Immune checkpoint inhibitors (ICIs) have demonstrated marked clinical effects worldwide, and “cancer immunotherapy” has been recognized as a feasible option for cancer treatment. Significant treatment responses have already been attained for malignant melanoma and lung cancer, ahead of gynecologic cancer. In cervical cancer, however, results are only available from phase II trials, not from phase III trials. Cervical cancer is a malignant tumor and is the fourth most common cancer among women worldwide. Since the introduction of angiogenesis inhibitors, treatment for recurrent and advanced cervical cancers has improved in the past five years, but median overall survival is 16.8 months for advanced cervical cancer, and all-stage five-year overall survival rate is 68%, indicating that treatment effects remain inadequate. For this reason, the development of new therapeutic approaches is imperative. We describe herein the KEYNOTE-158 and CheckMate 358 clinical trials, which were conducted for cervical cancer, and discuss future directions, including potential combinations with concurrent chemoradiation therapy (CCRT), as noted for other types of cancer.

Cancer immunotherapy relies upon the ability of T cells to infiltrate tumors. The endothelium constitutes a barrier between the tumor and effector T cells, and the ability to manipulate local vascular permeability could be translated into effective immunotherapy. Here, we show that in the context of adoptive T cell therapy, antitumor T cells, delivered at high enough doses, can overcome the endothelial barrier and infiltrate tumors, a process that requires local production of C3, complement activation on tumor endothelium and release of C5a. C5a, in turn, acts on endothelial cells promoting the upregulation of adhesion molecules and T-cell homing. Genetic deletion of C3 or the C5a receptor 1 (C5aR1), and pharmacological blockade of C5aR1, impaired the ability of T cells to overcome the endothelial barrier, infiltrate tumors, and control tumor progression in vivo, while genetic chimera mice demonstrated that C3 and C5aR1 expression by tumor stroma, and not leukocytes, governs T cell homing, acting on the local endothelium. In vitro, endothelial C3 and C5a expressions were required for endothelial activation by type 1 cytokines. Our data indicate that effective immunotherapy is a consequence of successful homing of T cells in response to local complement activation, which disrupts the tumor endothelial barrier.

Cervical cancer is a malignant neoplastic disease that is the fourth most commonly occurring cancer in women worldwide. Since the introduction of angiogenesis inhibitors, treatments for recurrent and advanced cervical cancers have improved significantly in the past five years. However, the median overall survival in advanced cervical cancer is 16.8 months, with a 5-year overall survival rate of 68% for all stages, indicating that the effects of the treatment are still unsatisfactory. The development of a new treatment method is therefore imperative. Recently, in the clinical oncology field, remarkable progress has been made in immunotherapy. Immunotherapy is already established as standard therapy in some fields and in some types of cancers, and its clinical role in all areas, including the gynecology field, will change further based on the outcomes of currently ongoing clinical trials. This manuscript summarizes the results from previous clinical trials in cervical cancer and describes the ongoing clinical trials, as well as future directions.

PurposeThere are no reports on the use of neoadjuvant chemotherapy (NAC) in non-squamous cell cervical carcinoma. We examined the effectiveness and safety of paclitaxel/carboplatin (TC) and docetaxel/carboplatin (DC).MethodsStage Ib2 to IIb disease was present in 23 patients scheduled for radical hysterectomy. We administered 1–3 courses of either the TC or the DC regimen. Anti-tumor effects were found superior by Response Evaluation Criteria in Solid Tumors. Safety was assessed with National Cancer Institute Common Terminology Criteria for Adverse Events.ResultsMedian age was 50 years (range 32–63 years), with stage Ib2 in 6 cases (26.1 %) and IIb in 17 cases (73.9 %). Complete response was achieved in 5 cases (21.7 %), partial response in 13 (56.5 %), stable disease in 5 (21.7 %); the response rate was 78.3 %, and surgery completion rate was 78.3 %. Leukopenia or neutropenia ≥grade 3 was seen in 12 (52.2 %) and 21 (91.3 %) cases, respectively, with grade 3 febrile neutropenia in 2 cases (8.7 %) and no anemia or thrombocytopenia ≥grade 3. Median progression-free survival was 26 months (95 % Cl, 13.5–38.5 months); median overall survival was 35 months (95 % Cl, 20.9–49.1 months).ConclusionNAC for non-squamous cell cervical carcinoma showed potent anti-tumor effects and manageable adverse events.

