{"search_session":{},"preferences":{"l":"en","queryLanguage":"en"},"patentId":"020-963-284-970-217","frontPageModel":{"patentViewModel":{"ref":{"entityRefId":"020-963-284-970-217","entityRefType":"PATENT"},"entityMetadata":{"linkedIds":{"empty":true},"tags":[],"collections":[{"id":11761,"type":"PATENT","title":"Dartmouth College Patent Portfolio","description":"","access":"OPEN_ACCESS","displayAvatar":true,"attested":false,"itemCount":2493,"tags":[],"user":{"id":91044780,"username":"Cambialens","firstName":"","lastName":"","created":"2015-05-04T00:55:26.000Z","displayName":"Cambialens","preferences":"{\"usage\":\"public\",\"beta\":false}","accountType":"PERSONAL","isOauthOnly":false},"notes":[{"id":8400,"type":"COLLECTION","user":{"id":91044780,"username":"Cambialens","firstName":"","lastName":"","created":"2015-05-04T00:55:26.000Z","displayName":"Cambialens","preferences":"{\"usage\":\"public\",\"beta\":false}","accountType":"PERSONAL","isOauthOnly":false},"text":"
Search Applicants and Owners separately: Dartmouth colle*. Select more for logical variants. Add to collection. Select all patents in the collection and expand by simple families. Add to collection. Total patents: 2346
Search Applicants and Owners separately: Dartmouth colle*. Select more for logical variants. Add to collection. Select all patents in the collection and expand by simple families. Add to collection. Total patents: 2346
(a) introducing into one or more primary human T cells isolated from a human donor at least one small-hairpin RNA (shRNA) which each target a nucleic acid that encodes a component of a functional TCR that is endogenously expressed by an unmodified primary human T cell isolated from said human donor, wherein expression of said at least one shRNA reduces the expression of the endogenous TCR by blocking or inhibiting the expression of at least one targeted component of said endogenous TCR, and\n
(b) further introducing into said one or more primary human T cells isolated from a human donor at least one nucleic acid that results in the expression of a functional exogenous non-TCR receptor that comprises a chimeric receptor comprising a ligand binding domain and a signaling domain;\n
wherein the one or more cells obtained by steps (a) and (b) are suitable for use in human therapy, and further wherein the cells obtained by steps (a) and (b) elicit no or a reduced graft-versus-host disease (GVHD) response in a histoincompatible human recipient as compared to the GVHD response elicited by a primary human T cell or primary human T cells isolated from the same human donor either of which are only modified as in (b)."],"number":1,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 1, which further comprises determining whether the resultant modified primary human T cells comprise reduced expression of the targeted TCR component by at least one of: (a) detecting the level of expression of said targeted TCR component in the resultant modified primary human T cell or cells; (b) detecting whether the resultant modified primary human T cell or cells elicit a GVHD response in a human subject;\n
and (c) comparing the level of gamma interferon produced by cells modified as in steps (a) and (b) of claim 1 in response to allogeneic cells compared to the level of gamma interferon produced by a primary human T cell or cells isolated from the same donor but only modified as in step (b) of claim 1 in response to allogeneic cells."],"number":2,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 1, which further comprises purifying or enriching the primary human T cells obtained by steps (a) and (b) by removing human primary T cells that retain moderate to high expression of the targeted TCR component."],"number":3,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 1, wherein step (a) comprises introducing multiple shRNAs that target the same TCR component or different TCR components."],"number":4,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 1, wherein said shRNAs target one or more TCR components selected from TCR-α, TCR-β, CD3-γ, CD3-δ, and CD3-ε."],"number":5,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 1, wherein the at least one functional exogenous non-TCR comprises a ligand binding domain obtained from an anti-tumor chimeric antigen receptor or anti-tumor antibody."],"number":6,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 1, wherein the ligand binding domain of the at least one functional exogenous non-TCR comprises a pathogen-associated receptor and the resultant modified primary human T cell or cells can be used to treat infectious disease."],"number":7,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 7, wherein said infectious disease to be treated is caused by a CMV, HIV-1, HIV-2, HBV, HCV, or hantavirus infection."],"number":8,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 1, wherein the chimeric receptor comprises a NKG2D, NKG2A, NKG2C, NKG2F, LLT1, AICL, CD26, or NKRP1 polypeptide."],"number":9,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 1, wherein the chimeric receptor comprises a receptor that binds to MIC-A, MIC-B, estrogen, progesterone, RON, or one or more members of the ULBP/RAET1 family."],"number":10,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 1, wherein the chimeric receptor comprises a NKG2D ligand binding domain and a CD3-ζ signaling domain."],"number":11,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 1, wherein the resultant modified human primary T cells are suitable for use in treating cancer."],"number":12,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 1, which further comprises formulating the resultant modified primary human T cells with at least one pharmaceutically acceptable carrier in order to obtain a composition suitable for human therapy."],"number":13,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 1, which further comprises administering to a human subject having cancer a therapeutically effective amount of the resultant modified primary human T cells."],"number":14,"annotation":false,"claim":true,"title":false},{"lines":["A method of producing one or more modified primary human T cells, which modified primary human T cells are derived from primary human T cells isolated from a human donor that (i) are modified to functionally impair or to reduce expression of the endogenous T cell receptor (TCR), and (ii) are further modified to express at least one functional exogenous non-TCR that comprises a chimeric receptor comprising a ligand binding domain and a signaling domain, said method including the following:\n
