Until recently, chemotherapy, including platinum-based reagents and taxanes, has been at the center of medical therapy for solid tumors, including gynecologic cancers; however, the so-called molecular target reagents have begun to drastically change cancer treatment. Among those, immunotherapeutic drugs represent the newest and most promising modality in the field of oncology. Although immune-based cancer treatment has long been viewed as a promising modality, only recently has its clinical efficacy equaled or surpassed conventional chemotherapy.

The development of novel immunotherapy has been achieved by the introduction of the so-called “immune checkpoint inhibitor” drugs, especially those with antibodies that block the PD-L1/PD-1 (programmed cell death ligand-1/programmed cell death-1) immune signal. PD-1 was originally identified as a molecule that is physiologically expressed in specific immune cells, and it is regarded as an inhibitor of immune overreaction such as autoimmune disease [2]. However, later findings indicate that PD-1 plays an important role in host-tumor immunity (Fig. 4.3). Two ligands for PD-1, PD-L1 and PD-L2, were subsequently identified [2], and the expression of PD-L1 in cancer cells was reported in various malignant tumors. In addition, immune-inhibitory signals via PD-1 on immune cells have been associated with poorer clinical courses of various cancers [2]. Therefore, if we can block the signal by some means, we can expect the restoration of tumor immunity and clinical benefits (Fig. 4.4). In fact, as mentioned below, studies have increasingly reported the clinical effectiveness of immunotherapies targeting the PD-L1/PD-1 signal, namely, the immune checkpoint inhibitor [2].

In 2010, the first Phase I study using an anti-PD-1 antibody, nivolumab, was conducted on various solid tumors including melanoma, non-small cell lung cancer, renal cell carcinoma, and prostate and colorectal cancer [3]. In 2012, a Phase I study using nivolumab was conducted on 296 patients with non-small cell lung cancer, melanoma, or renal cell carcinoma. The clinical response was surprisingly high given that the mean RR values of this study were 18%, 28%, and 27%, respectively, taking into consideration that the patients had refractory disease [4]. Following this trial, numerous trials for various malignancies have been conducted or are being conducted using both anti-PD-1 and anti-PD-L1 antibodies.

The efficacy of nivolumab and pembrolizumab, another anti-PD-1 antibody for melanoma, which is known to be relatively sensitive to immunotherapy, was investigated in Phase III trials. In a trial with nivolumab, which was used as a first-line treatment, the 1-year overall survival rate was 73% for nivolumab and only 42% for the control dacarbazine [5]. In another Phase III trial for advanced melanoma, nivolumab treatment also showed a threefold higher response rate compared with chemotherapy [6]. Another Phase III trial compared three immunotherapies: pembrolizumab every 2 weeks, pembrolizumab every 3 weeks, and ipilimumab every 3 weeks; the results showed that treatment with pembrolizumab every 2 weeks or every 3 weeks exhibited a better response rate than treatment with ipilimumab every 3 weeks [7].

Lung cancer is another malignancy in which the efficacy of anti-PD-L1/PD-1 therapy has been shown. A randomized Phase III trial comparing nivolumab to docetaxel in patients with advanced NSCLC indicated that the overall survival rate at 1 year was significantly better for the nivolumab group than for the docetaxel group [8, 9]. In early phase trials, anti-PD-L1 antibodies have also shown promising efficacy in patients with NSCLC [10, 11].

The CTLA-4 receptor has a similar function to PD-1, and it is known as another “immune checkpoint molecule.” By stimulating CD80/CD86 on antigen-presenting cells, CTLA-4 induces the arrest of effector T cells, which ultimately leads to immunosuppression. Therefore, the abrogation of the CTLA-4 signal by the anti-CTLA-4 antibody can be expected to have antitumor effect by restoring T cell activity [12, 13]. The anti-CTLA-4 antibody ipilimumab was approved by the FDA for metastatic melanoma. Recently, a combination effect of ipilimumab and nivolumab has been reported, suggesting that these two immune checkpoint molecules have independent functions [14, 15].

