First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response

Yap, Timothy A.; Gainor, Justin F.; Callahan, Margaret K.; Pachynski, Russell K.; LoRusso, Patricia; Kummar, Shivaani; Gibney, Geoffrey T.; Burris, Howard A.; Tykodi, Scott S.; Rahma, Osama E.; Seiwert, Tanguy Y.; Papadopoulos, Kyriakos P.; Murphy, Mariela Blum; Hanson, Amanda; Hashambhoy-Ramsay, Yasmin; McGrath, Lara; Hooper, Ellen; Xiao, Xiaoying; Cohen, Heather; Fan, Martin; Felitsky, Daniel; Hart, Courtney; McComb, Rachel; Brown, Karen; Sepahi, Ali; Jiménez, Judith; Zhang, Weidong; Baeck, Johan; Laken, Haley; Murray, Richard M.; Trehu, Elizabeth; Harvey, Christopher J.

doi:10.1158/1078-0432.ccr-21-4256

Cited by 40 publications

(22 citation statements)

References 25 publications

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“…In these cells, ICOS plays an important role in cell activation, maintenance, and survival [75]. Emerging research is highlighting the importance of ICOS co-stimulation to deliver efficient anti-tumour effector T cell responses [76][77][78], with various ICOS agonist antibodies currently in clinical trial showing promising results [79,80]. Targeting this co-stimulatory pathway could be also beneficial to boost adaptive immunity and improve disease outcomes in secondary dengue infections.…”

Section: Discussionmentioning

confidence: 99%

Integrated systems immunology approach identifies impaired effector T cell memory responses as a feature of progression to severe dengue fever

et al. 2023

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Background Typical symptoms of uncomplicated dengue fever (DF) include headache, muscle pains, rash, cough, and vomiting. A proportion of cases progress to severe dengue hemorrhagic fever (DHF), associated with increased vascular permeability, thrombocytopenia, and hemorrhages. Progression to severe dengue is difficult to diagnose at the onset of fever, which complicates patient triage, posing a socio-economic burden on health systems. Methods To identify parameters associated with protection and susceptibility to DHF, we pursued a systems immunology approach integrating plasma chemokine profiling, high-dimensional mass cytometry and peripheral blood mononuclear cell (PBMC) transcriptomic analysis at the onset of fever in a prospective study conducted in Indonesia. Results After a secondary infection, progression to uncomplicated dengue featured transcriptional profiles associated with increased cell proliferation and metabolism, and an expansion of ICOS+CD4+ and CD8+ effector memory T cells. These responses were virtually absent in cases progressing to severe DHF, that instead mounted an innate-like response, characterised by inflammatory transcriptional profiles, high circulating levels of inflammatory chemokines and with high frequencies of CD4low non-classical monocytes predicting increased odds of severe disease. Conclusions Our results suggests that effector memory T cell activation might play an important role ameliorating severe disease symptoms during a secondary dengue infection, and in the absence of that response, a strong innate inflammatory response is required to control viral replication. Our research also identified discrete cell populations predicting increased odds of severe disease, with potential diagnostic value.

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Section: Discussionmentioning

confidence: 99%

Integrated systems immunology approach identifies impaired effector T cell memory responses as a feature of progression to severe dengue fever

et al. 2023

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“…100,101 Inducible T-cell costimulator agonist (vopratelimab) either alone or in combination with nivolumab was evaluated in a phase I/II ICONIC trial involving 201 patients with advanced solid malignancies. 102 The phase I study aimed at evaluating the safety and tolerability. 102 In phase II, the study focused on patients with ICOS-positive tumors to evaluate the pharmacokinetics, pharmacodynamics and predictive biomarkers for vopratelimab response.…”

