Discussion
high-grade precancerous cervical lesions, precancerous cervical disease, CIN, HPV-16 infection
ADVERSE EVENTS, CIN 2, CIN 1, CIN, CIN 3, REGRESSION, REGRESSION
We found that oral administration of IGMKK16E7 in patients with HPV-16–positive CIN 2 and 3 drove histopathological regression to normal (complete response) at 24 weeks after the first dose. Linear complete response dose responses for IGMKK16E7 were clearly demonstrated in both overall and subgroup analyses. Differences in the complete response rate between high-dose and placebo groups appeared to diverge by 24 weeks, but not by 16 weeks, after the first dose. In our safety analysis set, adverse events did not occur in the IGMKK16E7 recipients at a higher incidence than that in placebo recipients. More than 50% of IGMKK16E7 recipients experienced no adverse events. These observations show IGMKK16E7 to be less invasive and to be characterized by an improved safety profile compared with injectable vaccinations.Particularly novel in this clinical trial was the use of the intestinal mucosa for induction of cellular immune responses against CIN 2/3 through oral vaccine administration. Notably, our double-blind, randomized trial demonstrated that complete response rates increase in a linear dose-dependent manner, strongly supporting that histopathological regression to normal is a pharmacological effect of IGMKK16E7. There are no previously reported randomized clinical trials of therapeutic HPV vaccines that demonstrate dose-dependent histopathological regression of precancerous cervical disease. IGMKK16E7 is the first HPV therapeutic oral vaccine with efficacy comparable with that of the best parenteral vaccine so far evaluated in placebo-controlled efficacy trials (Complete response, but not complete response plus partial response, efficacy was detected in comparisons of IGMKK16E7 and placebo recipients. Regression to normal seems to require a more stringent induction of antigen-specific immune response than regression to CIN 1, but when considering potential for use as a therapeutic agent, combined pathological regression to normal and viral clearance is the most favorable parameter to evaluate the clinical efficacy of HPV therapeutic vaccine. Because there was no stastical difference between vaccine and placebo for viral clearance in this trial, further improvement of IGMKK16E7 is desired to achieve the therapeutic effect of viral clearance. Indeed, partial response occurred more frequently in placebo and low-dose (15% and 17%, respectively) than in intermediate- and high-dose recipients (5% and 9%, respectively). Spontaneous regression was noted in all treatment groups. This is not surprising, especially in patients with CIN 2, and can even occasionally occur in patients with CIN 3 (Results from immunological analyses support a pharmacological effect of IGMKK16E7. Higher numbers of circulating E7-specific, IFN-γ–producing cells (spot-forming cells) in patients with histopathological improvement is consistent with the involvement of an E7-specific Th1 response in histopathological lesion regression. The number of spot-forming cells measured at the endpoint was not IGMKK16E7 dose dependent; however, spot-forming cells at baseline varied widely among recipients, and the measured spot-forming cells after administration may have been affected not only by the pharmacological effect of vaccine but also by baseline spot-forming cells. To account for this possibility, the change in spot-forming cells before and after treatment observed in patients with complete response was represented by treatment group. In the full analysis set, the complete response rate of those recipients with a spot-forming cell change higher than the median value (hyper-responders) increased in a dose-dependent manner. Of note, some of the placebo recipients were also hyper-responders. It may not be surprising that some patients had a preexisting E7-specific T-cell population in their peripheral blood monocytes that was present but not fully effective because they had persistent HPV-16 infection. These cells would also be expanded by the E7 stimulation used in our experimental immunologic assay design. However, unlike hyper-responders in the high-dose group who exhibited a higher level of complete response than those in the placebo group, none of the hyper-responsive individuals who had received placebo have a complete response, suggesting their E7-specific T cells may not have had antineoplastic activity against CIN 2 or 3. IGMKK16E7-induced E7-specific T cells may acquire and exert more favorable antineoplastic characteristics. Further immunological analysis of the specific characteristics of these 2 sets of E7-specific T cells will be addressed in future studies. A phase III IGMKK16E7 clinical trial will be conducted in the future.Our efficacy and safety data highlight the therapeutic promise of orally administered IGMKK16E7 as a safe, noninvasive, and effective nonsurgical intervention for patients with high-grade precancerous cervical lesions.