The expression of PD-L1 in tumor tissue is the most investigated candidate for predicting the effectiveness of anti-PD-L1/PD-1 therapy. There have been many studies of the expression of PD-L1 in cancers, including urothelial cancers, gastrointestinal cancer, lung cancer, breast cancer, melanoma, and ovarian cancer [2, 16, 17]. In many of these cancers, PD-L1 expression is correlated with poor patient outcomes, suggesting that PD-L1 expression has a biologically favorable effect on the survival of cancer cells [18]. However, as a biomarker, PD-L1 expression has not received a stable appraisal. Neither all of the cancers nor all of the cases show an association between the expression of PD-L1 and the effects of anti-PD-L1/PD-1 therapy [2, 19]. This discrepancy is partly due to the unstable evaluation of PD-L1 expression using various anti-PD-L1 antibodies in each study. However, the role of PD-L1 in the cancer immune landscape is not fully understood yet, and further biological clarification is needed to determine if PD-L1 expression could serve as an immunologic biomarker.

Another possible candidate for an immunological biomarker is the mutation burden, that is, the total amount of mutation. Cancers in which immune checkpoint inhibition is effective are known to have more genetic mutations. Moreover, within one cancer type, it is thought that immune checkpoint inhibition may be effective when an individual case has more mutations [2, 20, 21]. In a study of colorectal cancer, the anti-PD-1 antibody pembrolizumab was effective only in patients with a mismatch repair deficiency, who naturally harbor many genetic mutations, while it was not effective in patients without a mismatch repair deficiency and who had fewer mutations [22]. Therefore, the mismatch deficiency or mutation burden of each cancer could be a predictive biomarker in anti-PD-1 therapy. Similarly, it has been reported that patients with more transversion mutations, which are known to be a “smoking signature,” were more sensitive to pembrolizumab [23].

Although it is not still clear whether whole mutation burden or specific mutation phenotype can be used as predictive biomarkers, recent advancements in analyzing mutation in a comprehensive way may contribute to the development of a practical biomarker for immunotherapy [24, 25]. Development of biomarkers is also expected to contribute to the personalization of immunotherapy as mentioned below.

Therapeutic cancer vaccines have been regarded as a potentially promising modality for cancer treatment. These vaccines are usually generated by tumor-specific antigens. By administering these tumor antigens, an immune reaction of specifically targeted tumor cells is elicited, which causes tumor cell distraction by multiple mechanisms including cytotoxic cell-mediated tumor lysis. However, with rare exceptions, most of the past trials of cancer vaccine as a monotherapy failed, suggesting that cancer cells possess the capability to escape from systemic tumor immunity. Nevertheless, it is expected that, in combination with strategies that prevent tumor immune escape such as the anti-PD-1 antibody, cancer vaccines may enhance the effect of immunotherapy. In fact, an animal study has shown that a combination of the stimulator of interferon gene (STING) and anti-PD-1 resulted in enhanced innate immunity and improved response [26].

Cancer vaccines are theoretically an ideal tool for precision and personalized medicine because tumor antigens, which are the main element of cancer vaccines, are thought to vary among cancers. Therefore, by estimating immunogenicity in each case by analyzing the expression of possible tumor antigens, one can predict whether cancer vaccination is suitable for each cancer patient. Additionally, cancer vaccines may be optimized according to the tumor antigens that each cancer expresses.

An apparent target of cancer vaccines that can serve as tumor antigens is nonsynonymous mutations in cancer cells. Mutant proteins resulting from a genetic mutation can be detected by the immune system as non-self epitopes and can elicit an immune reaction to the cancer cells [27]. It is still unclear whether host-tumor immunity depends on the absolute number of mutant proteins or on specific types of mutations. In any case, whole-genome-based analysis of cancer cells may soon clarify what types of mutations contribute to tumor immunity. Based on the results of next-generation sequencing, a personalized vaccine consisting of multiple mutant proteins may be produced in each case [28].

