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.

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) cellactivating receptor, to the CD3Z 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. [Cancer Res 2007;67(10):5003-8]

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Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable and potentially curative therapeutic efficacy against B cell leukemia in clinical trials. A CAR strategy can target any tumor surface antigens as long as an antigen-binding receptor can be generated. New CARs which target solid tumors and have the potential to target multiple tumor types are needed. In this study, B7H6, a ligand for the NK cell activating receptor NKp30, was targeted to create a CAR which targets multiple tumor types. B7H6 is expressed on various primary human tumors, including leukemia, lymphoma, and gastrointestinal stromal tumors (GISTs), but it is not constitutively expressed on normal tissues. B7H6-specific CAR T cells have robust cellular cytotoxicity and IFN-γ secretion when co-cultured with B7H6+ tumor cells, and they exhibit little self-reactivity to immature dendritic cells (iDCs) or pro-inflammatory monocytes. In vivo, B7H6-specific CAR T cells greatly enhanced the survival of RMA/B7H6 lymphoma bearing mice. The long-term survivor mice were protected against a B7H6-deficient tumor re-challenge. This CAR therapy also decreased tumor burden in a murine ovarian cancer model. In conclusion, B7H6-specific CARs have the potential to treat B7H6+ hematologic and solid tumors.

Substantial evidence showed that T cells are the key effectors in immune-mediated tumor eradication. However, most T cells do not exhibit anti-tumor specificity. In this study, a bispecific T cell engager (BiTE) approach was utilized 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 (GISTs), but it is not constitutively expressed on normal tissues. In this study, data show that B7H6-specific BiTEs direct T cells to mediate cellular cytotoxicity and IFN-γ secretion upon co-culturing with B7H6+ tumors. Furthermore, B7H6-specific BiTE exhibited no self-reactivity to pro-inflammatory 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 a RMA lymphoma tumor re-challenge. 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.