Biomarkers and uses thereof for selecting immunotherapy intervention
Inventors
Liles, W. Conrad • Turtle, Cameron J. • Maloney, David G. • Riddell, Stanley R. • Wurfel, Mark M. • Lopez, Jose • Chung, Dominic • Chen, Junmei
Assignees
University of Washington • Bloodworks Northwest • Fred Hutchinson Cancer Center
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Publication Number
US-11397183-B2
Publication Date
2022-07-26
Expiration Date
Abstract
The instant disclosure provides biomarkers and methods for identifying subjects at risk of developing cytokine release syndrome (CRS), neurotoxicity, or both after adoptive immunotherapy to guide preemptive intervention, modified therapy, or the like. For example, adverse event biomarkers may be measured in a subject before pre-conditioning chemotherapy, before immunotherapy (e.g., adoptive immunotherapy infusion comprising a chimeric antigen receptor (CAR) modified T cell), or shortly after pre-conditioning chemotherapy and/or immunotherapy. Exemplary biomarkers include temperature, cytokine levels and endothelial activation biomarkers, such as angiopoietin 2, von Willebrand factor (vWF), ratio of angiopoietin 2 to angiopoietin 1, and ratio of ADAMTS13 to vWF. Also provided are methods of treating subjects identified as at risk of developing cytokine release syndrome (CRS), neurotoxicity, or both to minimize such potential adverse events.
Core Innovation
The invention describes a method for reducing the risk of an adverse event associated with T cell immunotherapy by measuring biomarkers of endothelial activation in a biological sample from a mammalian subject with a hematologic malignancy. The measurements are performed prior to administration of the T cell immunotherapy or within 0 to 8 days following administration, and the endothelial-activation biomarker level and specified ratios are compared to a normal sample to determine whether the subject is at risk.
The method includes measuring selected biomarkers of endothelial activation, including Angiopoietin-2, VCAM-1, von Willebrand factor antigen (vWF Ag), ADMA, CCL26, endothelin-1, osteoprotegerin, CD142 tissue factor, E-selectin, P-selectin, P-selectin cofactor CD63/LAMP3, PAI-1, α-fucosyltransferase VI, circulating endothelial cells, endothelial microparticles, and any combination thereof. In addition, the method evaluates the ratio of Angiopoietin-2:Angiopoietin-1, the ratio of VCAM-1:Angiopoietin-1, the level of Angiopoietin-1, and the ratio of ADAMTS13:vWF Ag, using changes versus the normal sample as a basis for risk identification.
When the measured biomarker level or ratios are increased or reduced according to defined directions versus a normal sample, the subject is identified as at risk of developing an adverse event associated with the T cell immunotherapy. The adverse event comprises cytokine release syndrome (CRS), neurotoxicity, or both, and after identification, pre-emptive treatment for the adverse event and/or administration of the T cell immunotherapy at a reduced dose is performed.
Claims Coverage
The document provides one independent claim. It covers a full workflow: measuring endothelial-activation biomarkers, including specified ratios, at defined time points, identifying risk versus a normal sample using specified increase/decrease criteria, and then administering pre-emptive treatment and/or reducing the immunotherapy dose.
Endothelial activation biomarker measurement for risk stratification
Measuring, in a biological sample from a mammalian subject having a hematologic malignancy, prior to administration of the T cell immunotherapy or within 0 to 8 days following administration, the level of a biomarker of endothelial activation selected from Angiopoietin-2, VCAM-1, von Willebrand factor antigen (vWF Ag), asymmetric dimethyl arginine (ADMA), CCL26, endothelin-1, osteoprotegerin, CD142 tissue factor, E-selectin, P-selectin, P-selectin cofactor CD63/LAMP3, PAI-1, α-fucosyltransferase VI, circulating endothelial cells, endothelial microparticles, or any combination thereof; the ratio of Angiopoietin-2:Angiopoietin-1; the ratio of VCAM-1:Angiopoietin-1; the level of Angiopoietin-1; or the ratio of ADAMTS13:vWF Ag.
Comparing biomarker changes to identify CRS and neurotoxicity risk
Identifying the subject as at risk of developing an adverse event associated with the T cell immunotherapy when the biomarker measured as increased is (a), (b), or (c) or when the biomarker measured as reduced is (d) or (e), as compared to a normal sample, wherein the adverse event comprises cytokine release syndrome (CRS), neurotoxicity, or both.
Pre-emptive intervention and/or reduced T cell immunotherapy dosing
Administering to the at risk subject pre-emptive treatment for the adverse event, administering the T cell immunotherapy at a reduced dose, or both.
The core inventive coverage is centered on endothelial-activation biomarker measurement, risk identification by comparison to a normal sample with defined increase/decrease criteria for CRS and/or neurotoxicity, and subsequent pre-emptive treatment and/or reduced dosing of the T cell immunotherapy.
Stated Advantages
Reduces the risk of an adverse event associated with T cell immunotherapy.
Enables identifying subjects as at risk for cytokine release syndrome (CRS), neurotoxicity, or both based on endothelial-activation biomarker results compared to a normal sample.
Documented Applications
Reducing the risk of cytokine release syndrome (CRS) and neurotoxicity associated with T cell immunotherapy in a mammalian subject with a hematologic malignancy.
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