Therapeutic Vaccination for Dysplasia: Early Efficacy

Abstract & Commentary

By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.

Source: Einstein MH, et al. Gynecol Oncol. 2007;106: 453-460.

Synopsis: SGN-0010, a novel heat shock fusion protein-based immunotherapeutic, demonstrates clinical efficacy in regressing cervix dysplasia in women with biopsy-proven CIN III.

Heat shock proteins have been of clinical interest in therapeutic vaccination based on their ability to induce significant T- and B-cell responses against microbial pathogens and tumor antigens. SGN-0010 (HspE7) is a novel therapeutic vaccine consisting of a fusion protein containing M. bovis BCG heat shock protein (Hsp65) covalently linked to the entire sequence of HPV 16 E7. Given observations of response of HPV-induced lesions in other disease sites to HspE7, the authors of the current study set out to examine the efficacy and toxicity of SGN-0010 in women with CIN III. Two cohorts were accrued. The first consisted of 31 patients with CIN III who were vaccinated (1 subcutaneous injection every month for 3 months) and observed for a total of 5 months upon which they underwent LEEP; cohort 2 were those with similar lesions (N=27) in whom following vaccination underwent LEEP at 7 months. Cervix lavage for HPV type (assessed by PCR) was done monthly until LEEP and at 12 months following vaccination. Overall, 13 (23%) of 58 evaluable patients achieved a complete resolution of their CIN III disease; an additional 55% had a partial resolution defined as a 50% or more reduction of the lesion size. Two patients were classified as having progression documented as microscopic invasive disease at LEEP. Patients in whom previous ablative or extirpative surgery was done for a history of dysplasia appeared more likely (not statistically significant) to have a complete response following vaccination. In addition, lower grade lesional inflammation was associated with response. Toxicity was minimal and limited to injection site reactions; the vast majority of which resolved at 7 days post injection. The authors report that the clinical activity of this novel fusion protein met pre-determined efficacy benchmarks and suggest further randomized trials are warranted.

Commentary

Vaccination success for the prevention of HPV infection has been documented and has led to the current availability of one, soon to be two, commercial products. The ultimate endpoint of these agents and their associated public health programs is prevention of cervix cancer development. Much about the long-term impact of these vaccines is currently unknown. However, it is clear that successful vaccination programs will depend upon population-wide vaccination and expansion of the current type-specific focus of the available agents. In addition, vaccination of infected individuals is less efficacious than HPV-naïve, and it is likely that any real benefit from these programs are decades off to fruition. Herein lies the clinical need for therapeutic vaccination of those with established infection manifested by high-grade dysplasia. Fortunately, a number of new vaccines and vaccine strategies are under development to address this cohort of women. The need is particularly evident given the association of pregnancy complications associated with repeated extirpative procedures on the cervix, the limited scope of HPV prevention vaccination and the difficulties effecting public health care policy mandating vaccination. The current trial is of interest because of its efficacy but highlights the difficulty in doing intervention/observation trials. Remarkably, nearly 1 in 4 patients with high grade biopsy-proven CIN III achieved pathologic complete response; over half had decrease in the size of their documented lesion. However, complete remission in this study was defined as resolution of the lesion or regression to CIN I/HPV and partial regression is denoted as 50% reduction in lesion size, but it is not clear what this means (area, largest dimension, quadrants involved, etc.). Additionally, while 2 of the pCR's had resolution of HPV infection following vaccination, very little other information is presented on the viral status of the other patients or the serial observations of HPV status over the treatment interval. Finally, the lack of a control group and the non-blinded nature of the design makes it difficult to interpret whether these results, while better than historical data, represent true measures of efficacy. Nevertheless, the potential benefit, particularly to young women with high-grade cervix dysplasia, is vast and does warrant further controlled clinical investigation.