Immunotherapy against HPV16/18 – A Phase I Clinical Trial

Considering that we recently covered these topics in lecture, I thought I would blog about a new Phase I clinical trial.  This trial analyzed immunotherapy targeting human papillomavirus (HPV) serotypes 16 and 18. 

In the U.S., HPV is the most common sexually transmitted disease.  The virus causes several different cancers.  For instance, among women, it can cause cervical cancer and among men, although it is quite rare, penile cancer.  Gardasil and Cervarix are the two [for some reason controversial: safety? (here, here, here and here) and promiscuity? (here)] immunizations against HPV.  They were first approved only for young women, and are now being recommended for young men.  There are 130 strains of the HPV virus, Gardasil protects against serotypes 6, 11, 16 and 18.  The latter two strains are considered to cause up to 75% of cervical cancer cases.  Nevertheless, what about individuals who already have HPV and have developed precancerous cervical dysplasias?  That is where this trial comes into play.  Among infected individuals, the researchers attempted to stimulate immune responses against HPV by using VGX-3100, a therapeutic HPV16/18 candidate vaccine.  Interestingly, it is believed that some individuals are potentially genetically programmed to fight off precancerous lesions caused by HPV, which may make this vaccine unnecessary for them.  The trial researchers estimated that this occurs among 10-25% of women, but what if you aren’t one of those individuals?

The researchers enrolled 18 women with high-grade precancerous lesions.  Outside of the small sample size, they also implemented a non-randomized clinical trial.  With those limitations in mind, one has merit to be incredulous, but remember this is a Phase I trial (Note: A Phase II trial is currently underway where they are following 150 subjects with the plan of then following 500 during Phase III).  The subjects in the study were administered increasing doses (0.3, 1 and 3 mg/plasmid) of plasmid DNA encoding HPV-16 and -18 E6/E7 antigens (i.e. oncogenes related to HPV serotypes 16 and 18).  Essentially, the vaccine is attempting to “train” the T cells to recognize and potentially eliminate HPV infected cells.  The vaccine contains a section of DNA that codes for an antigen.  DNA vaccines are limited based on being able to enter the target cell, but this was overcome by in vivo electroporation (EP), which contributes a minute electrical charge permitting entry.  The researchers discovered T cell response in 14/18 subjects based on Th1 (a helper T cell that secretes IFN-γ and IL-2, which classically activates M1 – “angry” macrophage and helps stimulate killer T cells, respectively) and close to a 90% response with regard to cytotoxic T lymphocytes (CTL – killer T cells).  Further, they found high levels of functional cellular immunity with regard to CD4 and CD8 T cells, which are indicators of helper and killer cells, respectively.  Continuing, they discovered a potential dose effect based on peak IFN-γ levels among individuals who received 3 mg injections, relative to 0.3 and 1 mg.  Lastly, 6-months after the trial, 11/14 subjects displayed persistent IFN-γ levels and several produced fully functional HPV-specific CTLs, both are indicative of memory responses.

This trial appears to be promising and I look forward to the results of the subsequent phases; however, I would like to pose a couple questions.

1. Scenario (a more interesting way to ask, “Are you confident in these results?”): You have $10,000 of available money that you can do one of two things with a.) deposit the money into a bank account and earn interest OR b.) use the money to buy shares of this stock.  NOTE: It is currently trading at 0.70 cents/share.  Which one would you choose?
2. The results display an effective immune response to the virus, but at this stage, would it have to be against the tumor (in some way) to be effective?  What do you think?

References

Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy against HPV16/18 generates potent Th1 and cytotoxic cellular immune responses. Sci Transl Med. 2012; 4(155). DOI: 10.1126/scitranslmed.3004414

http://www.clinicaltrials.gov/ct2/show/NCT00685412

http://www.cdc.gov/hpv/cancer.html

http://www.fiercevaccines.com/special-reports/vgx-3100

Safety:

http://www.sciencedirect.com/science/article/pii/S0140673609606917

http://archpedi.jamanetwork.com/article.aspx?articleid=1363509

http://www.nejm.org/doi/full/10.1056/NEJMoa0909537

http://www.cdc.gov/vaccines/vac-gen/side-effects.htm#hpvcervarix

Promiscuity:

http://pediatrics.aappublications.org/content/early/2012/10/10/peds.2012-1516.full.pdf+html