IP Library › Granted Patent US 12,404,316
Granted Patent B2
US 12,404,316 · App. 17/824,650 · Granted Sep 2, 2025

Transgenic T cell and chimeric antigen receptor T cell compositions and related methods

Inventors: Michel W. J. Sadelain (New York, NY); Justin Gabriel Andre Francois Eyquem (New York, NY); Jorge Mansilla-Soto (Forest Hills, NY)
Assignee: Memorial Sloan Kettering Cancer Center
C07K14/7051A61K40/11A61K40/31A61K40/4211C12N5/0636C12N9/22C12N15/63C12N15/86A61K40/50A61K2239/31A61K2239/38A61K2239/48C12N2510/00C12N2830/001
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,404,316
App. No.
17/824,650
Granted
Sep 2, 2025
Kind
B2
Abstract

The invention provides a T cell wherein one or more therapeutic transgenes is integrated at a within the genome of the cell such that expression of the transgene is under control of an endogenous promoter of the T cell. The invention additional provides methods of making and using such cells to treat a subject with T cell therapy. The invention also provides a T cell wherein a recombinant nucleic acid sequence encoding a chimeric antigen receptor (CAR) is integrated at a first site within the genome of the cell such that the CAR is expressed by the cell at the surface of the cell, and wherein integration of the nucleic acid encoding the CAR at the first site reduces or prevents expression of a functional T cell receptor (TCR) complex at the surface of the cell. The invention additional provides methods of making and using such cells to treat a subject with CAR therapy.

Claims (15)

1. A method of treating a human subject with CAR therapy in need thereof, comprising administering to the subject a therapeutically effective amount of a human T cell wherein a promoter-less recombinant nucleic acid sequence encoding a CAR is integrated at a site in the genome of the cell, said site being the first exon of the T cell receptor (TCR) alpha chain gene, such that the CAR is expressed under control of the endogenous TCR alpha chain gene promoter, to produce said CAR at the surface of the cell, and wherein integration of the nucleic acid sequence encoding the CAR at said site prevents expression of a functional TCR alpha chain.

2. The method of claim 1 , which comprises administering to the subject an isolated population of T cells comprising a plurality of the human T cell.

3. The method of claim 1 , which comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the human T cell; and a pharmaceutically acceptable carrier.

4. The method of claim 1 , wherein the CAR therapy is to promote an immune response, the subject has cancer, and the CAR binds to a cancer antigen of a cancer in the subject.

5. The method of claim 4 wherein the CAR binds to CD19.

6. The method of claim 1 , wherein the CAR therapy is to promote an immune response, the subject has an infectious disease, and the CAR binds to an antigen of a pathogen of the infectious disease.

7. The method of claim 1 , wherein the CAR therapy is to suppress an immune response, the human T cell is a T regulatory cell, the subject has an autoimmune disorder, and the CAR binds to an autoimmune antigen of the autoimmune disorder.

8. The method of claim 1 , wherein the nucleic acid sequence encoding the CAR is integrated into the site by targeted homologous recombination.

9. A method of treating cancer in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of a human T cell wherein a promoter-less recombinant nucleic acid sequence encoding a CAR is integrated at a site in the genome of the cell, said site being the first exon of the T cell receptor (TCR) alpha chain gene, such that the CAR is expressed under control of the endogenous TCR alpha chain gene promoter, to produce said CAR at the surface of the cell, wherein integration of the nucleic acid sequence encoding the CAR at said site prevents expression of a functional TCR, and wherein the CAR binds to a cancer antigen of the cancer in the subject.

10. The method of claim 9 wherein the CAR binds to CD19.

11. The method of claim 9 , which comprises administering to the subject an isolated population of T cells comprising a plurality of the human T cell.

12. The method of claim 9 , which comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the human T cell; and a pharmaceutically acceptable carrier.

13. The method of claim 9 , wherein the cancer is selected from the group consisting of a carcinoma, sarcoma, leukemia, lymphoma, multiple myeloma, melanoma, brain tumor, spinal cord tumor, germ cell tumor, neuroendocrine tumor, and carcinoid tumor.

