Methods for selecting therapy for a cancer patient
Inventors
Patel, Shashankkumar J. • Restifo, Nicholas P.
Assignees
US Department of Health and Human Services
Publication Number
US-11312998-B2
Publication Date
2022-04-26
Expiration Date
2037-11-07
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Abstract
Disclosed are methods of selecting a therapy for a cancer patient and methods of treating cancer in the patient. The methods comprise detecting a mutation in one or more genes in a cancer cell from the patient, wherein the one or more genes is selected from the group consisting of PTCD2, TWF1, DEFB134, BBS1, SOX10, APLNR, CD58, COL17A1, CRKL, hsa-mir-101-2, hsa-mir-548s, MAD2L1, MLANA, PSMB5, RNPS1, RPL10A, RPL23, SRP54, TAF3, TAP1, TAP2, TAPBP, TBXAS1, GMIP, OTOA, LAIR1, CLEC1, GPSM3, TRAF1, JAK2, TAPBPL, ICAM1, LILRA1, LILRA3, STAT1, and HLA-F. Also disclosed are methods of screening for one or more genes, the mutation of which confers resistance to T cell-mediated cytolytic activity.
Core Innovation
The invention provides methods of selecting therapy for a cancer patient comprising detecting a mutation in one or more genes in a cancer cell from the patient that decreases expression and/or activity of the encoded polypeptide(s). The genes include PTCD2, TWF1, DEFB134, BBS1, SOX10, APLNR, CD58, COL17A1, CRKL, hsa-mir-101-2, hsa-mir-548s, MAD2L1, MLANA, PSMB5, RNPS1, RPL10A, RPL23, SRP54, TAF3, TAP1, TAP2, TAPBP, TBXAS1, GMIP, OTOA, LAIR1, CLEC1, GPSM3, TRAF1, JAK2, TAPBPL, ICAM1, LILRA1, LILRA3, STAT1, and HLA-F. When a mutation that decreases expression or activity is present, a therapy that is not a T cell therapy is selected; when such a mutation is absent, a T cell therapy is selected.
The invention addresses the problem that somatic gene mutations in cancer cells may impair T cell mediated cytolysis of cancer cells, thus reducing the effectiveness of immunotherapies, especially T cell therapies. Current immunotherapy options require improved methods to identify genetic mutations that confer resistance to T cell-mediated cytolysis to enable better patient selection for appropriate therapies.
Claims Coverage
The patent discloses 6 main inventive features covering methods of selecting therapy and treating cancer based on gene or polypeptide mutation detection and expression level measurement, and screening for genes conferring resistance to T cell-mediated cytolysis.
Therapy selection based on APLNR gene mRNA or polypeptide expression level
A method of selecting and treating a cancer patient by measuring mRNA and/or polypeptide levels of the APLNR gene in cancer and noncancerous cells, comparing them, selecting non-T cell therapy if reduced in cancer cells, selecting T cell therapy if not reduced, and treating accordingly.
Decrease in APLNR expression or polypeptide level confers resistance to T cell-mediated cytolysis
Reduced level of APLNR gene expression or polypeptide in cancer cells confers resistance to T cell-mediated cytolysis, indicating this biomarker's role in therapy selection.
Therapies excluding T cell based therapies
Therapies which are not T cell therapies include surgical resection, chemotherapy, radiotherapy, NK cell therapy, B cell therapy, gene therapy, anti-cancer vaccine therapy, targeted drug inhibitor therapy, or combinations thereof.
Inclusion of T cell therapies using cells with or without modified T cell receptors
T cell therapies comprise one or more T cells or cells modified to express a T cell receptor, regardless of cell origin or modification history.
Measuring CD58 gene expression levels for therapy selection
The method can further include measuring the mRNA and/or polypeptide levels of the CD58 gene in the cancer cells for therapy selection.
Measuring BBS1 gene expression levels for therapy selection
The method can further include measuring the mRNA and/or polypeptide levels of the BBS1 gene in the cancer cells for therapy selection.
The claims cover methods of selecting and treating cancer patients by detecting mutations or expression changes in genes, especially APLNR, and related genes like CD58 and BBS1, to guide choice between T cell and non-T cell therapies, as well as screening methods for genes conferring T cell resistance.
Stated Advantages
Provides improved methods of identifying genetic mutations which impair T cell mediated cytolysis of cancer cells.
Enables selecting therapies that are more effective by avoiding T cell therapies for patients whose cancer cells harbor mutations that confer resistance to T cell-mediated cytolysis.
Allows identification of genes that modulate resistance to T cell killing, which are potentially useful biomarkers for immunotherapy response.
Offers a two cell-type CRISPR assay platform enabling high-throughput identification of genes involved in T cell-cancer cell interactions with higher library representation and specificity than single cell or in vivo screens.
Documented Applications
Selecting therapy for cancer patients by detecting mutation or expression changes in key genes to choose between T cell therapy and non-T cell therapy.
Treating cancer in a patient with a therapy selected based on mutation or expression status of genes associated with T cell-mediated cytolysis resistance.
Screening genes in cancer cells to identify those whose mutation confers resistance to T cell-mediated cytolytic activity using CRISPR/Cas9 and T cell co-culture assays.
Use of the two cell-type CRISPR assay system (2CT assay) to identify genes involved in tumor sensitivity or resistance to T cell-mediated cytolysis.
Correlation analysis of gene expression from patient tumor biopsies and TCGA data for predicting patient response and survival following immunotherapy such as CTLA4 blockade.
Modulating tumor cell gene expression or mutation status (e.g., APLNR knockout) to study or influence response to adoptive cell transfer or checkpoint blockade immunotherapies in preclinical models.
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