Over the past decade, the ability of cancer cells to evade immune destruction has become recognized as one of the hallmarks of cancer. This understanding has paved the way for the development of novel therapeutic agents that can enhance activation of antitumor immune responses or reverse immunosuppressive mechanisms through which tumors escape immune-mediated rejection. The treatment of gynecologic cancers remains a therapeutic challenge, as these malignancies are often diagnosed in advanced stages, and many patients relapse despite appropriate management. Clinical trials have shown efficacy for various immunotherapeutic strategies, especially the use of tumor-targeting antibodies; enhancement of tumor antigen presentation, such as with vaccines and toll-like receptor agonists; and the targeting of immunosuppressive mechanisms, such as via checkpoint blockade. Emerging data on new and combination approaches currently under investigation provide a strong rationale for these approaches.
Each year almost 90,000 women in the United States are diagnosed with gynecologic malignancies, and over 28,000 will die from their disease. Many women with early-stage disease are cured with a combination of surgery, radiation, and chemotherapy. However, especially in the case of ovarian cancer, the malignancies are often diagnosed at advanced stages, and many patients relapse despite appropriate management. The treatment of gynecologic cancers represents a therapeutic challenge, and there is an unmet clinical need for new therapies.
Over the past decades, the field of tumor immunology has gained much attention as the ability of cancer cells to evade immune destruction has become recognized as one of the hallmarks of cancer. Cancer immune surveillance, considered to be an important host protection process for preventing carcinogenesis, relies on components of both the innate and the adaptive immune systems. Recognition of tumor cells by the immune system initially involves the uptake of tumor cell fragments by professional antigen-presenting cells (APCs), such as dendritic cells (DCs). The processing of the tumor fragments involves digestion of the tumor proteins into small peptides, which then get loaded onto major histocompatibility complex (MHC) class I and class II proteins and presented on the surface of the APCs. Some of the displayed peptides represent tumor-associated antigens (TAAs), which are either new peptides resulting from specific mutations (neoantigens) or peptides representing the proteins preferentially expressed in cancer cells over normal tissues (eg, cancer-testis antigens, differentiation antigens).
Activated APCs then migrate to the tumor-draining lymph nodes, where they present the MHC-peptide complexes to naive T cells. Activation of T cells specific for the MHC-peptide complex requires two separate signals: (1) interaction of the MHC-peptide complex with a T-cell receptor, and (2) interaction of the costimulatory receptor CD28 on the surface of T cells with its ligand (B7-1, B7-2) on the surface of APCs. Following activation, tumor-specific T cells then migrate through the systemic vasculature to the tumor sites, where recognition of TAAs on the surface of tumor cells leads to T-cell–mediated tumor cell lysis.
Recognition of the steps involved in the antitumor immune response has paved the way for the development of novel therapeutic agents that can enhance activation of these responses or reverse immunosuppressive mechanisms that allow tumors to escape from immune-mediated rejection. Various stages of the antitumor immune response can be targeted, and the approaches used to do this can be categorized into three general strategies: (1) augmenting tumor antigen presentation, utilizing agents such as vaccines, toll-like receptor (TLR) agonists, and oncolytic viruses; (2) focusing on enhancement of T-cell activity, either through adoptive cell approaches or through the targeting of activating and inhibitory proteins on T cells; and (3) targeting additional immune inhibitory mechanisms in the tumor microenvironment (Figure).
A number of immunotherapeutic approaches have been tested in gynecologic malignancies. In this review, we will summarize clinical trials that have used various immunotherapeutic strategies, with a particular focus on recently emerging data for new agents and combinations.
In 2015, there were an estimated 21,290 new cases of epithelial ovarian cancer in the United States, with 14,180 deaths, representing 2.4% of all US cancer deaths. Epithelial ovarian cancer is the fifth leading cause of cancer death among women, accounting for more deaths than any other cancer of the female reproductive system. Unfortunately, the majority of patients with epithelial ovarian cancer relapse despite appropriate treatment, and ultimately they die from their disease.
While it was originally felt that epithelial ovarian cancer would not respond well to immunotherapy, research has, in fact, demonstrated a key role for the immune system in the control of epithelial ovarian cancer cell growth. This is supported by the observation that increased levels of tumor-infiltrating lymphocytes (TILs) in ovarian cancer were associated with improved prognosis, with a 5-year survival of 38% in patients whose tumors contained T cells, and 4.5% in those whose tumors did not contain T cells. In a separate study focusing on the subtypes of T cells in ovarian cancer, a higher frequency of tumor-infiltrating CD8+ lymphocytes and increased ratios of CD8+ lymphocytes to regulatory T cells (Tregs) were also found to be associated with improved survival. In addition, tumor-reactive antibodies and T cells have been isolated from the peripheral blood of patients with epithelial ovarian cancer, suggesting a spontaneous antitumor immune response.[10,11] These studies have provided the rationale for exploring different immunotherapeutic strategies in epithelial ovarian cancer.
