Efficacy and safety results from neopembrov study, a randomized phase II trial of neoadjuvant chemotherapy (CT) with or without pembrolizumab (P) followed by interval debulking surgery and standard systemic therapy ± P for advanced high-grade serous carcinoma (HGSC): A GINECO study.

Savoye, Aude Marie; Mouret-Reynier, Marie-Ange; Chabaud, Sylvie; Derbel, Olfa; Kalbacher, Elsa; Leheurteur, Marianne; Martínez, Alejandra; Cornila, Corina; Martinez, Mathilde; Bengrine, Leila; Priou, Frank; Cloarec, Nicolas; Vénat-Bouvet, Laurence; Selle, Frédèric; Berton, Dominique; Collard, Olivier; Joly, Florence; Trédan, Olivier

doi:10.1200/jco.2021.39.15_suppl.5500

Cited by 10 publications

(8 citation statements)

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“…Patients receiving nivolumab showed increased proliferation of tumor infiltrating and peripheral T cells (30). The addition of anti-PD-L1 blockade to the perioperative chemotherapy treatment has since been evaluated in several clinical trials and found to be safe and effective (31,32). Such a protocol might well reduce the recurrence rate in patients that undergo resection of colorectal liver metastasis by targeting innate immune cells expressing PD-L1 that are found within the operative site after tumor resection.…”

Section: Discussionmentioning

confidence: 99%

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Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment

et al. 2021

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While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. Herein, to induce a NET-rich TME, we performed liver Ischemia/Reperfusion (I/R) in an established cancer metastasis model or directly injected NETs in subcutaneous tumors. In this NET-rich TME, the majority of CD4+ and CD8+ tumor infiltrating lymphocytes expressed multiple inhibitory receptors, in addition these cells showed a functional and metabolic exhausted phenotype. Targeting of NETs in vivo by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells. In vitro, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion and dysfunction; an effect abrogated by using PD-L1 KO NETs or culturing NETs with PD-1 KO T cells. Furthermore, we found elevated levels of sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. Neutrophils isolated from patients after surgery were primed to form NETs and induced exhaustion and dysfunction of human CD4+ and CD8+ T cells. We next targeted PD-L1 in vivo by injecting a blocking antibody during liver I/R. A single dose of anti-PD-L1 during surgery lead to diminished tumors at 3 weeks and functional T cells in the TME. Our data thus reveal that NETs have the capability of suppressing T cell responses through metabolic and functional exhaustion and thereby promote tumor growth. Furthermore, targeting of PD-L1 containing NETs at time of surgery with DNAse or anti-PD-L1 lead to diminished tumor growth, which represents a novel and viable strategy for sustaining immune competence within the TME.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment

et al. 2021

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“…This study did not show any difference with the addition of pembrolizumab. 86 In conclusion, while endometrial and CCs are ready for prime-time immunotherapy clinical trials in the neoadjuvant setting, OC still has a long way to go where the value of current neoadjuvant immunotherapy-based regimens appears to be limited.…”

Section: Gynecologic Malignanciesmentioning

confidence: 98%

Neoadjuvant immunotherapy of locoregionally advanced solid tumors

Tarhini

Eads

Moore

et al. 2022

J Immunother Cancer

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Definitive management of locoregionally advanced solid tumors presents a major challenge and often consists of a combination of surgical, radiotherapeutic and systemic therapy approaches. Upfront surgical treatment with or without adjuvant radiotherapy carries the risks of significant morbidities and potential complications that could be lasting. In addition, these patients continue to have a high risk of local or distant disease relapse despite the use of standard adjuvant therapy. Preoperative neoadjuvant systemic therapy has the potential to significantly improve clinical outcomes, particularly in this era of expanding immunotherapeutic agents that have transformed the care of patients with metastatic/unresectable malignancies. Tremendous progress has been made with neoadjuvant immunotherapy in the treatment of several locoregionally advanced resectable solid tumors leading to ongoing phase 3 trials and change in clinical practice. The promise of neoadjuvant immunotherapy has been supported by the high pathologic tumor response rates in early trials as well as the durability of these responses making cure a more achievable potential outcome compared with other forms of systemic therapy. Furthermore, neoadjuvant studies allow the assessment of radiologic and pathological responses and the access to biospecimens before and during systemic therapy. Pathological responses may guide future treatment decisions, and biospecimens allow the conduct of mechanistic and biomarker studies that may guide future drug development. On behalf of the National Cancer Institute Early Drug Development Neoadjuvant Immunotherapy Working Group, this article summarizes the current state of neoadjuvant immunotherapy of solid tumors focusing primarily on locoregionally advanced melanoma, gynecologic malignancies, gastrointestinal malignancies, non-small cell lung cancer and head and neck cancer including recent advances and our expert recommendations related to future neoadjuvant trial designs and associated clinical and translational research questions.

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“…In the neoadjuvant setting, pembrolizumab has been investigated in combination with carboplatin and paclitaxel for four cycles, followed by interval debulking surgery and standard adjuvant treatment (+/− bevacizumab) with or without pembrolizumab up to 2 years in a phase 2 randomized trial, and the results have been presented at the 2021 American Society of Medical Oncology (ASCO) conference [ 43 ]. The addition of the immune checkpoint inhibitor resulted in a small increase in ORR and complete cytoreduction rate without difference in median PFS.…”

Section: Immune Checkpoints In Eocmentioning

confidence: 99%

Chasing Immune Checkpoint Inhibitors in Ovarian Cancer: Novel Combinations and Biomarker Discovery

Colombo,

Karakasis,

Suku

et al. 2023

Cancers

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A deep understanding of the tumor microenvironment and the recognition of tumor-infiltrating lymphocytes as a prognostic factor have resulted in major milestones in immunotherapy that have led to therapeutic advances in treating many cancers. Yet, the translation of this knowledge to clinical success for ovarian cancer remains a challenge. The efficacy of immune checkpoint inhibitors as single agents or combined with chemotherapy has been unsatisfactory, leading to the exploration of alternative combination strategies with targeted agents (e.g., poly-ADP-ribose inhibitors (PARP)and angiogenesis inhibitors) and novel immunotherapy approaches. Among the different histological subtypes, clear cell ovarian cancer has shown a higher sensitivity to immunotherapy. A deeper understanding of the mechanism of immune resistance within the context of ovarian cancer and the identification of predictive biomarkers remain central discovery benchmarks to be realized. This will be critical to successfully define the precision use of immune checkpoint inhibitors for the treatment of ovarian cancer.

show abstract

Efficacy and safety results from neopembrov study, a randomized phase II trial of neoadjuvant chemotherapy (CT) with or without pembrolizumab (P) followed by interval debulking surgery and standard systemic therapy ± P for advanced high-grade serous carcinoma (HGSC): A GINECO study.

Cited by 10 publications

References 0 publications

Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment

Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment

Neoadjuvant immunotherapy of locoregionally advanced solid tumors

Chasing Immune Checkpoint Inhibitors in Ovarian Cancer: Novel Combinations and Biomarker Discovery

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