Pembrolizumab plus GX-188E therapeutic DNA vaccine in patients with HPV-16-positive or HPV-18-positive advanced cervical cancer: interim results of a single-arm, phase 2 trial

Youn, Jin Won; Hur, Soo-Young; Woo, Jung Won; Kim, Yong‐Man; Lim, Myong Cheol; Park, Soo‐Jin; Seo, Sang Soo; No, Jae Hong; Kim, Byoung-Gie; Lee, Jae Kwan; Shin, So Jin; Kim, Kyungun; Chaney, Marya; Choi, Yuyoung; Suh, You Suk; Park, Jong Sup; Sung, Young Chul

doi:10.1016/s1470-2045(20)30486-1

Cited by 91 publications

(62 citation statements)

References 30 publications

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“…The cellular responses persisted out to a year on the study, and flow-cytometric analysis showed induction of HPV16-specific PD-1 + CD8 + T cells (96). More recently, an interim analysis of a single-arm phase II trial of a DNA vaccine encoding the E6/E7 protein of HPV16 and 18 in a vector encoding the adjuvant FLT3L (branded GX-188E) with pembrolizumab in recurrent/advanced cervical cancer showed 11/26 patients with response, 4 of which were complete at 24 weeks as assessed by RECIST (97). This provides a rationale for further exploring combination of vaccines and ICB to potentiate T cell-specific responses clinically.…”

Section: Therapeutic Vaccination Strategiesmentioning

confidence: 99%

Tumor Immunity and Immunotherapy for HPV-Related Cancers

et al. 2021

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Human papillomavirus (HPV) infection drives tumorigenesis in the majority of cervical, oropharyngeal, anal, and vulvar cancers. Genetic and epidemiologic evidence has highlighted the role of immunosuppression in the oncogenesis of HPV-related malignancies. Here we review how HPV modulates the immune microenvironment and subsequent therapeutic implications. We describe the landscape of immunotherapies for these cancers with a focus on findings from early-phase studies exploring antigen-specific treatments, and discuss future directions. Although responses across these studies have been modest to date, a deeper understanding of HPV-related tumor biology and immunology may prove instrumental for the development of more efficacious immunotherapeutic approaches.Significance: HPV modulates the microenvironment to create a protumorigenic state of immune suppression and evasion. Our understanding of these mechanisms has led to the development of immunomodulatory treatments that have shown early clinical promise in patients with HPV-related malignancies. This review summarizes our current understanding of the interactions of HPV and its microenvironment and provides insight into the progress and challenges of developing immunotherapies for HPV-related malignancies.

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Section: Therapeutic Vaccination Strategiesmentioning

confidence: 99%

Tumor Immunity and Immunotherapy for HPV-Related Cancers

et al. 2021

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“…Youn et al reported that GX-188E vaccination enhanced the proportion of clinical responders to immune checkpoint inhibitors (ICBs) by adding HPV-speci c T cells [26]. Compared with pembrolizumab alone, the ORR increased from 17% to 42% [5,26]. Another study also con rmed the necessity for therapeutic vaccineinduced T cell populations in immunotherapy.…”

Section: Discussionmentioning

confidence: 98%

“…Recent advances have been achieved in the research and development of therapeutic HPV vaccines to enhance T cell activity, including protein, polypeptide and live vector, nucleic acid, and cellular vaccines. Youn et al reported that GX-188E vaccination enhanced the proportion of clinical responders to immune checkpoint inhibitors (ICBs) by adding HPV-speci c T cells [26]. Compared with pembrolizumab alone, the ORR increased from 17% to 42% [5,26].…”

Section: Discussionmentioning

confidence: 99%

HPV16 E6-specific T Cell Response and HLA-A Alleles Are Related to the Prognosis of Patients With Cervical Cancer 