Therapies to enhance tumor antigen recognition
Strategies that aim to enhance tumor recognition by the immune system can be collectively grouped into vaccines and innate immune activators; included in the second group are TLR agonists, type I interferon (IFN), and oncolytic viruses.
Vaccines. The identification of unique differentiation proteins expressed in epithelial ovarian cancer has led to the exploration of various vaccination approaches, including simple vaccine preparations consisting of specific peptides and proteins, as well as more complex strategies, such as engineered cellular vaccines, DC vaccines, virus-vectored vaccines, and oncolytic viruses. The majority of studies have explored the cancer-testis antigens (eg, NY-ESO-1) and proteins known to be overexpressed in epithelial ovarian cancer (eg, p53, survivin, and MUC1); a comprehensive review of vaccination strategies that have been explored in epithelial ovarian cancer is published elsewhere. Although many studies have demonstrated induction of an immune response to the vaccines, very few have demonstrated clinical benefit. It is likely that these strategies are insufficient to overcome immune tolerance to self-antigens and to result in efficient activation of antigen-specific T cells, although they may prove to be valuable in combination with other therapies.
Innate immune activators. Another strategy for enhancing tumor antigen presentation by APCs involves agents that target the innate immune response. Antigen processing and presentation by APCs requires activation signals, which are provided via activation of pattern-recognition receptors (PRRs) such as TLRs. TLRs recognize signature molecules that are broadly shared by various pathogens and, in addition, sense “danger signals” in the tumor microenvironment, which consist of endogenous molecules produced by dying cells. A phase I study of VTX-2337 (motolimod), a small-molecule agonist of TLR8, in combination with liposomal doxorubicin in patients with advanced epithelial ovarian cancer, demonstrated safety and evidence of immune activation and clinical benefit. A phase II study evaluating motolimod in combination with liposomal doxorubicin (ClinicalTrials.gov identifier: NCT01666444) is ongoing.
Activated APCs produce type I IFN, which plays a role in the antiviral immune response; it has also been demonstrated to be indispensible for tumor antigen presentation by APCs. Although type I IFN has been evaluated in various cancer types and is approved for use as adjuvant therapy in patients with resected melanoma, in a study by Alberts et al, systemic or intraperitoneal administration of IFNα had limited activity in patients with epithelial ovarian cancer and was associated with frequent toxicities.
Oncolytic viruses have inherent properties that allow them to replicate in cancer cells while sparing normal tissues. While serving as tumor-debulking agents, oncolytic viruses also activate the innate immune response on multiple levels through the release of tumor antigens, PRR ligands, and danger signals, and via production of type I IFN. Several trials using oncolytic viruses in patients with epithelial ovarian cancer have demonstrated safety and durable clinical benefit in some patients.
Overall, strategies to enhance tumor antigen presentation by the innate immune system have been demonstrated to be safe, but to date, their efficacy has been marginal. The future of drugs that enhance tumor antigen presentation in patients with epithelial ovarian cancer probably will be seen in combination therapies in which the T-cell response primed with a vaccine or an innate immune activator is further driven through therapies targeting T-cell activation and adaptive immune responses.
Therapies to enhance T-cell activation
The survival, proliferation, and activation of T cells are controlled by a variety of factors, including cytokines and a range of immunostimulatory and inhibitory receptors. Several studies have explored agents targeting T cells as immunotherapy in epithelial ovarian cancer, including drugs that target pathways of T-cell activation, as well as adoptive T-cell strategies.
Cytokines. The cytokines interleukin (IL)-2 and IL-12 are potent activators of T-cell proliferation and cytotoxicity. Their use as anticancer agents has been explored in multiple types of cancer, including ovarian. The use of both agents, administered systemically, is limited by toxicity. A phase I/II study of intraperitoneal IL-2 in patients with persistent or recurrent epithelial ovarian cancer showed an overall response rate of 25.7%, although the regimen was associated with significant toxicity. A different strategy for delivery of IL-12—the use of IL-12–expressing plasmids—has been explored. In a recent study, 22 patients with recurrent epithelial ovarian cancer who received intraperitoneal EGEN-001, an IL-12 plasmid formulated with lipopolymer, demonstrated a 35% stable disease rate.
Immune checkpoint blockade. Identification of the costimulatory and coinhibitory receptors that regulate T-cell activation led to the development of antibodies that target these receptors. Targeting such receptors, an approach termed “immune checkpoint blockade,” has demonstrated significant activity in preclinical cancer models and in clinical trials. In particular, antibodies targeting the inhibitory receptors cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1), as well as the PD-1 ligand (PD-L1), are the agents of this type that are most advanced in clinical development, with the CTLA-4–targeting agent ipilimumab approved for use in treating metastatic melanoma and the PD-1–targeting agents nivolumab and pembrolizumab approved for use in treating melanoma and non–small-cell lung cancer.