14. The method of claim 9 , wherein the cancer is a blood cancer.

15. The method of claim 14 , wherein the cancer is a lymphoma or leukemia.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 15, 2025
From: MANSILLA-SOTO, JORGE; SADELAIN, MICHEL W. J.; EYQUEM, JUSTIN GABRIEL ANDRE FRANCOIS
To: MEMORIAL SLOAN KETTERING CANCER CENTER
Reel/Frame 071718/0114 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 15, 2025
From: SADELAIN, MICHEL W. J.; EYQUEM, JUSTIN GABRIEL ANDRE FRANCOIS; MANSILLA-SOTO, JORGE
To: MEMORIAL SLOAN KETTERING CANCER CENTER
Reel/Frame 071718/0122 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 15, 2025
From: MANSILLA-SOTO, JORGE; SADELAIN, MICHEL W. J.; EYQUEM, JUSTIN GABRIEL ANDRE FRANCOIS
To: MEMORIAL SLOAN KETTERING CANCER CENTER
Reel/Frame 071718/0103 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 15, 2025
From: SADELAIN, MICHEL W. J.; EYQUEM, JUSTIN GABRIEL ANDRE FRANCOIS; MANSILLA-SOTO, JORGE
To: MEMORIAL SLOAN KETTERING CANCER CENTER
Reel/Frame 071718/0171 →
Continuity (6)
Division 16091494
Provisional Application 62462243 · Feb 22, 2017
Provisional Application 62461677 · Feb 21, 2017
Provisional Application 62323675 · Apr 16, 2016
Provisional Application 62323623 · Apr 15, 2016
Related Publication 20220411753A1 · Dec 29, 2022
References Cited (400)
US 4956778A · Naito · 1990 [cited by applicant]
US 5091513A · Huston et al. · 1992 [cited by applicant]
US 5132405A · Huston et al. · 1992 [cited by applicant]
US 5399346A · Anderson et al. · 1995 [cited by applicant]
US 7446190B2 · Sadelain et al. · 2008 [cited by applicant]
US 8697359B1 · Zhang · 2014 [cited by applicant]
US 8802374B2 · Jensen · 2014 [cited by applicant]
US 8945868B2 · Collingwood et al. · 2015 [cited by applicant]
US 9181527B2 · Sentman · 2015 [cited by applicant]
US 9273283B2 · Sentman · 2016 [cited by applicant]
US 9587020B2 · Wu et al. · 2017 [cited by applicant]
US 9663763B2 · Sentman · 2017 [cited by applicant]
US 9821011B1 · Sentman · 2017 [cited by applicant]
US 9822340B1 · Sentman · 2017 [cited by applicant]
US 9937207B2 · Gregory et al. · 2018 [cited by applicant]
US 9938497B2 · Sentman · 2018 [cited by applicant]
US 9969975B1 · Jantz et al. · 2018 [cited by applicant]
US 10286007B2 · Galetto et al. · 2019 [cited by applicant]
US 10287606B2 · Valamehr et al. · 2019 [cited by applicant]
US 10450585B2 · Lee et al. · 2019 [cited by applicant]
US 10858628B2 · Valamehr et al. · 2020 [cited by applicant]
US 11377637B2 · Sadelain et al. · 2022 [cited by applicant]
US 20030093818A1 · Belmont et al. · 2003 [cited by applicant]
US 20050196754A1 · Drmanac et al. · 2005 [cited by applicant]
US 20100273213A1 · Mineno et al. · 2010 [cited by applicant]
US 20110059056A1 · Grawunder et al. · 2011 [cited by applicant]
US 20110158957A1 · Bonini et al. · 2011 [cited by applicant]
US 20110213288A1 · Choi et al. · 2011 [cited by applicant]
US 20120321667A1 · Sentman · 2012 [cited by applicant]
US 20130280222A1 · Kay et al. · 2013 [cited by applicant]
US 20140068797A1 · Doudna et al. · 2014 [cited by applicant]
US 20140271581A1 · Hyde et al. · 2014 [cited by applicant]
US 20150368342A1 · Wu et al. · 2015 [cited by applicant]
US 20150376650A1 · Auerbach et al. · 2015 [cited by applicant]
US 20160009813A1 · Themeli et al. · 2016 [cited by applicant]
US 20160081314A1 · Thurston et al. · 2016 [cited by applicant]
US 20160184362A1 · Duchateau et al. · 2016 [cited by applicant]
US 20160272999A1 · Duchateau et al. · 2016 [cited by applicant]
US 20170130200A1 · Moriarity et al. · 2017 [cited by applicant]
US 20170143765A1 · Wu et al. · 2017 [cited by applicant]
US 20170198306A1 · Valton et al. · 2017 [cited by applicant]
US 20170211099A1 · Auerbach et al. · 2017 [cited by applicant]
US 20170224735A1 · Hyde et al. · 2017 [cited by applicant]
US 20170240918A1 · Ortiz et al. · 2017 [cited by applicant]