The presence or absence of lymph node metastasis by computed tomography imaging was the only significant prognostic factor identified during the pre-NAC period.

Objective Perifosine exhibits anti-tumor activity by inhibiting AKT phosphorylation. The purpose of this phase II basket trial was to evaluate the efficacy and safety of perifosine monotherapy for ovarian, endometrial, and cervical cancers. Methods Recurrent or persistent ovarian, endometrial, or cervical cancer patients were assigned to PIK3CA wild-type or mutant groups. Each patient received 600 mg oral perifosine on day 1 followed by a maintenance dose of 100 mg daily. The primary endpoint was disease control rate; secondary endpoints included response rate, progression-free survival, overall survival, and safety. Immunohistochemical staining and targeted sequencing were used to explore new biomarkers in such patients. Results Sixteen and 5 ovarian, 17 and 7 endometrial, and 18 and 8 cervical cancer patients with PIK3CA wild-type and mutant, respectively, were enrolled. Disease control rates (wild-type/mutant) were 12.5/40.0%, 47.1/14.3%, and 11.1/25.0% in ovarian, endometrial, and cervical cancer, respectively. The most common grade 3/4 toxicities were anemia (22.5%) and anorexia (11.3%). Immunohistochemical staining revealed that the disease control rate in patients with negative phosphatase and tensin homolog (PTEN) expression was 50.0%, and the odds ratio of positive to negative patients was 0.24 in all patients. Conclusions Perifosine monotherapy showed good tolerability but expected efficacy was not achieved. Modest efficacy was demonstrated in ovarian cancer patients with PIK3CA mutations and endometrial cancer patients with PIK3CA wild-type; no difference was observed between PIK3CA wild-type and mutant in cervical cancer. Absence of PTEN expression may be predictive of clinical efficacy with perifosine monotherapy.

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IntroductionSurfactin (SF) is a cyclic lipopeptide that has potent mucosal adjuvant properties. However, immunological mechanisms of SF adjuvant action have not yet been elucidated. As some cyclic lipopeptides, such as polymyxin, can stimulate histamine release from mast cells, we hypothesized that mast cell activation is critical for SF adjuvanticity.Methods/ResultsWe observed that following intranasal immunization with ovalbumin (OVA) plus SF, the titers of the OVA‐specific antibody (Ab) in the mucosal secretions and plasma of mast cell‐deficient mice were significantly lower than those in congenic normal mice, although OVA‐specific Ab did not entirely disappear from mast cell‐deficient mice. SF induced degranulation of mast cells and release of histamine in vitro. To investigate whether SF stimulated mast cells in vivo, we measured body temperature of mice immunized intranasally with OVA plus SF because histamine level affects body temperature. Following immunizations, body temperature of immunized congenic normal mice transiently decreased, whereas body temperature of mast cell‐deficient mice did not change. Plasma levels of OVA‐specific IgE Ab were not significantly different in mast cell‐deficient and congenic normal mice. These findings suggest that SF directly affected mast cells in an IgE Ab‐independent fashion. Furthermore, we analyzed the effects of SF on MC/9 mast cells cultured in vitro. MC/9 cells stimulated by SF released not only histamine but also leukotriene B4 and prostaglandin D2. Moreover, SF up‐regulated mRNA expression levels of Tnf, Ccr5, and Il4 genes in mast cells. These cytokines may play a facilitating role in OVA‐specific immune responses in mice.ConclusionOverall, our results showed that mast cell activation partially mediated SF adjuvanticity.