Recently, a new class of drugs, called checkpoint inhibitors (CI), has shown encouraging results in potentiating the immune response. The targets of these drugs are immune checkpoint molecules expressed on immune cells (CTLA4 and PD1 ) and their ligand (PDL1), which is usually effective in mediating signals to attenuate the immune reactions. The binding of these molecules by CI is the trigger in determining the T-cell activation during T cell priming.
Nivolumab and pembrolizumab are mAb directed against the PD-1 receptors. They produced durable responses in approximately 20% of unselected patients with advanced non-small cell lung cancer (NSCLC). In Europe, the use of CI is approved for metastatic melanoma (Ipilimumab, Pembrolizumab) and I/II line NSCLC (Nivolumab). Thanks to their selective action on immune cells, their toxicity profile is favourable.
The low toxicity profile and the encouraging immunotherapeutic effects, supported the experimentation of immune checkpoint inhibitors in several fields. Several trials are currently testing these molecules in combination with chemotherapy in other malignancies, including cervical cancer. Recently, immunotherapy against HPV using a viral gene delivery platform to immunize against HPV 16 (genes E6 and E7), combined with PD-1 blockade, has shown to increase therapeutic effect in mouse with cervical cancer as compared to the vaccine alone. Analysis of the microenvironment and of the subpopulation lymphocytes revealed that when CI have been administrated, a reduction in tumor PD-L1 expression on tumor cells and reduced PD-1(+) TILs is observed.
In this proposal, we hypothesize that patients with chronic HPV infection who are receiving systemic treatment with immune check point inhibitors for a different indication will clear their HPV infection significantly more often as compared to a control group of patients with chronic HPV infection.
76 patients (19 cases and 57 controls) will be enrolled in the study.
This is the first trial investigating the efficacy of immune check point inhibitors in clearing HPV infection. Additionally, as of now, no other similar trial have been registered on the clinical trial webpage (www.clinicaltrials.gov).
In the past decade, the field of immunotherapy has made significant progress thanks to the development of new drugs such as the check point inhibitors. These are currently FDA recognized standard of treatment in specific clinical scenarios, such as metastatic melanoma and primary/recurrent NSCLC and are being investigated in multiple other oncologic settings such as maintenance treatment in previously untreated ovarian cancer patients, etc. If the ongoing oncologic trials will show positive results, the indication to the use of these drugs will expand. Given the peculiar mechanism of action of these drugs that interact with T-lymphocyte receptors to revert an immunosuppressive state, their employment may be hypothesized in various other clinical conditions as well.
The immune system plays a pivotal role in various clinical conditions, including the HPV infection. As a result, this infection is more aggressive in patients with non-controlled HIV and in transplanted patients who are under chronic immune suppression.
This project, serves as a proof of principle to investigate if these drugs are effective in accelerating and increasing the HPV infection clearance rates. If this is proven to be true, immunotherapy may be seriously regarded as a treatment strategy in patients with persistent HPV infection for whom no other treatment options are now available.
At present, treatment options for HPV related diseases include a prophylactic vaccine and excisional biopsies in case of histologically proven cervical dysplastic lesions. There is a lack of therapeutic options for patients who have already contracted an HPV infection but have not developed histologic lesions yet. Immunotherapy seems to have the perfect characteristics to fill this gap. If effective, such a treatment may prevent the occurrence of dysplastic lesions and cervical cancer. Although the occurrence of a cervical dysplasia per se is not a severe clinical condition, the morbidity of its management is substantial with an increased risk of infertility, first and second trimester abortion and preterm delivery. Furthermore, the clinical controls recommended to follow up this condition are a significant burden for the health system and, finally, this condition causes significant distress to a large number of patients because of its oncologic potential. Finally, a higher clearance of the HPV infection will ultimately translate in a reduced number of invasive cervical cancer cases.
Once the concept has been proven, appropriate dosages and effectiveness will have to be tested on a larger cohort of women with persistent HPV infection. Future trials will also aim to test the effectiveness of these drugs on patients with HPV-related dysplastic lesions of the cervix. If these drugs prove to be effective enough, a medical treatment may ultimately substitute a surgical one even in this setting.
As a consequence, patients enrolled in this trial will not be subjected to any experimental therapy but will be tested for a possible phenomenon (clearance of chronic HPV infection) related to their standard treatment with immune check point inhibitors that has not been investigated yet and that may have a significant impact in cervical cancer prevention.