HPV vaccines - A review of the first decade.

Pre-adolescent girls (9-15years) have the option of receiving a two dose HPV vaccine series at either a six month or one year interval to provide protection from HPV 16, the most prevalent type associated with cervical cancers, as well as several other less prevalent types. This series of vaccinations is highly likely to protect her from HPV infection until she enters the routine screening program, whether that be primary HPV testing or a combination of HPV testing and cytology. The two dose program has been recommended by the World Health Organization (WHO) since 2015. For women 15years and older, the three dose vaccine schedule is still recommended. The past ten years of Gardasil use has provided evidence of reduced HPV 16/18 infections in countries where there has been high coverage. Gardasil9 has replaced Gardasil. Gardasil9 has the same rapid anti-HPV 18 and HPV45 titer loss as Gardasil did. Cervarix remains equivalent to Gardasil9 in the prevention of HPV infections and precancers of any HPV type; Cervarix also has demonstrated sustained high antibody titers for at least 10years. One dose of Cervarix provides protection against HPV 16/18 infection with robust antibody titers well above natural infection titers. This may offer the easiest and most cost effective vaccination program over time, especially in low and lower middle income countries. Cervical cancer screening must continue to control cancer incidence over the upcoming decades. Future studies of prophylactic HPV vaccines, as defined by the WHO, must demonstrate protection against six month type specific persistent infections, not actual cervical cancer precursor disease endpoints, such as cervical intraepithelial neoplasia grade 3 (CIN 3) or adenocarcinoma in situ (AIS). This simplifies and makes less expensive future comparative studies between existing and new generic vaccines.

Phase II study of Vigil® DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer.

OBJECTIVES: The majority of women with Stage III/IV ovarian cancer who achieve clinical complete response with frontline standard of care will relapse within 2years. Vigil immunotherapy, a GMCSF/bi-shRNA furin DNA engineered autologous tumor cell (EATC) product, demonstrated safety and induction of circulating activated T-cells against autologous tumor in Phase I trial Senzer et al. (2012, 2013) . Our objectives for this study include evaluation of safety, immune response and recurrence free survival (RFS). METHODS: This is a Phase II crossover trial of Vigil (1.0×107 cells/intradermal injection/month for 4 to 12 doses) in Stage III/IV ovarian cancer patients achieving cCR (normal imaging, CA-125≤35units/ml, physical exam, and no symptoms suggestive of the presence of active disease) following primary surgical debulking and carboplatin/paclitaxel adjuvant or neoadjuvant chemotherapy. Patients received Vigil or standard of care during the maintenance period. RESULTS: Forty-two patients were entered into trial, 31 received Vigil and 11 received standard of care. No≥Grade 3 toxicity related to product was observed. A marked induction of circulating activated T-cell population was observed against individual, pre-processed autologous tumor in the Vigil arm as compared to pre-Vigil baseline using IFNγ ELISPOT response (30/31 negative ELISPOT pre Vigil to 31/31 positive ELISPOT post Vigil, median 134 spots). Moreover, in correlation with ELISPOT response, RFS from time of procurement was improved (mean 826days/median 604days in the Vigil arm from mean 481days/median 377days in the control arm, p=0.033). CONCLUSION: In conjunction with the demonstrated safety, the high rate of induction of T-cell activation and correlation with improvement in RFS justify further Phase II/III assessment of Vigil.

B7H6-Specific Bispecific T Cell Engagers Lead to Tumor Elimination and Host Antitumor Immunity.

Substantial evidence showed that T cells are the key effectors in immune-mediated tumor eradication; however, most T cells do not exhibit antitumor specificity. In this study, a bispecific T cell engager (BiTE) approach was used to direct T cells to recognize B7H6(+) tumor cells. B7H6 is a specific ligand for the NK cell-activating receptor NKp30. B7H6 is expressed on various types of primary human tumors, including leukemia, lymphoma, and gastrointestinal stromal tumors, but it is not constitutively expressed on normal tissues. Data from this study showed that B7H6-specific BiTEs direct T cells to mediate cellular cytotoxicity and IFN-γ secretion upon coculturing with B7H6(+) tumors. Furthermore, B7H6-specific BiTE exhibited no self-reactivity to proinflammatory monocytes. In vivo, B7H6-specific BiTE greatly enhanced the survival benefit of RMA/B7H6 lymphoma-bearing mice through perforin and IFN-γ effector mechanisms. In addition, long-term survivor mice were protected against an RMA lymphoma tumor rechallenge. The B7H6-specific BiTE therapy also decreased tumor burden in murine melanoma and ovarian cancer models. In conclusion, B7H6-specific BiTE activates host T cells and has the potential to treat various B7H6(+) hematological and solid tumors.

Catumaxomab for the treatment of malignant ascites in patients with chemotherapy-refractory ovarian cancer: a phase II study.

