ICOS agonism by JTX-2011 (vopratelimab) requires initial T cell priming and Fc cross-linking for optimal T cell activation and anti-tumor immunity in preclinical models

Hanson, Amanda; Elpek, Kutlu G.; Duong, Ellen; Shallberg, Lindsey; Fan, Martin; Johnson, Calvin M.; Wallace, Marianne; Mabry, George R.; Sazinsky, Stephen L.; Pepper, Lauren R.; Shu, Chengyi J.; Sathyanarayanan, Sriram; Zuerndorfer, Sarah; Simpson, Tyler R.; Gostissa, Monica; Briskin, Michael; Law, Deborah; Michaelson, Jennifer S.; Harvey, Christopher J.

doi:10.1371/journal.pone.0239595

Cited by 30 publications

(17 citation statements)

References 36 publications

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“…5 aiii) as has previously been described 39 , 40 . By contrast, ICOS antibody treatment decreased T regulatory cells in the tumor when used as a single agent and also in combination with RT (ICOS Ab vs. Isotype p < 0.01; RT + ICOS Ab vs. RT p < 0.01), in line with the reported Treg depletion activity of this antibody in preclinical studies 35 . The non-Treg population of CD4 + T cells (CD4 + FoxP3 − ) were not significantly changed in proportion following treatment, and CD8 + T cell infiltrates were increased with RT and by ICOS antibody treatment (RT vs. Isotype p < 0.05; ICOS Ab vs. Isotype p < 0.05; RT + ICOS Ab vs. RT p = 0.0632) (Fig.…”

Section: Resultssupporting

confidence: 73%

“…However, given the observation that ICOS is a potential costimulatory molecule that is upregulated on T cells following radiation therapy (Fig. 1 ), we tested the effect of combining radiation with a novel ICOS agonist antibody 35 . We have previously demonstrated that for optimal tumor control, co-stimulatory antibodies such as OX40 antibody require different timing when compared to blocking antibodies such as anti-CTLA4 relative to the delivery of radiation therapy 36 .…”

Section: Resultsmentioning

confidence: 99%

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ICOS is upregulated on T cells following radiation and agonism combined with radiation results in enhanced tumor control

Blair

Baird

Bambina

et al. 2022

Sci Rep

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Multiple preclinical studies have shown improved outcomes when radiation therapy is combined with immune modulating antibodies. However, to date, many of these promising results have failed to translate to successful clinical studies. This led us to explore additional checkpoint and co-stimulatory pathways that may be regulated by radiation therapy. Here, we demonstrate that radiation increases the expression of inducible T cell co-stimulator (ICOS) on both CD4 and CD8 T cells in the blood following treatment. Moreover, when we combined a novel ICOS agonist antibody with radiation we observed durable cures across multiple tumor models and mouse strains. Depletion studies revealed that CD8 T cells were ultimately required for treatment efficacy, but CD4 T cells and NK cells also partially contributed to tumor control. Phenotypic analysis showed that the combination therapy diminished the increased infiltration of regulatory T cells into the tumor that typically occurs following radiation alone. Finally, we demonstrate in a poorly immunogenic pancreatic tumor model which is resistant to combined radiation and anti-PD1 checkpoint blockade that the addition of this novel ICOS agonist antibody to the treatment regimen results in tumor control. These findings identify ICOS as part of a T cell pathway that is modulated by radiation and targeting this pathway with a novel ICOS antibody results in durable tumor control in preclinical models.