Adoptive T cell transfer therapy has long been in use in clinical settings [1]. Initially, autologous lymphocytes are extracted from an excised tumor specimen. They are then cocultured with IL2, which facilitates ex vivo growth. T cells are expanded to as high as one hundred billion and then transferred into patients. Clinical studies have shown that this has a significant clinical effect in at least some types of tumors. However, clinical efficacy has been shown in only a few types of tumors such as melanoma. Obstacles include technical difficulties in expanding effective T cells given costs and time limitations.

Recently, adoptive transfer therapy has moved into a new stage by adapting to increase patient specificity [29]. This has been enabled by genetically engineering T cells with chimeric antigen receptors (CARs) and by modifying T cell receptors to redirect the specificity of T cells. These strategies have been shown to be effective for personalization by making T cells recognize a specific antigen that is expressed by an individual tumor. There are, however, several issues still to be addressed. First, antigen recognition should lead to functionally effective cytotoxicity. Second, engineered T cells should persist long enough in vivo to exert a clinical effect. Third, they should be effectively trafficked to the target site. In vitro experiments show promising results regarding these issues, but the results should be confirmed in clinical settings.

Several trials have been conducted on CA-125, the most common tumor marker of ovarian cancer, which is expected to serve as a tumor antigen. Although oregovomab, an antibody targeting CA-125, has been demonstrated to elicit anti-CA-125 T cell responses [30], a randomized, placebo-controlled Phase III trial in a maintenance setting of patients with advanced ovarian cancer showed no significant survival benefit [31]. Likewise, farletuzumab, a monoclonal antibody against folate receptor alpha, failed to show apparent efficacy in combination with chemotherapy in large studies [32].

The efficacy of cancer vaccines such as specific peptides, proteins, and DC vaccines has also been investigated in clinical trials. Significant cellular and antibody response to the antigens were observed in most of them, but the clinical benefit of vaccination has not been clearly shown. The primary function of IFN-γ is to augment the antitumor immune response. However, a Phase III trial of IFN-γ plus carboplatin/paclitaxel versus carboplatin/paclitaxel alone for advanced ovarian carcinomas was discontinued early due to the significantly shorter OS time of the patients who were receiving IFN-γ [33, 34].

We have conducted a first principal investigator-initiated Phase II clinical trial of nivolumab. Two cohorts, 1 or 3 mg/kg, n = 10 each, were tested for 20 platinum-resistant recurrent ovarian cancer patients [35]. The response rate for 3 mg/kg was 20%, including two cases of a durable complete response. The overall response rate for all 20 patients was 15%. The median progression-free survival and overall survival rates were 3.50 months and 20.0 months, respectively. The results of Phase Ib clinical trials with the anti-PD-1 antibody pembrolizumab and the anti-PD-L1 antibody avelumab have also been reported. In a pembrolizumab trial of 26 patients with PD-L1 positive advanced ovarian cancer, the response rate was 11.5% [36]. In another Phase Ib trial of avelumab with 75 patients with recurrent or refractory ovarian cancer, the response rate was 10.7% [37]. Considering that most of the patients recruited for these trials were heavily treated, including for platinum-resistant tumors, the results are thought to be promising and warrant further confirmation. One of 11 patients with ovarian cancer treated with ipilimumab led to an objective response [38]. Table 4.1 lists ongoing trials of immune checkpoint inhibitors in gynecologic cancers.

Immunotherapy for endometrial cancer is not popular because the prognosis for a patient with this disease is much better than it is for a patient with ovarian cancer, and surgery can cure the patient in a majority of cases. However, it is likely that in specific cases of endometrial cancer, immunotherapy may be very effective. As mentioned above, for colon cancer, pembrolizumab has been shown to be more effective for patients with mismatch repair deficiency compared to those without [22]. Considering that approximately 20–30% of endometrial cancers have a mismatch repair deficiency phenotype, these specific patients could be good candidates for immune checkpoint inhibition, thus enabling precision treatment according to the characteristics of the tumor.