Most often, a human papillomavirus (HPV) infection early in life is the reason for getting cervical cancer. One can get infected by coming directly into contact with infected skin or mucous membrane. This can occur during sexual intercourse, but also via non-sexual pathways. For instance the virus can be transmitted during childbirth. Some 80 percent of all sexually active people are infected at least once in their life with HPV. Most often the infection is overcome within a period of up to two years without health problems. Sometimes however, a persistent infection arises. Only rarely does a cervical carcinoma develop over several years from such a chronic persistent infection.
Let me introduce HPV
HPV is a non-enveloped virus belonging to the Papillomaviridae family. Its DNA consists of about 8,000 base pairs. The genome can be sub-categorised into an early region and a late region. The various sections code for a total of eight viral proteins which – in correlation with the region and its length – are called E1, E2, E4, E5, E6, E7 and L1 and L2.
These viral proteins have differing functions. E1 and E2, for example, are needed by the virus for replication and transcription, E4 for the release of cytokeratin, and using E5 the virus induces the host cell to produce growth factors. With respect to vaccines, E6, E7 and L1, which encodes for the main component of capsid proteins, are of most interest.
HPV and cancer
At present, more than 150 types of HPV are recognised. About 40 types of HPV infect the genital area and the anus in particular, but only twelve so-called high-risk HPVs are linked to an increase in likelihood of developing a cervical cancer at some later date. The most important high-risk HPVs are HPV 16 and HPV 18, which are able to be detected in approximately 70 percent of cervical cancers. This does not however mean that infection from these two high-risk HPVs will inevitably lead to cancer.
Following infection, HPV switches off control mechanisms. Oncoproteins E6 and E7 are mainly responsible for this. Viral E6 forms a complex with p53, thus ensuring that p53 is degraded more rapidly and so leads to the situation whereby it is unable to prevent the development of cancer. E7 can bind many different proteins. Among these are the tumor suppressors of the retinoblastoma family. The result is that cell division is stimulated.
Treatment of cervical cancer
Since 2007 a preventive vaccine has been available. This protects against certain types of HPV. In the instance of already existing illness and tissue changes it has however no effect. Current treatment approaches for already ill women are – depending on the extent and size of the tumor and the age and capacity of the patient – surgery, chemotherapy and radiotherapy. If the disease is detected when still in the early stage, the patients have a good chance of recovery.
In recurrent metastatic cervical cancer cases, chemotherapy and radiation can remove the tumor to a limited extent – however, if the patient is treated repeatedly, toxicity also increases. Molecular biological methods barely play a role in treatment and therapeutic vaccines are not yet available.
Listeria as a vaccine against cancer
The bacterium Listeria monocytogenes triggers so-called listeriosis. This disease is similar to the flu in its symptoms such as nausea, vomiting and diarrhoea. If the immune system is intact, the infection is normally asymptomatic – the disease is dangerous, among others times, during pregnancy. The listeria finds its way into the body via contaminated food substances. Once in the small intestine the pathogens penetrate the enterocytes or M-cells. Although they are then phagocytised by macrophages, the bacteria can however use a toxin, listeriolysine O, to escape from the endosome and proliferate in the cytoplasm of the host cell.
The bacteria-specific antigens are presented by both MHC-1 as well as MHC 2 complexes, through which both CD8 + T-cells and CD4 + T- cells are activated. This combination makes the bacteria interesting as a therapeutic vaccine. This was reason enough for the American company Advaxis to develop a therapeutic vaccine using attenuated Listeria. The bacteria lack a certain transcription factor which is important for the virulence factor. ADXS-HPV – the name of the vaccine – attacks the virus protein E7 and can be used for treatment of advanced cervical cancer involving various HPV infections. This is because the E7 proteins of different HPV are very similar.
Not the first therapeutic vaccine
ADXS-HPV is not the first therapeutic vaccine. For example, researchers at the University of Pennsylvania, Philadelphia, developed a vaccine consisting of two DNA plasmids. This contains the E6 and E7 oncogenes. After injection, an electric field is generated using a special device so as to facilitate uptake of the plasmids in the immune cells. Subsequently, there is a defence reaction in which T cells are also formed. These patrol throughout the body and attack the cells infected by HPV.
The DNA vaccine has already been tested in a randomised clinical phase 2b study involving 167 participants. The primary objective of the study, namely recovery from or regression of the cancer, was achieved with 48 percent of women in the vaccination group and with 30 percent in the control group. According to researchers, the vaccine was well tolerated. The manufacturer Inovio has indicated the intention to have these vaccines tested in a Phase 3 study.
ADXS-HPV in the test phase
ADXS-HPV was tested in a single-arm, open-label phase 2 study of 26 and 24 women with recurrent or metastatic cervical cancer (stage 1 or 2). The aim of the study was to determine the efficacy and tolerability of the vaccine. Progression free survival, overall survival and objective response made up the secondary endpoints. The patients received either one, two, three or more doses of the vaccine.
According to Advaxis the 12-month survival rate of the 18 women at stage 1, who were administered three or more treatments, amounted to almost 56 percent. Of the women who had been administered the vaccine at least three times after six months, 8 of 12 participants (67 percent) were still alive, compared to 42 percent (10 of 24).
In both stages, the 12-month overall survival was about 38 percent. Assuming that only 25 percent of women under standard therapy survive for one year, this would translate to an increase in the survival rate with vaccine of 52 percent. This figure was taken from literature, not derived by them.
The disadvantage of the treatment is the adverse side effects. About 90 percent of the participants complained of symptoms such as fatigue, fever, nausea, chills or “cytokine release syndrome”, during which inflammatory cytokines are released. The problems with this study are the non-blinded study design (that could be a reason for the high number of side effects) and the low number of participants. Advaxis nonetheless has confidence in its vaccine and has expressed the desire to soon begin testing in a multinational, randomised phase 3 trial.