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US 12,630,802 B2Granted
Methods of isolating T cells and T cell receptors having antigenic specificity for a cancer-specific mutation from peripheral blood
AssigneeThe United States of America, as represented by the Secretary, Department of Health and Human Services
InventorsAlena Gros, Steven A. Rosenberg
Life of this patent
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Abstract
Disclosed are methods of isolating T cells and TCRs having antigenic specificity for a mutated amino acid sequence encoded by a cancer-specific mutation. Also disclosed are related methods of preparing a population of cells, populations of cells, TCRs, pharmaceutical compositions, and methods of treating or preventing cancer.
Claims19
A method of treating cancer in a patient, the method comprising:
- obtaining a bulk population of peripheral blood mononuclear cells (PBMCs) from a sample of peripheral blood from the patient;
- selecting T cells that express programmed cell death 1 (PD-1) from the bulk population;
- separating the T cells that express PD-1 from cells that do not express PD-1 to obtain a T cell population enriched for T cells that express PD-1;
- identifying one or more genes in the nucleic acid of a cancer cell of the patient, each gene containing a cancer-specific mutation that encodes a mutated amino acid sequence;
- inducing autologous antigen presenting cells (APCs) of the patient to present the mutated amino acid sequence;
- co-culturing T cells from the population enriched for T cells that express PD-1 with the autologous APCs that present the mutated amino acid sequence;
- selecting T cells that (a) were co-cultured with the autologous APCs that present the mutated amino acid sequence and (b) have antigenic specificity for the mutated amino acid sequence presented in the context of a major histocompatibility complex (MHC) molecule expressed by the patient, thereby isolating T cells having antigenic specificity for the mutated amino acid sequence encoded by the cancer-specific mutation;
- and
- administering the isolated T cells to the patient in an amount effective to treat cancer in the patient.
6 more elements
A method of treating cancer in a patient, the method comprising:
- obtaining a first population of peripheral blood mononuclear cells (PBMCs) from a sample of peripheral blood from the patient;
- selecting T cells that express programmed cell death 1 (PD-1) from the bulk population;
- separating the T cells that express PD-1 from cells that do not express PD-1 to obtain a T cell population enriched for T cells that express PD-1;
- isolating nucleotide sequence(s) that encode(s) one or more T cell receptor(s) (TCRs), or antigen-binding portion(s) thereof, from the T cells of the population enriched for T cells that express PD-1;
- introducing the nucleotide sequence(s) encoding the TCR(s), or antigen binding portion(s) thereof, into further population(s) of PBMCs to obtain T cells that express the TCR(s), or antigen binding portion(s) thereof;
- identifying one or more genes in the nucleic acid of a cancer cell of the patient, each gene containing a cancer-specific mutation that encodes a mutated amino acid sequence;
- inducing autologous antigen presenting cells (APCs) of the patient to present the mutated amino acid sequence;
- co-culturing the T cells that express the TCR(s), or antigen binding portion(s) thereof, with the autologous APCs that present the mutated amino acid sequence;
- a
- selecting T cells that (a) were co-cultured with the autologous APCs that present the mutated amino acid sequence and (b) have antigenic specificity for the mutated amino acid sequence presented in the context of a major histocompatibility complex (MI-IC) molecule expressed by the patient, thereby isolating T cells having antigenic specificity for the mutated amino acid sequence encoded by the cancer-specific mutation;
- and
- administering the isolated T cells to the patient in an amount effective to treat cancer in the patient.
9 more elements
A method of treating cancer in a patient, the method comprising:
- obtaining a bulk population of peripheral blood mononuclear cells (PBMCs) from a sample of peripheral blood from the patient;
- selecting T cells that express programmed cell death 1 (PD-1) from the bulk population;
- separating the T cells that express PD-1 from cells that do not express PD-1 to obtain a T cell population enriched for T cells that express PD-1;
- identifying one or more genes in the nucleic acid of a cancer cell of the patient, each gene containing a cancer-specific mutation that encodes a mutated amino acid sequence;
- inducing autologous antigen presenting cells (APCs) of the patient to present the mutated amino acid sequence;
- co-culturing T cells from the population enriched for T cells that express PD-1 with the autologous APCs that present the mutated amino acid sequence;
- selecting T cells that (a) were co-cultured with the autologous APCs that present the mutated amino acid sequence and (b) have antigenic specificity for the mutated amino acid sequence presented in the context of a major histocompatibility complex (MHC) molecule expressed by the patient;
- isolating a nucleotide sequence that encodes a TCR, or an antigen-binding portion thereof, from the selected T cells that have antigenic specificity for the mutated amino acid sequence, wherein the TCR, or the antigen-binding portion thereof, has antigenic specificity for the mutated amino acid sequence;
- introducing the nucleotide sequence encoding the isolated TCR, or the antigen-binding portion thereof, into host cells to obtain host cells that express the TCR, or the antigen-binding portion thereof;
- and
- administering the host cells that express the TCR, or the antigen-binding portion thereof, to the patient, in an amount effective to treat cancer in the patient.
8 more elements
Dependencies are inferred from the claim text.