Heat shock fusion protein-based immunotherapy for treatment of cervical intraepithelial neoplasia III

Mark H. Einstein, Anna S. Kadish, Robert D. Burk, Mimi Kim, Scott Wadler, Howard Streicher, Gary L. Goldberg, Carolyn D. Runowicz

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Objectives.: SGN-00101 (HspE7, Nventa, San Diego, CA) is a novel therapeutic vaccine consisting of a fusion protein containing an M. bovis BCG heat shock protein (Hsp65) covalently linked to the entire sequence of HPV 16 E7. This trial was designed to evaluate the efficacy and toxicities of HspE7 in women with CIN III. Methods.: HIV (-) women with biopsy-proven CIN III were eligible. Two cohorts were accrued; one cohort to establish efficacy and a second cohort with a longer follow-up period to improve the precision of the trial to estimate response rates. Each patient underwent 3 monthly subcutaneous vaccinations with 500 μg of HspE7 followed by monthly colposcopic follow-up for 1 month in cohort 1 and an extended observation period (2 months) in cohort 2. All patients then underwent a LEEP or cone biopsy of the cervix. A complete pathologic response (pCR) was defined as no evidence of CIN or CIN I (only HPV changes). A partial response (PR) was defined as colposcopic lesion regression of > 50% in size. Cervicovaginal lavage samples were obtained at each visit for HPV typing using MY09/ MY11 HPV PCR. Results.: Seventy-two patients were registered and screened, of whom 64 were eligible. Fifty-eight patients completed the trial and were evaluable (31 in cohort 1, 27 in cohort 2). There were no significant epidemiologic or HPV type differences between the 2 cohorts so responses were combined for analysis. Of the 58 evaluable patients, 13 (22.5%) had a pCR; 32 (55%) had a PR and 11 (19%) had stable disease. Two (3.5%) patients in cohort 2 had microinvasive disease and were defined as progressive disease. Thirty-three of 58 (57%) of the patients were infected with HPV 16 prior to vaccination or in subsequent visits. There was no significant difference in regression in women infected with HPV 16 compared to those without HPV 16 infection (88% vs. 70%; p = 0.12). Women who had a previous LEEP or ablation for CIN were 2.7 times more likely to have a complete response compared to patients without previous treatment, although the difference was not statistically significant (95% CI for rate ratio: 0.95-6.19, p = 0.10). At a cellular level, there was a significant association between local inflammation and response; lower grade of lesional inflammation correlated with a response to HspE7 (p = 0.04 using Wilcoxon rank sum test). Conclusions.: HspE7 appeared to demonstrate activity in women with CIN III and met a priori assumptions for efficacy; however, it is unclear whether this response was due to natural regression rather than treatment effect. HspE7, which targets the HPV 16 E7 oncoprotein, had efficacy in patients infected with HPV types other than 16, suggesting cross-reactivity. A larger randomized, controlled trial is needed to better define efficacy and to identify subsets of women most likely to benefit from immunotherapy.

Original languageEnglish (US)
Pages (from-to)453-460
Number of pages8
JournalGynecologic Oncology
Volume106
Issue number3
DOIs
StatePublished - Sep 2007

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Cervical Intraepithelial Neoplasia
Heat-Shock Proteins
Immunotherapy
Human papillomavirus 16
Therapeutics
Nonparametric Statistics
Vaccination
Inflammation
Biopsy
Therapeutic Irrigation
Oncogene Proteins
Mycobacterium bovis
Cervix Uteri
Vaccines
Randomized Controlled Trials
Observation
HIV
Polymerase Chain Reaction

Keywords

  • Heat shock protein
  • HPV
  • HPV E7 protein
  • Immunotherapy

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Oncology

Cite this

Heat shock fusion protein-based immunotherapy for treatment of cervical intraepithelial neoplasia III. / Einstein, Mark H.; Kadish, Anna S.; Burk, Robert D.; Kim, Mimi; Wadler, Scott; Streicher, Howard; Goldberg, Gary L.; Runowicz, Carolyn D.

In: Gynecologic Oncology, Vol. 106, No. 3, 09.2007, p. 453-460.

