A non-oncogenic HPV 16 E6/E7 vaccine enhances treatment of HPV expressing tumors.

Human papillomaviruses (HPVs) are the causative factor for >90% of cervical cancers and 25% of head and neck cancers. The incidence of HPV positive (+) head and neck squamous cell carcinomas has greatly increased in the last 30 years. E6 and E7 are the two key viral oncoproteins that induce and propagate cellular transformation. An immune response generated during cisplatin/radiation therapy improves tumor clearance of HPV(+) cancers. Augmenting this induced response during therapy with an adenoviral HPV16 E6/E7 vaccine improves long-term survival in pre-clinical models. Here, we describe the generation of an HPV16 E6/E7 construct, which contains mutations that render E6/E7 non-oncogenic, while preserving antigenicity. These mutations do not allow E6/E7 to degrade p53, pRb, PTPN13, or activate telomerase. Non-oncogenic E6/E7 (E6(Δ)/E7(Δ)) expressed as a stable integrant, or in the [E1-, E2b-] adenovirus, lacks the ability to transform human cells while retaining the ability to induce an HPV-specific immune response. Moreover, E6(Δ)/E7(Δ) plus chemotherapy/radiation statistically enhances clearance of established HPV(+) cancer in vivo.

Impaired PTPN13 phosphatase activity in spontaneous or HPV-induced squamous cell carcinomas potentiates oncogene signaling through the MAP kinase pathway.

Human papillomaviruses (HPVs) are a causative factor in over 90% of cervical and 25% of head and neck squamous cell carcinomas (HNSCCs). The C terminus of the high-risk HPV 16 E6 oncoprotein physically associates with and degrades a non-receptor protein tyrosine phosphatase (PTPN13), and PTPN13 loss synergizes with H-Ras(V12) or ErbB2 for invasive growth in vivo. Oral keratinocytes that have lost PTPN13 and express H-Ras(V12) or ErbB2 show enhanced Ras/RAF/MEK/Erk signaling. In co-transfection studies, wild-type PTPN13 inhibited Ras/RAF/MEK/Erk signaling in HEK 293 cells that overexpress ErbB2, EGFR or H-Ras(V12), whereas an enzymatically inactive PTPN13 did not. Twenty percent of HPV-negative HNSCCs had PTPN13 phosphatase mutations that did not inhibit Ras/RAF/MEK/Erk signaling. Inhibition of Ras/RAF/MEK/Erk signaling using MEK inhibitor U0126 blocked anchorage-independent growth in cells lacking PTPN13. These findings show that PTPN13 phosphatase activity has a physiologically significant role in regulating MAP kinase signaling.

[Two pneumococcal vaccines: the 7-valent conjugate vaccine (Prevenar) for children up to the age of 5 years and the 23-valent polysaccharide vaccine (Pneumo 23) for the elderly and specific groups at risk]. / Twee pneumokokkenvaccins: voor kinderen tot 5 jaar het 7-valente conjugaatvaccin (Prevenar) en voor ouderen en specifieke risicogroepen het 23-valente polysacharidevaccin (Pneumo 23).

Despite the availability of antibiotics and the care offered by intensive-care units, invasive pneumococcal disease still causes serious illness with high morbidity and mortality. Currently, two vaccines are available in the Netherlands that offer protection against invasive pneumococcal disease: a 7-valent conjugated vaccine and a 23-valent polysaccharide vaccine. Case reports and pharmaceutical use as registered by the Foundation for Pharmaceutical Statistics (SFK) show that general practitioners and pharmacists are not always aware of the appropriate use of both vaccines. For vaccination against pneumococci in children aged 0-5 years, general practitioners should prescribe only the conjugated vaccine. The non-conjugated polysaccharide vaccine is intended especially for the elderly and specific groups at risk. Pharmacists should verify that the pneumococcal vaccines they hand out on prescription are recommended for the age-group of the individuals to whom the vaccine will be administered.