TY - JOUR
T1 - Clinical and immunologic biomarkers for histologic regression of high-grade cervical dysplasia and clearance of HPV16 and HPV18 after immunotherapy
AU - Morrow, Matthew P.
AU - Kraynyak, Kimberly A.
AU - Sylvester, Albert J.
AU - Dallas, Michael
AU - Knoblock, Dawson
AU - Boyer, Jean D.
AU - Yan, Jian
AU - Vang, Russell
AU - Khan, Amir S.
AU - Humeau, Laurent
AU - Sardesai, Niranjan Y.
AU - Kim, J. Joseph
AU - Plotkin, Stanley
AU - Weiner, David B.
AU - Trimble, Cornelia L.
AU - Bagarazzi, Mark L.
N1 - Funding Information:
The authors thank the patients who participated in this study and the entire HPV-003 clinical team from the participating study sites and Histologix and OracleBio for assistance with IHC staining and digital image analysis and FlowMetric for aid in flow cytometry. This work was supported by Inovio Pharmaceuticals Inc.
Publisher Copyright:
© 2017 AACR.
PY - 2018/1/15
Y1 - 2018/1/15
N2 - Purpose: As previously reported, treatment of high-grade cervical dysplasia with VGX-3100 resulted in complete histopathologic regression (CR) concomitant with elimination of HPV16/18 infection in 40.0% of VGX-3100-treated patients compared with only 14.3% in placebo recipients in a randomized phase IIb study. Here, we identify clinical and immunologic characteristics that either predicted or correlated with therapeutic benefit from VGX-3100 to identify parameters that might guide clinical decisionmaking for this disease. Experimental Design: We analyzed samples taken from cervical swabs, whole blood, and tissue biopsies/resections to determine correlates and predictors of treatment success. Results: At study entry, the presence of preexisting immunosuppressive factors such as FoxP3 and PD-L1 in cervical lesions showed no association with treatment outcome. The combination of HPV typing and cervical cytology following dosing was predictive for both histologic regression and elimination of detectable virus at the efficacy assessment 22 weeks later (negative predictive value 94%). Patients treated with VGX-3100 who had lesion regression had a statistically significant >2-fold increase in CD137 + perforin + CD8 + T cells specific for the HPV genotype causing disease. Increases in cervical mucosal CD137 + and CD103 + infiltrates were observed only in treated patients. Perforin + cell infiltrates were significantly increased >2-fold in cervical tissue only in treated patients who had histologic CR. Conclusions: Quantitative measures associated with an effector immune response to VGX-3100 antigens were associated with lesion regression. Consequently, these analyses indicate that certain immunologic responses associate with successful resolution of HPV-induced premalignancy, with particular emphasis on the upregulation of perforin in the immunotherapy-induced immune response.
AB - Purpose: As previously reported, treatment of high-grade cervical dysplasia with VGX-3100 resulted in complete histopathologic regression (CR) concomitant with elimination of HPV16/18 infection in 40.0% of VGX-3100-treated patients compared with only 14.3% in placebo recipients in a randomized phase IIb study. Here, we identify clinical and immunologic characteristics that either predicted or correlated with therapeutic benefit from VGX-3100 to identify parameters that might guide clinical decisionmaking for this disease. Experimental Design: We analyzed samples taken from cervical swabs, whole blood, and tissue biopsies/resections to determine correlates and predictors of treatment success. Results: At study entry, the presence of preexisting immunosuppressive factors such as FoxP3 and PD-L1 in cervical lesions showed no association with treatment outcome. The combination of HPV typing and cervical cytology following dosing was predictive for both histologic regression and elimination of detectable virus at the efficacy assessment 22 weeks later (negative predictive value 94%). Patients treated with VGX-3100 who had lesion regression had a statistically significant >2-fold increase in CD137 + perforin + CD8 + T cells specific for the HPV genotype causing disease. Increases in cervical mucosal CD137 + and CD103 + infiltrates were observed only in treated patients. Perforin + cell infiltrates were significantly increased >2-fold in cervical tissue only in treated patients who had histologic CR. Conclusions: Quantitative measures associated with an effector immune response to VGX-3100 antigens were associated with lesion regression. Consequently, these analyses indicate that certain immunologic responses associate with successful resolution of HPV-induced premalignancy, with particular emphasis on the upregulation of perforin in the immunotherapy-induced immune response.
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U2 - 10.1158/1078-0432.CCR-17-2335
DO - 10.1158/1078-0432.CCR-17-2335
M3 - Article
C2 - 29084917
AN - SCOPUS:85040735420
SN - 1078-0432
VL - 24
SP - 276
EP - 294
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -