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Inhibition of the novel immune checkpoint CEACAM1 to enhance anti-tumor immunological activity.
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2016
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Immune CheckpointIntercellular Ceacam1-ceacam1 InteractionsTumor ImmunologyCancer ImmunosurveillanceAnti-tumor Immunological ActivityImmunologyTumor ImmunityImmunoeditingImmunologic MechanismImmune Checkpoint InhibitorImmunomodulationImmunotherapeuticsGene Expression AnalysisImmune Cell TherapyImmunotherapyMedicineCell BiologyCancer Research
3044 Background: Blockade of co-inhibitory immune receptors has become a promising approach for cancer immunotherapy. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a recently characterized immune checkpoint. Expression of CEACAM1 on tumors induces a co-inhibitory signal to CEACAM1-positive T and NK cells through homophilic interactions. Methods: CM-24 (MK-6018) is a humanized anti-CEACAM1 IgG4 antibody with high affinity and selectivity for CEACAM1. The effect of CM-24 alone or in combination was examined in vitro using tumor-infiltrating lymphocytes (TIL) and peripheral blood mononuclear cells. The anti-tumor efficacy of CM-24 was studied in vivo in subcutaneous xenograft and lung metastasis models of melanoma treated with IV injection of mlanoma-reactive TIL. Gene expression analysis of CEACAM1 and other genes of potential relevance to patient response to CEACAM1 were examined in a large cohort of human tumor samples. Results: CM-24 was demonstrated to be a potent blocker of intercellular CEACAM1-CEACAM1 interactions and reversed the inhibition of activated lymphocytes by restoring the phosphorylation of ZAP70. In addition, CM-24 enhanced the anti-tumor activity of TIL in the melanoma xenograft and lung metastasis models. CM-24 also showed synergistic activity with immune checkpoint blockers targeting PD-1 or PD-L1. The gene expression analysis of CEACAM1 and other genes in 18,000+ solid tumor samples allowed us to identify tumor types which represent potential indications for CM-24 therapy and to identify gene expression profiles as candidate biomarkers of response to CM-24 as monotherapy or in combination with a PD-1 or PD-L1 antagonist. Conclusions: CM-24 increases the cytotoxic activity of lymphocytes against malignant cells and has shown effective anti-tumor activity in various in vitro and in vivo models. Treatment with CM-24 either as monotherapy or in combination with anti-PD-1 treatment such as pembrolizumab may be beneficial. First-in-man clinical trial with CM-24 is ongoing.