Cai

Fan

et al. 2021

Preprint

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Background: It is worthwhile to identify more epitopes as target to design T cell-based therapeutic interventions that can benefit cervical cancer patients whose disease cannot be well controlled with current treatment modalities. This study investigated T cell response to HPV16 E6 and E7 in patients with cervical squamous cell carcinoma (CSCC). Also, the human leukocyte antigen (HLA)-A allele distribution was compared among patients and evaluated as factors to predict prognosis in these patients.Materials and Methods: This study recruited a total of 76 patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IIB–IIIB CSCC. Mononuclear cells were isolated from the peripheral blood before any treatment and then enzyme-linked immunosorbent spot (ELISpot) assay was employed to measure the E6 and E7-specific T cell response. HLA‐A alleles were typed using Sanger sequence‐based typing techniques with DNA extracted from the peripheral blood. The correlation between the T cell responses, HLA‐A allele distribution and patient prognosis were analysed using the Kaplan–Meier method, univariate and multivariate Cox proportional hazard models.Results: The frequency of HPV E6-specific T cell responses in patients with pelvic lymph node metastasis was lower than that in patients without metastasis (P=0.022). The 5-year overall survival (OS) rates of patients were 87.5% for the multiple overlapping peptide group, 72.7% for the 1–2 overlapping peptide group, and 47.7% for the negative group (P=0.032). Cox regression analysis indicated that the presence of HLA*A02:07 was independently associated with worse OS (hazard ratio [HR] 3.042; 95% confidence interval [CI]: 1.348–6.862; P=0.007), while concurrent chemoradiation therapy (CCRT) was independently associated with better OS (HR 0.475; 95% CI: 0.232–0.975; P= 0.042).Conclusion: The results of our study demonstrated that the level of HPV16 E6-specific T cell response and HLA*A02:07 were correlated with prognosis in patients with advanced CSCC.

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“…NCT03444376 is an ongoing single-arm, open-label phase IB-II clinical trial of the combination of GX-188E (a DNA vaccine shown to induce HPV E6-and E7-specific T-cell responses and lesion regression in patients with cervical precancer) with pembrolizumab in 60 patients with advanced, non-resectable HPV-positive CC. Most recently, their interim analysis of 36 patients, of which 26 patients were evaluable for interim activity assessment with at least one postbaseline tumor assessment at week 10, were published in The Lancet Oncology [76]. At 24 weeks, 11 (42%; 95% CI 23-63) of 26 patients achieved an overall response; four (15%) had a complete response and seven (27%) had a PR.…”

Section: Pembrolizumab Combined With Immunotherapymentioning

confidence: 99%

Targeting the PD-1 Axis with Pembrolizumab for Recurrent or Metastatic Cancer of the Uterine Cervix: A Brief Update

Verhoeven

Quatannens

Trinh

et al. 2021

IJMS

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Even though cervical cancer is partly preventable, it still poses a great public health problem throughout the world. Current therapies have vastly improved the clinical outcomes of cervical cancer patients, but progress in new systemic treatment modalities has been slow in the last years. Especially for patients with advanced disease this is discouraging, as their prognosis remains very poor. The pathogen-induced nature, the considerable mutational load, the involvement of genes regulating the immune response, and the high grade of immune infiltration, suggest that immunotherapy might be a promising strategy to treat cervical cancer. In this literature review, we focus on the use of PD-1 blocking therapy in cervical cancer, pembrolizumab in particular, as it is the only approved immunotherapy for this disease. We discuss why it has great clinical potential, how it opens doors for personalized treatment in cervical cancer, and which trials are aiming to expand its clinical use.

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Pembrolizumab plus GX-188E therapeutic DNA vaccine in patients with HPV-16-positive or HPV-18-positive advanced cervical cancer: interim results of a single-arm, phase 2 trial

Cited by 91 publications

References 30 publications

Tumor Immunity and Immunotherapy for HPV-Related Cancers

Tumor Immunity and Immunotherapy for HPV-Related Cancers

HPV16 E6-specific T Cell Response and HLA-A Alleles Are Related to the Prognosis of Patients With Cervical Cancer

Targeting the PD-1 Axis with Pembrolizumab for Recurrent or Metastatic Cancer of the Uterine Cervix: A Brief Update

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Pembrolizumab plus GX-188E therapeutic DNA vaccine in patients with HPV-16-positive or HPV-18-positive advanced cervical cancer: interim results of a single-arm, phase 2 trial

Cited by 91 publications

References 30 publications

Tumor Immunity and Immunotherapy for HPV-Related Cancers

Tumor Immunity and Immunotherapy for HPV-Related Cancers

HPV16&nbsp;E6-specific T Cell Response and HLA-A Alleles Are Related to the Prognosis of Patients With Cervical Cancer&nbsp;

Targeting the PD-1 Axis with Pembrolizumab for Recurrent or Metastatic Cancer of the Uterine Cervix: A Brief Update

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HPV16 E6-specific T Cell Response and HLA-A Alleles Are Related to the Prognosis of Patients With Cervical Cancer