MONITORING HEALTH AND DISEASE STATUS USING CLONOTYPE PROFILES
First Claim
1. A method of monitoring a disease in a patient, the method comprising the steps of:
- (a) identifying one or more patient-specific clonotypes correlated with a disease by determining a clonotype profile from a sample of lymphocytes in a disease-related tissue, the sample comprising a repertoire of clonotypes from the disease-related tissue; and
(b) determining a clonotype profile from a sample of peripheral blood cells to identify a presence, absence and/or level of the one or more patient-specific clonotypes correlated with the disease, such peripheral blood sample comprising a repertoire of clonotypes.
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Abstract
There is a need for improved methods for determining the diagnosis and prognosis of patients with conditions, including autoimmune disease and cancer, especially lymphoid neoplasms, such as lymphomas and leukemias. Provided herein are methods for using DNA sequencing to identify personalized, or patient-specific biomarkers in patients with lymphoid neoplasms, autoimmune disease and other conditions. Identified biomarkers can be used to determine and/or monitor the disease state for a subject with an associated lymphoid disorder or autoimmune disease or other condition. In particular, the invention provides a sensitive method for monitoring lymphoid neoplasms that undergo clonal evolutions without the need to development alternative assays for the evolved or mutated clones serving as patient-specific biomarkers.
192 Citations
61 Claims
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1. A method of monitoring a disease in a patient, the method comprising the steps of:
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(a) identifying one or more patient-specific clonotypes correlated with a disease by determining a clonotype profile from a sample of lymphocytes in a disease-related tissue, the sample comprising a repertoire of clonotypes from the disease-related tissue; and (b) determining a clonotype profile from a sample of peripheral blood cells to identify a presence, absence and/or level of the one or more patient-specific clonotypes correlated with the disease, such peripheral blood sample comprising a repertoire of clonotypes. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34)
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35. A method of monitoring a disease in a patient, the method comprising the steps of:
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(a) comparing a clonotype profile from a sample of lymphocytes of an individual afflicted with a disease and a clonotype profile from the same individual from a sample of lymphocytes enriched on the basis of cell surface markers associated with the disease to identify one or more patient-specific clonotypes correlated with the disease; and (b) determining a level of each of the one or more patient-specific clonotypes in a clonotype profile from a sample of peripheral blood cells, such sample comprising a repertoire of clonotypes thereof. - View Dependent Claims (36, 37, 38, 39, 40, 41, 42, 43, 44)
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45. A method of simultaneously measuring lymphocyte numbers and clonotype expression levels in a sample, the method comprising the steps of:
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obtaining from an individual a sample comprising T cells and/or B cells; sequencing spatially isolated individual molecules derived from genomic DNA of said cells, such spatially isolated individual molecules comprising a number of clonotypes corresponding to a number of lymphocytes in the sample; sequencing spatially isolated individual molecules derived from RNA of said cells, such spatially isolated individual molecules comprising numbers of clonotypes corresponding to expression levels thereof in the lymphocytes of the sample; and determining clonotype expression levels in lymphocytes of the sample by comparing for each clonotype the number determined from isolated individual molecules derived from genomic DNA of said cells and the number determined from isolated individual molecules derived from RNA of said cells. - View Dependent Claims (46, 47, 48, 49, 50, 51, 52)
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53. A method of simultaneously measuring lymphocyte numbers and lymphocyte clonality in a sample, the method comprising the steps of:
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obtaining from an individual a sample comprising T cells and/or B cells; sequencing spatially isolated individual molecules derived from nucleic acid of said cells, such spatially isolated individual molecules comprising a number of clonotypes corresponding to a number of lymphocytes in the sample; determining the number of lymphocytes from the number of spatially isolated individual molecules; determining abundances of different sequences of the spatially isolated individual molecules to generate a clonotype profile and a measure of clonality based thereon. - View Dependent Claims (54, 55, 56, 57, 58, 59)
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60. A method of monitoring responsiveness to a vaccination of an individual, the method comprising the steps of:
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enriching after a vaccination a sample of lymphocytes from peripheral blood of an individual to obtain a sample of vaccine-responsive lymphocytes; determining a clonotype profile from the sample of vaccine-responsive lymphocytes to identify one or more patient-specific clonotypes correlated with vaccine response; determining a level of each of the one or more patient-specific clonotypes in a clonotype profile from a sample of peripheral blood cells obtained at one or more subsequent times to monitor the responsiveness of the individual to the vaccination.
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61. A method of monitoring a lymphoproliferative disorder in a patient, the method comprising the steps of:
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(a) identifying one or more patient-specific clonotypes correlated with a lymphoproliferative disorder by determining a clonotype profile from lymphocytes from a sample of bone marrow, the sample comprising a repertoire of clonotypes; and (b) determining at a later time a clonotype profile from a sample of bone marrow or peripheral blood cells to identify a presence, absence and/or level of the one or more patient-specific clonotypes correlated with the disease, such latter bone marrow sample or peripheral blood sample comprising a repertoire of clonotypes.
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Specification