Sequential Ipilimumab After Chemoradiotherapy in Curative-Intent Treatment of Patients With Node-Positive Cervical Cancer

Mayadev, Jyoti; Enserro, Danielle; Lin, Yvonne G.; Silva, Diane M. Da; Lankes, Heather A.; Aghajanian, Carol; Ghamande, Sharad; Moore, Kathleen N.; Kennedy, Vanessa; Fracasso, Paula M.; Schilder, Russell J.

doi:10.1001/jamaoncol.2019.3857

Cited by 74 publications

(65 citation statements)

References 35 publications

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“…28 Therapeutic vaccines offer antigen-specific education of T cells, but historically vaccines alone have done little to address the immunosuppressive nature of the often experience recurrence of disease, showed that checkpoint inhibitor therapy was safe in combination with CRT. 29 In addition, CRT upregulated PD1 expression on peripheral CD8+ and CD4+ cells, suggesting that T cells are activated and patients may benefit from PD1/PDL1 targeting therapies. Positive results from phase II clinical trials, such as the combination of anti-PD1 nivolumab and ISA101 HPV16 long peptide vaccine, 10 provide evidence of the effectiveness of combining two different types of immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulation to enhance the efficacy of an HPV therapeutic vaccine

Rumfield

Pellom

Morillon

et al. 2020

J Immunother Cancer

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BackgroundWhile prophylactic human papillomavirus (HPV) vaccines will certainly reduce the incidence of HPV-associated cancers, these malignancies remain a major health issue. PDS0101 is a liposomal-based HPV therapeutic vaccine consisting of the immune activating cationic lipid R-DOTAP and HLA-unrestricted HPV16 peptides that has shown in vivo CD8+ T cell induction and safety in a phase I study. In this report, we have employed the PDS0101 vaccine with two immune modulators previously characterized in preclinical studies and which are currently in phase II clinical trials. Bintrafusp alfa (M7824) is a first-in-class bifunctional fusion protein composed of the extracellular domains of the transforming growth factor-β receptor type II (TGFβRII) fused to a human IgG1 monoclonal antibody blocking programmed cell death protein-1 ligand (PDL1), designed both as a checkpoint inhibitor and to bring the TGFβRII ‘trap’ to the tumor microenvironment (TME). NHS-interleukin-12 (NHS-IL12) is a tumor targeting immunocytokine designed to bring IL-12 to the TME and thus enhance the inflammatory Th1 response.MethodsWe employed TC-1 carcinoma (expressing HPV16 E6 and E7 and devoid of PDL1 expression) in a syngeneic mouse model in monotherapy and combination therapy studies to analyze antitumor effects and changes in immune cell types in the spleen and the TME.ResultsAs a monotherapy, the PDS0101 vaccine generated HPV-specific T cells and antitumor activity in mice bearing HPV-expressing mEER oropharyngeal and TC-1 lung carcinomas. When used as a monotherapy in the TC-1 model, NHS-IL12 elicited antitumor effects as well as an increase in CD8+ T cells in the TME. When used as a monotherapy, bintrafusp alfa did not elicit antitumor effects or any increase in T cells in the TME. When all three agents were used in combination, maximum antitumor effects were observed, which correlated with increases in T cells and T-cell clonality in the TME.ConclusionThese studies provide the rationale for the potential clinical use of combinations of agents that can (1) induce tumor-associated T-cell responses, (2) potentiate immune responses in the TME and (3) reduce immunosuppressive entities in the TME.

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Section: Discussionmentioning

confidence: 99%

Immunomodulation to enhance the efficacy of an HPV therapeutic vaccine

Rumfield

Pellom

Morillon

et al. 2020

J Immunother Cancer

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“…Cervical cancer (CC) is one of the most common tumours, ranking fourth for both incidence and mortality in women worldwide [1][2][3]. CC is the result of continuous infection with some strains of human papillomavirus (HPV), such as HPV16 and HPV18 [4,5].…”

