Inhibition of the novel immune checkpoint CEACAM1 to enhance anti-tumor immunological activity.

Markel, Gal; Sapir, Yair; Mandel, Ilana; Hakim, Motti; Shaked, Rony; Meilin, Edna; McClanahan, Terri; Loboda, Andrey; Hashmueli, Sharon; Moshe, Tehila Ben

doi:10.1200/jco.2016.34.15_suppl.3044

Cited by 10 publications

(7 citation statements)

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“…Up-regulation of carcinoembryonic antigen-related cell-adhesion molecule 1 (CEACAM1), another inhibitory immune checkpoint molecule ( 153 ), on T cells leads to reduced proliferation and cytokine secretion causing T cell suppression and subsequent prolonged immunosuppression ( 154 , 155 ). Although not reported in adults with SII, the percentage of CEACAM1-positive CD4+ T cells in 12 preterm neonates with LOS is increased compared to 16 non-septic controls ( 155 ).…”

Section: Compromised T Cell Effector Cell Function In Adult and Neonamentioning

confidence: 99%

Sepsis-Induced Immunosuppression in Neonates

2018

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Neonates, especially those born preterm, are at increased risk of sepsis and adverse long-term effects associated with infection-related inflammation. Distinct neonatal immune responses and dysregulated inflammation are central to this unique susceptibility. The traditional separation of sepsis into an initial hyper-inflammatory response followed by hypo-inflammation is continually under review with new developments in this area of research. There is evidence to support the association of mortality in the early acute phase of sepsis with an overwhelming hyper-inflammatory immune response. Emerging evidence from adults suggests that hypo- and hyper-inflammation can occur during any phase of sepsis and that sepsis-immunosuppression is associated with increased mortality, morbidity, and risk to subsequent infection. In adults, sepsis-induced immunosuppression (SII) is characterised by alterations of innate and adaptive immune responses, including, but not limited to, a prominent bias toward anti-inflammatory cytokine secretion, diminished antigen presentation to T cells, and reduced activation and proliferation of T cells. It is unclear if sepsis-immunosuppression also plays a role in the adverse outcomes associated with neonatal sepsis. This review will focus on exploring if key characteristics associated with SII in adults are observed in neonates with sepsis.

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Section: Compromised T Cell Effector Cell Function In Adult and Neonamentioning

confidence: 99%

Sepsis-Induced Immunosuppression in Neonates

2018

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“…Thus, it will help the clinicians to make appropriate decisions for GCSF treatment. CS3R improvement can be achieved by humanized anti-CEACAM-1 IgG4 antibodylike MK-6018 [24,29] in the remaining HSCs of the BM of cirrhotic patients.…”

Section: Discussionmentioning

confidence: 99%

CSF3-Receptor Downregulation in Bone Marrow contributes to Ineffectiveness of GCSF in Advanced Liver Cirrhosis

Bihari

Baweja

Lal

et al. 2021

Preprint

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Introduction: Cirrhosis patients exhibit cytopenia and variable response to GCSF, with benefits in early cirrhosis. GCSF acts through the CSF3-receptor (CSF3R), and changes in CSF3R can affect the response. We investigated the possible mechanism for the lack of efficacy of GCSF in advanced cirrhosisMethodsCirrhotic patients (n = 127) and controls (n = 26) who underwent clinically indicated bone marrow (BM) examination were studied. BMs were assessed for RNA sequencing, qRT-PCR, and immunohistochemistry (IHC) for CSF3R and associated genes. Circulating GCSF, CSF3R, and carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) were measured. BM hematopoietic precursor cells and their alterations were examined by flow cytometry. The findings were validated, where the GCSF was administered as for liver regeneration (n = 22) and severe neutropenia (n = 15)ResultsThe mean age was 48.6 ± 13.4 years, 80.3% males. Gene set enrichment analysis showed lowered CSF3R in Child's C compared to A, confirmed by qRT-PCR and IHC. Circulatory CSF3R was also reduced in advanced cirrhosis. CSF3R decline was related to decrease hematopoietic stem cells (HSCs) and downregulation of CSF3R in remaining HSCs. CSF3R inhibitory protein CEACAM1 caused CSF3R downregulation. CEACAM-1, in turn, positively correlated with the increased lysosomal expression in HSCs. Peripheral blood-CSF3R was lesser in those cases who developed an infection Baseline CSF3R was also lower in G-CSF non-responders.ConclusionsCSF3R is downregulated in patients with advanced cirrhosis, and it could be the underlying cause of the inadequate response to GCSF.

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“…In early preclinical settings, anti-CEACAM1 antibody (CC1) combined with anti-TIM3 intervention generated a robust therapeutic efficacy in mouse intracranial glioma model [81]. Also, CM-24 (MK-6018), a humanized anti-CEACAM1 IgG4 antibody, was demonstrated to increase the cytotoxic activity of lymphocytes against cancer cells in various in vitro and in vivo models [82]. A first clinical trial utilizing CM-24 was initiated in 2015 (NCT02346955) either with CM-24 administered alone or in combination with pembrolizumab, but the study was terminated in 2017, as no efficacy was observed.…”

Section: Inhibition Of Negative Immune Checkpoints In Cancermentioning

confidence: 99%

Targeting Negative and Positive Immune Checkpoints with Monoclonal Antibodies in Therapy of Cancer

Marhelava

Pilch

Bajor

et al. 2019

Cancers

109

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The immune checkpoints are regulatory molecules that maintain immune homeostasis in physiological conditions. By sending T cells a series of co-stimulatory or co-inhibitory signals via receptors, immune checkpoints can both protect healthy tissues from adaptive immune response and activate lymphocytes to remove pathogens effectively. However, due to their mode of action, suppressive immune checkpoints may serve as unwanted protection for cancer cells. To restore the functioning of the immune system and make the patient’s immune cells able to recognize and destroy tumors, monoclonal antibodies are broadly used in cancer immunotherapy to block the suppressive or to stimulate the positive immune checkpoints. In this review, we aim to present the current state of application of monoclonal antibodies in clinics, used either as single agents or in a combined treatment. We discuss the limitations of these therapies and possible problem-solving with combined treatment approaches involving both non-biological and biological agents. We also highlight the most promising strategies based on the use of monoclonal or bispecific antibodies targeted on immune checkpoints other than currently implemented in clinics.

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Inhibition of the novel immune checkpoint CEACAM1 to enhance anti-tumor immunological activity.

Cited by 10 publications

References 0 publications

Sepsis-Induced Immunosuppression in Neonates

Sepsis-Induced Immunosuppression in Neonates

CSF3-Receptor Downregulation in Bone Marrow contributes to Ineffectiveness of GCSF in Advanced Liver Cirrhosis

Targeting Negative and Positive Immune Checkpoints with Monoclonal Antibodies in Therapy of Cancer

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