Research output: Contribution to journalArticle

Einstein, Mark H. ; Kadish, Anna S. ; Burk, Robert D. ; Kim, Mimi ; Wadler, Scott ; Streicher, Howard ; Goldberg, Gary L. ; Runowicz, Carolyn D. / Heat shock fusion protein-based immunotherapy for treatment of cervical intraepithelial neoplasia III. In: Gynecologic Oncology. 2007 ; Vol. 106, No. 3. pp. 453-460.
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abstract = "Objectives.: SGN-00101 (HspE7, Nventa, San Diego, CA) is a novel therapeutic vaccine consisting of a fusion protein containing an M. bovis BCG heat shock protein (Hsp65) covalently linked to the entire sequence of HPV 16 E7. This trial was designed to evaluate the efficacy and toxicities of HspE7 in women with CIN III. Methods.: HIV (-) women with biopsy-proven CIN III were eligible. Two cohorts were accrued; one cohort to establish efficacy and a second cohort with a longer follow-up period to improve the precision of the trial to estimate response rates. Each patient underwent 3 monthly subcutaneous vaccinations with 500 μg of HspE7 followed by monthly colposcopic follow-up for 1 month in cohort 1 and an extended observation period (2 months) in cohort 2. All patients then underwent a LEEP or cone biopsy of the cervix. A complete pathologic response (pCR) was defined as no evidence of CIN or CIN I (only HPV changes). A partial response (PR) was defined as colposcopic lesion regression of > 50{\%} in size. Cervicovaginal lavage samples were obtained at each visit for HPV typing using MY09/ MY11 HPV PCR. Results.: Seventy-two patients were registered and screened, of whom 64 were eligible. Fifty-eight patients completed the trial and were evaluable (31 in cohort 1, 27 in cohort 2). There were no significant epidemiologic or HPV type differences between the 2 cohorts so responses were combined for analysis. Of the 58 evaluable patients, 13 (22.5{\%}) had a pCR; 32 (55{\%}) had a PR and 11 (19{\%}) had stable disease. Two (3.5{\%}) patients in cohort 2 had microinvasive disease and were defined as progressive disease. Thirty-three of 58 (57{\%}) of the patients were infected with HPV 16 prior to vaccination or in subsequent visits. There was no significant difference in regression in women infected with HPV 16 compared to those without HPV 16 infection (88{\%} vs. 70{\%}; p = 0.12). Women who had a previous LEEP or ablation for CIN were 2.7 times more likely to have a complete response compared to patients without previous treatment, although the difference was not statistically significant (95{\%} CI for rate ratio: 0.95-6.19, p = 0.10). At a cellular level, there was a significant association between local inflammation and response; lower grade of lesional inflammation correlated with a response to HspE7 (p = 0.04 using Wilcoxon rank sum test). Conclusions.: HspE7 appeared to demonstrate activity in women with CIN III and met a priori assumptions for efficacy; however, it is unclear whether this response was due to natural regression rather than treatment effect. HspE7, which targets the HPV 16 E7 oncoprotein, had efficacy in patients infected with HPV types other than 16, suggesting cross-reactivity. A larger randomized, controlled trial is needed to better define efficacy and to identify subsets of women most likely to benefit from immunotherapy.",
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AU - Einstein, Mark H.

AU - Kadish, Anna S.

AU - Burk, Robert D.

AU - Kim, Mimi

AU - Wadler, Scott

AU - Streicher, Howard

AU - Goldberg, Gary L.

AU - Runowicz, Carolyn D.

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N2 - Objectives.: SGN-00101 (HspE7, Nventa, San Diego, CA) is a novel therapeutic vaccine consisting of a fusion protein containing an M. bovis BCG heat shock protein (Hsp65) covalently linked to the entire sequence of HPV 16 E7. This trial was designed to evaluate the efficacy and toxicities of HspE7 in women with CIN III. Methods.: HIV (-) women with biopsy-proven CIN III were eligible. Two cohorts were accrued; one cohort to establish efficacy and a second cohort with a longer follow-up period to improve the precision of the trial to estimate response rates. Each patient underwent 3 monthly subcutaneous vaccinations with 500 μg of HspE7 followed by monthly colposcopic follow-up for 1 month in cohort 1 and an extended observation period (2 months) in cohort 2. All patients then underwent a LEEP or cone biopsy of the cervix. A complete pathologic response (pCR) was defined as no evidence of CIN or CIN I (only HPV changes). A partial response (PR) was defined as colposcopic lesion regression of > 50% in size. Cervicovaginal lavage samples were obtained at each visit for HPV typing using MY09/ MY11 HPV PCR. Results.: Seventy-two patients were registered and screened, of whom 64 were eligible. Fifty-eight patients completed the trial and were evaluable (31 in cohort 1, 27 in cohort 2). There were no significant epidemiologic or HPV type differences between the 2 cohorts so responses were combined for analysis. Of the 58 evaluable patients, 13 (22.5%) had a pCR; 32 (55%) had a PR and 11 (19%) had stable disease. Two (3.5%) patients in cohort 2 had microinvasive disease and were defined as progressive disease. Thirty-three of 58 (57%) of the patients were infected with HPV 16 prior to vaccination or in subsequent visits. There was no significant difference in regression in women infected with HPV 16 compared to those without HPV 16 infection (88% vs. 70%; p = 0.12). Women who had a previous LEEP or ablation for CIN were 2.7 times more likely to have a complete response compared to patients without previous treatment, although the difference was not statistically significant (95% CI for rate ratio: 0.95-6.19, p = 0.10). At a cellular level, there was a significant association between local inflammation and response; lower grade of lesional inflammation correlated with a response to HspE7 (p = 0.04 using Wilcoxon rank sum test). Conclusions.: HspE7 appeared to demonstrate activity in women with CIN III and met a priori assumptions for efficacy; however, it is unclear whether this response was due to natural regression rather than treatment effect. HspE7, which targets the HPV 16 E7 oncoprotein, had efficacy in patients infected with HPV types other than 16, suggesting cross-reactivity. A larger randomized, controlled trial is needed to better define efficacy and to identify subsets of women most likely to benefit from immunotherapy.

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