US 20170296678A1 · Frost et al. · 2017 [cited by applicant]
CA 2945393A1 · 2015 [cited by applicant]
EP 1321477B1 · 2004 [cited by applicant]
EP 3004337B1 · 2017 [cited by applicant]
EP 2956175B1 · 2017 [cited by applicant]
JP 2012510812A · 2012 [cited by applicant]
WO WO2005026718A1 · 2005 [cited by applicant]
WO WO2010065123A1 · 2010 [cited by applicant]
WO WO2011011767A1 · 2011 [cited by applicant]
WO WO2011059836A2 · 2011 [cited by applicant]
WO WO2013026833A1 · 2013 [cited by applicant]
WO WO2013176915A1 · 2013 [cited by applicant]
WO WO2014059173A2 · 2014 [cited by applicant]
WO WO2014127261A1 · 2014 [cited by applicant]
WO WO2014165707A2 · 2014 [cited by applicant]
WO WO2014172584A1 · 2014 [cited by applicant]
WO WO2014186469A2 · 2014 [cited by applicant]
WO WO2014191128A1 · 2014 [cited by applicant]
WO WO2015140347A1 · 2015 [cited by applicant]
WO WO2015164740A1 · 2015 [cited by applicant]
WO WO2015172147A1 · 2015 [cited by applicant]
WO WO2015188056A1 · 2015 [cited by applicant]
WO WO2015188109A1 · 2015 [cited by applicant]
WO WO2016044745A1 · 2016 [cited by applicant]
WO WO2016081924A1 · 2016 [cited by applicant]
WO WO2016160721A1 · 2016 [cited by applicant]
WO WO2016166268A1 · 2016 [cited by applicant]
WO WO2017011519A1 · 2017 [cited by applicant]
WO WO2017062439A1 · 2017 [cited by applicant]
WO WO2017062451A1 · 2017 [cited by applicant]
WO WO2017078807A1 · 2017 [cited by applicant]
WO WO2017079673A1 · 2017 [cited by applicant]
WO WO2017087723A1 · 2017 [cited by applicant]
WO WO2017156484A1 · 2017 [cited by applicant]
WO WO2017165245A2 · 2017 [cited by applicant]
WO WO2017177137A1 · 2017 [cited by applicant]
WO WO2017180989A2 · 2017 [cited by applicant]
U.S. Appl. No. 62/008,359, filed Jun. 5, 2014, Sangamo Biosciences, Inc. [cited by applicant]
U.S. Appl. No. 62/237,394, filed May 20, 2015, Precision Biosciences, Inc. [cited by applicant]
U.S. Appl. No. 62/297,426, filed Feb. 19, 2016, Precision Biosciences, Inc. [cited by applicant]
U.S. Appl. No. 62/307,245, filed Mar. 11, 2016, Bluebird Bio, Inc. [cited by applicant]
U.S. Appl. No. 62/322,604, filed Apr. 14, 2016, Bluebird Bio, Inc. [cited by applicant]
Abate-Daga et al., “A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer,” Hum. Gene Ther., 25:1003-1012 (2014). [cited by applicant]
Adusumilli et al., “Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity,” Sci. Transl. Med., 6(261):261ra151 (2014). [cited by applicant]
Afkarian et al., “T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells,” Nat. Immunol., 3(6):549-557 (2002). [cited by applicant]
Agarwal et al., “Scaffold attachment region-mediated enhancement of retroviral vector expression in primary T cells,” J. Virol., 72:3720-3728 (1998). [cited by applicant]
Ahmad et al., “scFv antibody: principles and clinical application,” Clin. Dev. Immunol., 2012: ID980250 (2012). [cited by applicant]
Ahmed et al., “HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors,” Clin. Cancer Res., 16:474-485 (2010). [cited by applicant]
Ahmed et al., “Human Epidermal Growth Factor Receptor 2 (HER2)-Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma,” J Clin. Oncol., 33:1688-1696 (2015). [cited by applicant]
Ahmed et al., “Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression,” Mol. Ther., 17:1779-1787 (2009). [cited by applicant]
Ahmed et al., “Regression of experimental medulloblastoma following transfer of HER2-specific T cells,” Cancer Res., 67:5957-5964 (2007). [cited by applicant]
Allison et al., “Affinity and dose of TCR engagement yield proportional enhancer and gene activity in CD4+ T cells,” Elife, 5:e10134 (2016). [cited by applicant]
Anderson et al., “T-bet, a Th1 transcription factor regulates the expression of Tim-3,” Eur. J. Immunol., 40(3):859-866 (2010). [cited by applicant]