Section: Introductionmentioning

confidence: 99%

Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer

Zhang

Huang

et al. 2020

J Transl Med

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Background Methyltransferase-like 3 (METTL3) is a member of the m6A methyltransferase family and acts as an oncogene in cancers. Recent studies suggest that host innate immunity is regulated by the enzymes controlling m6A epitranscriptomic changes. Here, we aim to explore the associations between the levels of METTL3 and CD33+ myeloid-derived suppressor cells (MDSCs) in tumour tissues and the survival of patients with cervical cancer (CC). Methods Specimens of paraffin embedded tumour from 197 CC patients were collected. The expression levels of METTL3 and CD33 were measured by immunohistochemical (IHC) staining. The clinical associations of the IHC variants were analysed by Pearson’s or Spearman’s chi-square tests. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan–Meier method and log-rank test. Hazard ratios (HRs) and independent significance were obtained via Cox proportional hazards models for multivariate analyses. METTL3 in CD33+ cells or CC-derived cells was knocked down by METTL3-specific siRNA, and MDSC induction in vitro was performed in a co-culture system in the presence of METTL3-siRNA and METTL3-knockdown-CC-derived cells compared with that of the corresponding controls. Results We found that tumour tissues displayed increased levels of METTL3 and CD33+ MDSCs compared with tumour-adjacent tissues from the same CC patients. Importantly, METTL3 expression was positively related to the density of CD33+ cells in tumour tissues (P = 0.011). We further found that the direct CD33+CD11b+HLA-DR− MDSC induction and tumour-derived MDSC induction in vitro were decreased in the absence of METTL3. The level of METTL3 in tumour microenvironments was significantly related to advanced tumour stage. The levels of METTL3 and CD33+ MDSCs in tumour tissues were notably associated with reduced DFS or OS. Cox model analysis revealed that the level of METTL3 in tumour cells was an independent factor for patient survival, specifically for DFS (HR = 3.157, P = 0.022) and OS (HR = 3.271, P = 0.012), while the CD33+ MDSC number was an independent predictor for DFS (HR: 3.958, P = 0.031). Interestingly, in patients with advanced-disease stages (II–IV), METTL3 in tumour cells was an independent factor for DFS (HR = 6.725, P = 0.010) and OS (HR = 5.140, P = 0.021), while CD33+ MDSC density was an independent factor for OS (HR = 8.802, P = 0.037). Conclusion Our findings suggest that CD33+ MDSC expansion is linked to high levels of METTL3 and that METTL3 and CD33+ MDSCs are independent prognostic factors in CC.

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“…All 34 patients in the study completed CRT, 90% completed 4 cycles of ipilimumab (the other 10% completed 2 cycles), and the treatment was well tolerated. 18 In the 20 evaluable patients, the 1-year disease free survival was 74% (vs 55% in historical Surveillance, Epidemiology, and End Results databases). The therapy was well tolerated, with only 3 patients having grade 3 toxicities, which were self-limiting, and with 2 patients experiencing events of clinical interest (1 in each arm).…”

Section: Discussionmentioning

confidence: 96%

Results of an early safety analysis of a study of the combination of pembrolizumab and pelvic chemoradiation in locally advanced cervical cancer

Duska

Scalici

Temkin

et al. 2020

Cancer

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BACKGROUND: Immune checkpoint inhibitors are being considered for locally advanced cervical cancer (LACC) together with standard-of-care pelvic chemoradiation (CRT). However, the safety of the combination and its optimal schedule are unknown. Defining the safety of the combination is a primary objective of a study examining concurrent and sequential schedules. This article presents a safety analysis that was fully accrued and met reporting requirements. METHODS: Pembrolizumab was given after CRT (arm 1) or during CRT (arm 2) according to a randomized phase 2 design. Patients who were 18 years old or older and had LACC (stages IB-IVA according to the 2009 International Federation of Gynecology and Obstetrics system) were randomized 1:1 to the treatment regimens. The CRT was identical in the 2 arms. Pembrolizumab was administered every 3 weeks for 3 doses; no maintenance was allowed. All patients receiving any treatment were evaluated for safety. Safety assessments included the incidence and severity of adverse events (AEs) and the occurrence of protocol-defined dose-limiting toxicity (DLT) through 30 days after the last pembrolizumab infusion. RESULTS: As of August 2019, 52 of the 88 planned patients had completed treatment and were evaluable for toxicity. Treatment-related grade 2 or higher toxicity was experienced by 88%; 11 had at least 1 grade 4 AE, and another 23 had at least 1 grade 3 AE. Grade 1 or higher diarrhea was reported in 34 patients (65%; 50% of these were grade 1), and there was no difference between arms (63% in arm 1 vs 68% in arm 2). Two patients experienced 3 DLTs. Most patients completed cisplatin (100% in arm 1 vs 82% in arm 2); 83% in both arms completed all pembrolizumab. CONCLUSIONS: Preliminary results support the safety and feasibility of adding pembrolizumab to pelvic CRT concurrently or sequentially. Cancer 2020;126:4948-4956.

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Sequential Ipilimumab After Chemoradiotherapy in Curative-Intent Treatment of Patients With Node-Positive Cervical Cancer

Cited by 74 publications

References 35 publications

Immunomodulation to enhance the efficacy of an HPV therapeutic vaccine

Immunomodulation to enhance the efficacy of an HPV therapeutic vaccine

Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer

Results of an early safety analysis of a study of the combination of pembrolizumab and pelvic chemoradiation in locally advanced cervical cancer

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