumab, there were four patients with progressive disease, one stable response, and one patient who had a partial response but 89% reduction in tumor volume and a survival of 31 months [117]. In the eight patients that were treated with nivolumab, there were partial responses in four patients [117]. One vaginal melanoma patient had received both ipilimumab and nivolumab and had a partial response [117]. In CheckMate 358, the vulvovaginal cohort (two vaginal and three vulvar squamous cell carcinomas) was treated with nivolumab with one partial response observed in the vulvar cancer patient [118]. In a phase II basket trial of advanced rare tumors (including cohorts of squamous cell carcinoma of the vagina or vulva (two vaginal and one vulva), granulosa cell tumor of the ovary (four adult type and one juvenile type), and gynecologic extrapulmonary small cell carcinoma), patients were treated with pembrolizumab [119,120,121]. Although there were no confirmed responses, one vaginal cancer had an 81% reduction in her target tumor lesions, and one vulvar cancer patient had 30% reduction in her target tumor lesions but discontinued treatment due to a grade 3 mucositis before a confirmatory scan was performed for the partial response [119]. In the patients with granulosa cell tumor of the ovary, there were no responses, but the disease control duration was 565 and 453 days for 2 adult-type granulosa cell tumors [120]. In the cohort with gynecologic extrapulmonary small cell carcinoma, there were six cervical and one vulvar carcinomas [121]. However, pembrolizumab demonstrated minimal activity in these patients (no responses: one patient with stable disease and six with progressive disease) [121]. Future studies should evaluate the use of combinational immunotherapeutic regimens in these rare tumors.

6 Conclusion

Immunotherapeutic options hold modest but promising results in gynecologic cancers. Although a number of early studies have found limited clinical efficacy of vaccines as a monotherapeutic strategy, therapeutic vaccines may be useful as an adjunct in oncologic treatment as we await future trial results. Demonstrating impressive clinical responses in other solid tumors (e.g., metastatic melanoma), ACT and its utilization in gynecologic cancers are growing, and this approach has demonstrated promising early results in cervical and ovarian cancer. Additionally, immune checkpoint inhibitors have demonstrated durable clinical responses in various clinical trials, and this has resulted in granting approval for select patient populations (e.g., pembrolizumab for MSI-H/dMMR/TMB-H tumors and PD-L1 positive cervical cancers). Combination immune checkpoint inhibitor therapy demonstrates promise in the treatment of advanced/recurrent cervical cancer. Although immune checkpoint inhibitors have been the focus of interest in immunotherapy, there has been an explosion of new clinical trials in the recent years to investigate other modalities as well. With the modest results of using one immunotherapeutic agent, combination therapy utilizing agents from various immunotherapeutic/cytotoxic/targeted modalities is being investigated in multiple trials and to determine the optimal treatment regimens for right subset of patients. As demonstrated with the impressive response rates of pembrolizumab and lenvatinib in MSS endometrial cancer, combination therapy can overcome immune checkpoint inhibitor resistance. However, with a wealth of new immune-modulatory drugs, there will need to be a rethinking and innovation of clinical testing and trial design to optimize financial and clinical resources in pursuit of improved oncologic outcomes.