Anderson, “Prospects for human gene therapy,” Science, 226:401-409 (1984). [cited by applicant]
Andrake et al., “Retroviral Integrase: Then and Now,” Annu. Rev. Virol., 2(1):241-264 (2015). [cited by applicant]
Arakawa et al., “Targeting of T cells to CEA-expressing tumor cells by chimeric immune receptors with a highly specific single-chain anti-CEA activity,” Anticancer Res., 22:4285-4289 (2002). [cited by applicant]
Argani et al., “Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE).,” Clin. Cancer R… [cited by applicant]
Assenmacher et al., Cytometric Cytokine Secretion Assay, in Analyzing T Cell Responses: How to Analyze Cellular Immune Responses Against Tumor Associated Antigens, Nagorsen et al., eds., Springer, The Netherlands, Ch. 1… [cited by applicant]
Baba et al., “Mesothelin expression correlates with prolonged patient survival in gastric cancer,” J Surg. Oncol., 105:195-199 (2012). [cited by applicant]
Bacher et al., “Antigen-specific expansion of human regulatory T cells as a major tolerance mechanism against mucosal fungi,” Mucosal. Immunol., 7:916-928 (2014). [cited by applicant]
Bakhtiari et al., “Anti-MUCI nanobody can redirect T-body cytotoxic effector function,” Hybridoma, 28:85-92 (2009). [cited by applicant]
Barber et al., “Chimeric NKG2D expressing T cells eliminate immunosuppression and activate immunity within the ovarian tumor microenvironment,” J Immunol., 183:6939-6947 (2009). [cited by applicant]
Bayoglu et al., “Prognostic value of mesothelin expression in patients with triple negative and HER2-positive breast cancers,” Biomed. Pharmacother., 70:190-195 (2015). [cited by applicant]
Beard et al., “Multiple chimeric antigen receptors successfully target chondroitin sulfate proteoglycan 4 in several different cancer histologies and cancer stem cells,” J Immunother. Cancer, 2:25 (2014). [cited by applicant]
Beatty, “Engineered chimeric antigen receptor-expressing T cells for the treatment of pancreatic ductal adenocarcinoma,” Oncoimmunology, 3:e28327 (2014). [cited by applicant]
Best et al., “Transcriptional insights into the CD8(+) T cell response to infection and memory T cell formation,” Nat. Immunol., 14(4):404-412 (2013). [cited by applicant]
Blackburn et al., “Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection,” Natl. Immunol., 10(1):29-37 (2009). [cited by applicant]
Bluestone et al., “T cells in the control of organ-specific autoimmunity,” J. Clin. Invest., 125:2250-2260 (2015). [cited by applicant]
Bluestone et al., “Type 1 diabetes immunotherapy using polyclonal regulatory T cells,” Sci. Transl. Med., 7(315):315ra189 (2015). [cited by applicant]
Brentjens et al., “CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia,” Sci. Transl. Med., 5(177):177ra38 (2013). [cited by applicant]
Brentjens et al., “Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15,” Nature Medicine, 9:279-286 (2003). [cited by applicant]
Brentjens et al., “Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts,” Clin. Cancer Res., 13:5426-5435 (2007). [cited by applicant]
Brown et al., “Bioactivity and Safety of IL13Rα2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma,” Clin. Cancer Res., 21(18):4062-4072 (2015). [cited by applicant]
Brusko et al., “Human Antigen-Specific Regulatory T Cells Generated by T Cell Receptor Gene Transfer,” PLoS One, 5(7):e11726 (2010). [cited by applicant]
Bunos et al., “Automated isolation of primary antigen-specific T cells from donor lymphocyte concentrates: results of a feasibility exercise,” Vox Sanguinis, 109:387-393 (2015). [cited by applicant]
Burga et al., “Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T,” Cancer Immunol. Immunother., 64(7):817-829 (2015). [cited by applicant]
Burns et al., “A high molecular weight melanoma-associated antigen-specific chimeric antigen receptor redirects lymphocytes to target human melanomas,” