Methods for inhibiting resistance to immune blockade inhibitor therapy
AssigneeH. Lee Moffitt Cancer Center and Research Institute, Inc.
InventorJoseph MARKOWITZ
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Abstract
Disclosed are compositions and methods related to the use of nitric oxide inhibitors to reduce resistance to immune checkpoint inhibitors. In one aspect, disclosed herein are methods of detecting elevated NO or nitration of proteins in a biological sample from a subject with a cancer, and administering an NO inhibitor to the subject where immune suppressive cells have elevated levels of NO or protein nitration.
Claims58
A method of reducing immune checkpoint inhibitor resistance comprising administering a nitric oxide inhibitor to a subject being treated for a disease with an immune checkpoint inhibitor.
A combination therapy comprising an immune checkpoint inhibitor and a nitric oxide inhibitor.
A method of treating a cancer in a subject comprising administering to the subject a nitric oxide inhibitor and an immune checkpoint inhibitor.
A method of detecting resistance of a disease or condition in a subject to an immune checkpoint inhibitor comprising:
- a. obtaining a tissue sample from a subject that is receiving or that is likely to receive an immune checkpoint inhibitor for treatment of a disease or condition;
- and
- b. measuring the level of nitration in the tissue sample;
- wherein an increase in nitration relative to a control indicates that the disease or condition is resistant to an immune checkpoint inhibitor;
- and
- c. when a subject has a disease or condition that is resistant to an immune checkpoint inhibitor, administering to the subject a nitric oxide inhibitor.
A method of improving progression free survival (PFS) in a subject with a cancer resistant to conventional cancer therapy, the method comprising:
- a) obtaining biological sample from the subject,
- b) performing a multi-parameter phenotyping tool in R (MPATR) assay on the biological sample to analyze the nitric oxide (NO) levels in the biological sample;
- c) measuring the immune cell subtype producing NO;
- wherein the immune cell subtype are immune suppressive cells, or immune effector cells;
- wherein an increased level of NO in immune suppressive cells is an indication of cancer subject resistance to conventional cancer therapy;
- wherein NO in immune suppressive cells lead to shorter PFS,
- d) administering a NO inhibitor in combination with an immune checkpoint inhibitor to subjects with a cancer resistant to conventional cancer therapy having increased levels of NO in immune suppressive cells.
A multi-parameter phenotyping tool in R (MPATR) assay to identify nitration of proteins in an immune cell subtype, comprising:
- a) obtaining biological sample from a subject with a cancer that is resistant to conventional cancer therapy,
- b) measuring the immune cell subtype producing NO;
- wherein the immune cell subtype are immune suppressive cells or immune effector cells;
- and
- c) measuring the nitration of proteins in the immune cells;
- wherein an increased level of nitration of proteins in immune suppressive cells is an indication that the subject needs a NO inhibitor to overcome resistance to conventional cancer therapy.
A method of assessing the susceptibility of a cancer in a subject to an immune checkpoint inhibitor therapy comprising:
- a) obtaining a biological sample from the subject;
- b) detecting level of NO in the biological sample using flow cytometry;
- c) measuring immune cell subtype and NO level in the sample;
- wherein the immune cell subtypes are immune suppressive cells, or immune effector cells;
- d) analyzing the nitration of proteins associated with antigen presentation in the sample using LC-MS/MS;
- wherein increased NO level in immune suppressive cells and/or increased level of nitration of proteins in immune suppressive cells indicate poor immune checkpoint inhibitor therapy response in the subject;
- and wherein an increased level of NO level in immune effector cells indicates prolonged progression free survival (PFS);
- and
- e) administering NO inhibitor with the immune checkpoint inhibitor if NO is higher in immune suppressive cells.
A method of treating an unresectable stage III/IV melanoma in a subject resistant to immune checkpoint inhibitor therapy, comprising:
- a) measuring chronic NO levels after one year in a biological sample of the subject using a multi-parameter phenotyping tool in R (MPATR) assay;
- wherein increased NO levels indicate shorter PFS and poor response to immune checkpoint inhibitor therapy alone;
- and
- b) administering combination of NO inhibitor and immune checkpoint inhibitor to the subject if NO level is increased in immune suppressive cells.
A method of inhibiting epithelial to mesenchymal transition (EMT) in melanoma patients by administering combination of immune checkpoint inhibitors and NO inhibitors.
A composite model to determine a progression free survival (PFS) of a subject with a cancer, wherein the composite model comprises:
- a) obtaining a biological sample from the subject;
- b) measuring immune cell subtype;
- wherein the immune cell subtype are immune suppressive cells, or immune effector cells;
- c) measuring the nitration of proteins in the sample;
- wherein increased nitration of proteins in the immune suppressive cells indicate shorter PFS of the subject;
- and
- d) determining the subject's response to immune checkpoint inhibitor therapy;
- wherein an increased nitration of proteins in the immune suppressive cells is an indication of poor response to immune checkpoint inhibitor therapy.
Dependencies are inferred from the claim text.