OBJECTIVE: The aim of this study was to investigate the efficacy and safety of intraperitoneal catumaxomab in heavily pretreated patients with chemotherapy-refractory ovarian cancer and recurrent symptomatic malignant ascites. METHODS: The study is a single-arm open-label multicenter US phase II study. Patients received 4 three-hour intraperitoneal catumaxomab infusions (10, 20, 50, and 150 µg within 10 days). The primary end point was the percentage of patients with at least a 4-fold increase in the puncture-free interval (PuFI) relative to the pretreatment interval. The main secondary end points were puncture-free survival, overall survival, ascites symptoms, and safety. Time to first therapeutic puncture (TTPu) was analyzed post hoc. RESULTS: Forty patients were screened, and 32 patients (80%) were treated. Seven patients (23%) achieved the primary end point. The median PuFI was prolonged 2-fold from 12 to 27.5 days. The median TTPu was prolonged 4-fold from 12 to 52 days. The median puncture-free survival and overall survival were 29.5 and 111 days, respectively. Nineteen patients (59%) required puncture after catumaxomab treatment. Ascites symptoms improved in most of the 13 predefined categories. At study end, most symptoms were still improved compared with screening. The most frequent treatment-related adverse events were related to cytokine release (vomiting, nausea, pyrexia, fatigue, and chills) or intraperitoneal administration (abdominal pain). Transient increases in liver parameters and transient decreases in blood lymphocytes were regularly observed but were generally without clinical relevance. CONCLUSIONS: Catumaxomab prolonged PuFI and TTPu had a beneficial effect on quality of life, as shown by the improvement in ascites symptoms, and had an acceptable safety profile, which is consistent with its mode of action.

Primary strategies for HPV infection and cervical cancer prevention.

Counseling messages for tobacco cessation, condom use, circumcision, and selective choice in the number of sexual partners can help reduce the risk of cervical cancer. Other sexual behavioral and reproductive risk factors for cervical cancer are a younger age at first intercourse and at first full-term pregnancy as well as increasing duration of combined hormonal oral contraceptive use. Micronutrients and supplements can reduce the risk of human papillomavirus infection, persistence, progression, and regression. Some human papillomavirus infections can be prevented by vaccination. Cervical cancer is best prevented by screening.

Chimeric NKG2D receptor-bearing T cells as immunotherapy for ovarian cancer.

Despite advancements in the treatment of ovarian cancer, this disease continues to be a leading cause of cancer death in women. Adoptive transfer of tumor-reactive T cells is a promising antitumor therapy for many cancers. We designed a chimeric receptor linking NKG2D, a natural killer (NK) cell-activating receptor, to the CD3zeta chain of the T-cell receptor to target ovarian tumor cells. Engagement of chimeric NKG2D receptors (chNKG2D) with ligands for NKG2D, which are commonly expressed on tumor cells, leads to T-cell secretion of proinflammatory cytokines and tumor cytotoxicity. In this study, we show that >80% of primary human ovarian cancer samples expressed ligands for NKG2D on the cell surface. The tumor samples expressed MHC class I-related protein A, MICB, and UL-16 binding proteins 1 and 3. ChNKG2D-expressing T cells lysed ovarian cancer cell lines. We show that T cells from ovarian cancer patients that express chNKG2D secreted proinflammatory cytokines when cultured with autologous tumor cells. In addition, we show that chNKG2D T cells can be used therapeutically in a murine model of ovarian cancer. These data indicate that treatment with chNKG2D-expressing T cells is a potential immunotherapy for ovarian cancer.

Gliomatosis peritonei and teratomatous implant with carcinomatous transformation presenting 54 years following oophorectomy for dermoid cyst.

BACKGROUND: Gliomatosis peritonei is a rare condition associated with ovarian teratomas in which benign glial implants are identified on the peritoneal surfaces of the abdomen. The implants have been identified at initial surgery and at second-look laparotomy. CASE: Here, we present a case of an 82-year-old female who was diagnosed with gliomatosis peritonei 54 years after her initial surgery for an ovarian dermoid tumor. A separate teratomatous implant containing focally invasive adenocarcinoma was also present. CONCLUSION: This is by far the longest interval between initial diagnosis and identification of glial implants reported. Additionally, the presence of a separate malignant teratomatous implant suggests that teratomatous implants may retain malignant potential, in contrast to implants composed of purely benign glial tissue.

Vulvar epithelioid sarcoma in pregnancy.

BACKGROUND: Epithelioid sarcoma is a soft tissue tumor rarely found centrally and even less commonly on the vulva. Vulvar sarcoma in pregnancy is also exceedingly rare with only five cases reported to date, none of which have been an epithelioid sarcoma. CASE: We report a case of a 29-year-old woman presenting with a vulvar epithelioid sarcoma at 36 weeks of gestation. The patient underwent a radical resection 6 weeks postpartum followed by chemotherapy. Despite a radical hemivulvectomy and doxorubicin and ifosfamide chemotherapy, she developed pulmonary metastasis and died of tumor-related pulmonary failure secondary to her disease 612 months after diagnosis. To our knowledge this is the first case of a vulvar epithelioid sarcoma presenting during pregnancy. The English literature is reviewed and a total of 18 previous cases of vulvar epithelioid sarcoma have been reported outside of pregnancy. Insight into the biological behavior and therapeutic management of this disease is discussed. CONCLUSION: The optimal management of vulvar epithelioid sarcoma remains to be determined. However, it would seem that early and aggressive surgical resection provides the best possibility for cure. The role of radiation and/or chemotherapy remains to be determined.