Section: Inducible T-cell Costimulatormentioning

confidence: 99%

Tissue biomarkers of immune checkpoint inhibitor therapy

Davoudi,

Moradi,

Sadeghirad

et al. 2024

Immunol Cell Biol

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Cancer immunotherapy has been rejuvenated by the growing understanding of the immune system's role in tumor activity over the past two decades. During cancer initiation and progression, tumor cells employ various mechanisms that resemble peripheral immune tolerance to evade the antitumor responses of the immune system. Immune checkpoint molecules are the major mechanism of immune resistance that are exploited by tumor cells to inhibit T‐cell activation and suppress immune responses. The targeting of immune checkpoint pathways has led to substantial improvements in survival rates in a number of solid cancers. However, a lack of understanding of the heterogeneity of the tumor microenvironment (TME) has resulted in inefficient therapy responses. A greater understanding of the TME is needed to identify patients likely to respond, and those that will have resistance to immune checkpoint inhibitors (ICIs). Advancement in spatial single‐cell technologies has allowed deeper insight into the phenotypic and functional diversities of cells in the TME. In this review, we provide an overview of ICI biomarkers and highlight how high‐dimensional spatially resolved, single‐cell approaches provide deep molecular insights into the TME and allow for the discovery of biomarkers of clinical benefit.

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“…12,13 The ICOS agonist mAb, vopratelimab, has been investigated in combination with anti-PD-1 and anti-CTLA-4 mAb in the Phase I ICONIC trial (NCT02904226). [14][15][16] Furthermore, the first-in-human INDUCE-1 study (NCT02723955) explored the combination of the ICOS agonist mAb feladilimab with anti-PD-1, anti-TIM-3 mAb or chemotherapy, in patients with advanced solid tumors. 17,18 However, in spite of the initial results showing safety, tolerability, and clinical activity of ICOS agonists in heavily pretreated patients, more mature data failed to confirm their efficacy; thus, their therapeutic potential is being investigated further.…”

Section: Introductionmentioning

confidence: 99%

From Co-Stimulation to Co-Inhibition: A Continuum of Immunotherapy Care Toward Long-Term Survival in Melanoma

Simonetti¹,

Cutarella²,

Valente³

et al. 2023

OTT

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Harnessing the immune system with immune-checkpoint(s) blockade (ICB) has dramatically changed the treatment landscape of advanced melanoma patients in the last decade. Indeed, durable clinical responses and long-term survival can be achieved with anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) and anti-Programmed cell Death-1 (PD-1) monoclonal antibodies (mAb) either alone or in combination. Despite these unprecedented results, due to intrinsic or acquired resistance to ICB-based immunotherapy, about half of metastatic melanoma (MM) patients neither respond to therapy nor experience durable clinical benefit or long-term survival. To improve the efficacy of ICB therapy among a larger proportion of MM patients, in addition to the targeting of immune-checkpoint(s) inhibitors (ICI) such as CTLA-4 or PD-1, several co-stimulatory molecules, such as Inducible T-cell COStimulator (ICOS), CD137 and OX40, have been investigated in MM, with initial signs of activity. Thus, a number of MM patients have been exposed to co-inhibitory and co-stimulatory mAb in the course of their disease. Being aware of the clinical outcome of such patients may pave the way to novel and more effective clinical approaches and therapeutic sequences for MM patients. Here we report a paradigmatic clinical case of a cutaneous MM patient who achieved multiple and durable complete responses, leading to an extraordinary long-term survival with sequential ICB therapies, suggesting the possibility to build a highly effective continuum of care with co-inhibitory and co-stimulatory therapeutic mAb.

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First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response

Cited by 40 publications

References 25 publications

Integrated systems immunology approach identifies impaired effector T cell memory responses as a feature of progression to severe dengue fever

Integrated systems immunology approach identifies impaired effector T cell memory responses as a feature of progression to severe dengue fever

Tissue biomarkers of immune checkpoint inhibitor therapy

From Co-Stimulation to Co-Inhibition: A Continuum of Immunotherapy Care Toward Long-Term Survival in Melanoma

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