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Section: Resultssupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

ICOS is upregulated on T cells following radiation and agonism combined with radiation results in enhanced tumor control

Blair

Baird

Bambina

et al. 2022

Sci Rep

Self Cite

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“…Inducible endothelial ICOSLG expression has been described, particularly after inflammatory stimulation ( Khayyamian et al 2002 ; Klingenberg et al 2005 ), and regulates CD4 + ( Khayyamian et al 2002 ) and CD8 + T-lymphocyte functionality during cardiac allograft rejection ( Klingenberg et al 2005 ), suggesting that inflammatory-induced endothelial ICOSLG expression could activate and shape the local immune reaction at the site of injury or infection. In antitumoral immunity, Icos–Icosl signaling underpins successful antitumoral immune responses after blockade of the inhibitory ligand Ctla4 ( Fu et al 2011 ) or PD-1 ( Hanson et al 2020 ), providing rationale for the development of clinical ICOS-agonistic antibodies as second-generation immune oncology agents. These stimulating antibodies seem to avoid the superagonistic activity of earlier CD28 targeted therapies.…”

Section: Discussionmentioning

confidence: 99%

Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance

et al. 2022

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Senescence is a stress-responsive tumor suppressor mechanism associated with expression of the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells trigger their own immune-mediated elimination, which if evaded leads to tumorigenesis. Senescent parenchymal cells are separated from circulating immunocytes by the endothelium, which is targeted by microenvironmental signaling. Here we show that SASP induces endothelial cell NF-κB activity and that SASP-induced endothelial expression of the canonical NF-κB component Rela underpins senescence surveillance. Using human liver sinusoidal endothelial cells (LSECs), we show that SASP-induced endothelial NF-κB activity regulates a conserved transcriptional program supporting immunocyte recruitment. Furthermore, oncogenic hepatocyte senescence drives murine LSEC NF-κB activity in vivo. Critically, we show two distinct endothelial pathways in senescence surveillance. First, endothelial-specific loss of Rela prevents development of Stat1-expressing CD4+ T lymphocytes. Second, the SASP up-regulates ICOSLG on LSECs, with the ICOS–ICOSLG axis contributing to senescence cell clearance. Our results show that the endothelium is a nonautonomous SASP target and an organizing center for immune-mediated senescence surveillance.

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“…Agonists targeting co-stimulatory pathways could enhance T cell activity and revolve antitumor immune response [169]. A series of preclinical studies showed that co-stimulatory molecule agonists improved α-PD-1/PD-L1 efficacy [170][171][172][173][174][175][176]. At present, multiple clinical studies of co-stimulatory molecule agonists plus α-PD-1/PD-L1 are ongoing.…”

Section: Co-stimulatory Molecule Agonist Plus α-Pd-1/pd-l1mentioning

confidence: 99%

Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

et al. 2022

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Antibodies targeting programmed cell death protein-1 (PD-1) or its ligand PD-L1 rescue T cells from exhausted status and revive immune response against cancer cells. Based on the immense success in clinical trials, ten α-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) and three α-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for various types of cancers. Nevertheless, the low response rate of α-PD-1/PD-L1 therapy remains to be resolved. For most cancer patients, PD-1/PD-L1 pathway is not the sole speed-limiting factor of antitumor immunity, and it is insufficient to motivate effective antitumor immune response by blocking PD-1/PD-L1 axis. It has been validated that some combination therapies, including α-PD-1/PD-L1 plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other immune checkpoint inhibitors, agonists of the co-stimulatory molecule, stimulator of interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, or metabolic modulators, have superior antitumor efficacies and higher response rates. Moreover, bifunctional or bispecific antibodies containing α-PD-1/PD-L1 moiety also elicited more potent antitumor activity. These combination strategies simultaneously boost multiple processes in cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment. In this review, we summarized the synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other therapies. Moreover, we focused on the advances of α-PD-1/PD-L1-based immunomodulatory strategies in clinical studies. Given the heterogeneity across patients and cancer types, individualized combination selection could improve the effects of α-PD-1/PD-L1-based immunomodulatory strategies and relieve treatment resistance.

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ICOS agonism by JTX-2011 (vopratelimab) requires initial T cell priming and Fc cross-linking for optimal T cell activation and anti-tumor immunity in preclinical models

Cited by 30 publications

References 36 publications

ICOS is upregulated on T cells following radiation and agonism combined with radiation results in enhanced tumor control

ICOS is upregulated on T cells following radiation and agonism combined with radiation results in enhanced tumor control

Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance

Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

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