Identification of pathogenic immune cell subsets in checkpoint inhibitor-induced myocarditis
AssigneesU.S. Government as represented by the Department of Veterans Affairs, The Board of Trustees of the Leland Stanford Junior University
InventorsSean M. Wu, Han Zhu, Patricia Nguyen
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Abstract
This disclosure relates to methods helpful in diagnosing and treating immune check point inhibitor (ICI)-induced myocarditis as well as to using C-C chemokine receptor type 1 (CCR1), C-C chemokine receptor type 2 (CCR2), C-C chemokine receptor type 3 (CCR3) and C-C chemokine receptor type 5 (CCR5) antagonists and anti-CD45RA antibodies for treating ICI-induced myocarditis.
Claims28
A method for reducing an immune-related adverse event (irAE) in an immune checkpoint inhibitor (ICI)-treated human subject, wherein the irAE includes ICI-induced myocarditis, the method comprising administering to the subject a composition comprising one or more of the following:
- i. an inhibitor that antagonizes interaction of chemokine (C-C motif) ligand 5 (CCL5) with at least one of the following receptors:
- C-C chemokine receptor type 1 (CCR1), C-C chemokine receptor type 3 (CCR3) and/or C-C chemokine receptor type 5 (CCR5);
- ii. an inhibitor that antagonizes action of the C-C chemokine receptor type 2 (CCR2);
- iii. an antibody binding to and downregulating cytotoxic CD8+T effector cells that express one or more cytotoxicity markers and at least the following myocardial-tropic chemokines CCL3, CCL4, CCL4L2 and CCL5 (Temra CD8+ cells);
- and/or
- iv. an antibody binding to and downregulating monocytes/macrophages that express one or more cytotoxicity markers and either C-C chemokine receptor type 2 (CCR2) or C-C chemokine receptor type 5 (CCR5).
A method for testing a human subject undergoing treatment with an immune checkpoint inhibitor (ICI), the method comprising:
- 1) drawing a first blood sample from the human subject prior to administering the ICI;
- 2) drawing a second blood sample from the human subject after administering the ICI;
- and
- 3) measuring CCL5 protein and/or mRNA levels in the first sample and in the second sample;
- and/or measuring a number of specialized effector CD8+ T cells expressing one or more cytotoxicity markers and at least the following myocardial-tropic chemokines CCL4, CCL4L2 and CCL5 (Temra CD8+ cells) in the first sample and in the second sample and/or
- 4) measuring CCR2/CCR5 protein and/or mRNA levels in the first sample and in the second sample;
- and/or measuring a number of monocytes/macrophages expressing one or more cytotoxicity markers and at least the following chemokine receptors (CCR2 or CCR5) in the first sample and in the second sample.
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A method of identifying a human subject eligible for ICI-myocarditis treatment, wherein the human subject is undergoing treatment with an immune checkpoint inhibitor (ICI), the method comprising analyzing CD8+ T cell population in a peripheral blood sample of the human subject for presence of Temra CD8+ cells expressing myocardial-tropic chemokines:
- CCL3, CCL4, CCL4L2 and CCL5 and also expressing CD45RA, and wherein when the Temra CD8 cells are present in the blood sample, the human subject is eligible for ICI-myocarditis treatment.
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A method of treating ICI-induced myocarditis in a human subject, wherein the method comprises monitoring the human subject for a phenotypic shift in the activated Temra CD8+ population from an early cytotoxic and pro-inflammatory profile at the beginning of the ICI-induced myocarditis to a late exhaustion phenotype expressing markers of T-cell exhaustion, including KLRG, CX3CR1 and/or LAG3.
Dependencies are inferred from the claim text.