(a) introducing into one or more primary human T cells isolated from a human donor at least one nucleic acid that encodes a dominant-negative inhibitor protein that is capable of interrupting expression or function of the endogenous TCR, wherein said nucleic acid comprises a polynucleotide that encodes a variant of a polypeptide component of a functional TCR complex endogenously expressed by an unmodified primary T human cell isolated from said human donor, wherein said variant polypeptide TCR component is modified, compared to the unmodified polypeptide TCR component, by one or more of the following: (1) the variant polypeptide TCR component lacks key signaling motifs required for function of the unmodified polypeptide TCR component; (2) the variant polypeptide TCR component is modified such that it does not associate properly with other endogenous TCR components; or (3) the variant polypeptide TCR component is modified such that it is still capable of associating properly with other endogenous TCR components, but the resultant TCR complex containing the variant polypeptide TCR component is incapable of binding to ligands; and\n
(b) further introducing into said one or more primary human T cells isolated from a human donor at least one nucleic acid that results in the expression of a functional exogenous non-TCR receptor that comprises a chimeric receptor comprising a ligand binding domain and a signaling domain;\nwherein the one or more cells obtained by steps (a) and (b) are suitable for use in human therapy, and further wherein the cells obtained by steps (a) and (b) elicit no or a reduced graft-versus-host disease (GVHD) response in a histoincompatible human lrecipient as compared to the GVHD response elicited by a primary human T cell or primary human T cells isolated from the same human donor either of which are only modified as in (b)."],"number":15,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, wherein said variant polypeptide TCR component is derived from a TCR component selected from TCR-α, TCR-β, TCR-γ, TCR-δ, CD3-γ, CD3-δ, CD3-ε, and CD3-ζ."],"number":16,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, wherein said modified primary human T cells express more than one variant of a TCR component selected from TCR-α, TCR-β, TCR-γ, TCR-δ, CD3-γ, CD3-δ, CD3-ε, and CD3-ζ."],"number":17,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, wherein said variant polypeptide TCR component comprises deletions in the transmembrane portion of the TCR component that are required for TCR assembly."],"number":18,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, wherein said variant polypeptide TCR component comprises one of the following: (i) a modified TCR-α lacking an arginine residue at position 5 in the TCR-α transmembrane region; (ii) a modified TCR-α lacking a lysine residue at position 10 in the TCR-α transmembrane region; (iii) a modified TCR-β lacking a lysine residue at position 9 in the TCR-β transmembrane region; (iv) a modified CD3-γ lacking a glutamic acid residue in the transmembrane region of CD3-γ; (v) a modified CD3-δ or CD3-ε lacking an aspartic acid residue in the transmembrane region of CD3-δ or CD3-ε; and (vi) a modified CD3-ζ lacking an aspartic acid residue in the transmembrane region of CD3-ζ."],"number":19,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, which further comprises determining whether the resultant modified primary human T cells comprise a functionally impaired TCR or reduced expression of the endogenous TCR by at least one of: (a) detecting the level of expression of said variant polypeptide TCR component in the resultant modified primary human T cell or cells; (b) detecting whether the resultant modified cells elicit a GVHD response in a human subject; and (c) comparing the level of gamma interferon produced by said primary human T cell or cells obtained by steps (a) and (b) of claim 15 in response to allogeneic cells compared to the level of gamma interferon produced by a primary human T cell or cells isolated from the same donor but only modified as in (ii) step (b) of claim 15 in response to allogeneic cells."],"number":20,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, which further comprises purifying or enriching the primary human T cells obtained by steps (a) and (b) to by removing the human primary T cells that retain moderate to high expression of the targeted TCR component."],"number":21,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, wherein the at least one functional exogenous non-TCR comprises a ligand binding domain obtained from an anti-tumor chimeric antigen receptor or anti-tumor antibody."],"number":22,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, wherein the ligand binding domain of the at least one functional exogenous non-TCR comprises a pathogen-associated receptor and the resultant modified primary human T cell or cells can be used to treat infectious disease."],"number":23,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 23, wherein said infectious disease to be treated is caused by a CMV, HIV-1, HIV-2, HBV, HCV, or hantavirus infection."],"number":24,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, wherein the chimeric receptor comprises a NKG2D, NKG2A, NKG2C, NKG2F, LLT1, AICL, CD26, or NKRP1 polypeptide."],"number":25,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, wherein the chimeric receptor comprises a receptor that binds to MIC-A, MIC-B, estrogen, progesterone, RON, or one or more members of the ULBP/RAET1 family."],"number":26,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, wherein the chimeric receptor comprises a NKG2D ligand binding domain and a CD3-ζ signaling domain."],"number":27,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, wherein the resultant modified human primary T cells are suitable for use in treating cancer."],"number":28,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, which further comprises formulating the resultant modified primary human T cells with at least one pharmaceutically acceptable carrier in order to obtain a composition suitable for human therapy."],"number":29,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 15, which further comprises administering to a human subject having cancer a therapeutically effective amount of the resultant modified primary human T cells."],"number":30,"annotation":false,"claim":true,"title":false}]}},"filters":{"npl":[],"notNpl":[],"applicant":[],"notApplicant":[],"inventor":[],"notInventor":[],"owner":[],"notOwner":[],"tags":[],"dates":[],"types":[],"notTypes":[],"j":[],"notJ":[],"fj":[],"notFj":[],"classIpcr":[],"notClassIpcr":[],"classNat":[],"notClassNat":[],"classCpc":[],"notClassCpc":[],"so":[],"notSo":[],"sat":[]},"sequenceFilters":{"s":"SEQIDNO","d":"ASCENDING","p":0,"n":10,"sp":[],"si":[],"len":[],"t":[],"loc":[]}}