Based on these findings, therapy with immune checkpoint blockade has been evaluated in trials in patients with epithelial ovarian cancer. Despite its activity in metastatic melanoma, the efficacy of the CTLA-4–targeting antibody in epithelial ovarian cancer as a single agent has so far been limited. In 11 patients with epithelial ovarian cancer who received GVAX, an autologous tumor cell vaccine expressing granulocyte-macrophage colony-stimulating factor, treatment with ipilimumab led to an objective response in 1 patient that was durable for over 4 years. In comparison, emerging clinical data indicate that targeting of PD-1 and PD-L1 may be a promising strategy in epithelial ovarian cancer. In a phase I study of an anti–PD-L1 antibody in patients with advanced cancer, 22% of the 17 patients with epithelial ovarian cancer had evidence of an objective response or stable disease lasting at least 24 weeks. In a phase I study of the anti–PD-1 antibody nivolumab in 20 evaluable patients with epithelial ovarian cancer, the best overall response rate was 15%, which included 2 patients with durable complete responses; total disease control rate was 45%. Similar activity was reported for the PD-L1–blocking antibodies avelumab and pembrolizumab, with response rates ranging from 11% to 17% and disease control rates of up to 65%.[24,25] Larger studies using these agents are currently underway.
The combination of CTLA-4 and PD-1 blockade has been associated with additive and even synergistic activity in animal models. A recent phase III study evaluating combined CTLA-4 and PD-1 blockade (with ipilimumab and nivolumab, respectively) in patients with melanoma demonstrated enhanced response rate and progression-free survival compared with either agent alone, leading to recent US Food and Drug Administration approval of the combination for the treatment of melanoma, although the regimen did result in high rates of grade 3 toxicity. An ongoing NRG Oncology Group randomized phase II study (ClinicalTrials.gov identifier: NCT02498600) is comparing the combination of nivolumab and ipilimumab vs nivolumab alone to determine whether the combination is also active and safe in patients with epithelial ovarian cancer who have relapsed.
Adoptive T-cell therapies. Adoptive cell therapies (ACTs) rely on the infusion of large numbers of autologous tumor-reactive T cells that have been isolated from tumors and expanded in vitro. Early studies reported significant efficacy for this approach in epithelial ovarian cancer, although these studies were necessarily biased by the selection of patients from whom a sufficient quantity of TILs could be isolated. Additional studies using ACT in epithelial ovarian cancer are ongoing (ClinicalTrials.gov identifiers: NCT02482090, NCT01883297). As an alternative strategy, engineered T-cell technologies avoid the need for isolation of TILs. Using this strategy, peripheral-blood autologous lymphocytes are transduced either with a T-cell receptor that recognizes a specific tumor antigen MHC-peptide or with a chimeric antigen receptor (CAR) that recognizes a tumor-associated surface antigen. The efficacy of such approaches has been demonstrated in preclinical studies in which engineered T cells expressing a MUC16-specific CAR were associated with complete eradication of orthotopic ovarian xenografts. A phase I study using this strategy is currently in development (ClinicalTrials.gov identifier: NCT02498912). Additional studies using T cells targeting other ovarian cancer–associated proteins—such as folate receptor α, mesothelin (ClinicalTrials.gov identifier: NCT01583686), and NY-ESO-1 (ClinicalTrials.gov identifiers: NCT01567891, NCT02457650)—are also ongoing.
Therapies to block other mechanisms of immune inhibition
Despite provocative early clinical data, it is becoming increasingly apparent that the benefit of immune checkpoint blockade in epithelial ovarian cancer is not universal and that development of predictive biomarkers and combination therapies will be necessary. To this end, combination strategies using PD-1– and PD-L1–blocking antibodies together with antibodies targeting other mechanisms of T-cell activation (eg, glucocorticoid-induced tumor necrosis factor receptor–related protein [GITR], OX40, 4-1BB), as well as antibodies targeting other immune checkpoints (eg, lymphocyte-activation gene [LAG]-3 and T-cell immunoglobulin and mucin domain–containing [TIM]-3), are already entering clinical trials in various tumor types. In addition, several immune inhibitory mechanisms have been demonstrated to be associated with poor prognosis in epithelial ovarian cancer, including tumor-infiltrating Tregs, tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs), and expression of the enzyme indoleamine 2,3-dioxygenase (IDO) by the tumor or stromal cells. There is thus a strong rationale for targeting these mechanisms in combination with PD-1/PD-L1 blockade, and studies are currently underway to evaluate these strategies in different tumor types.
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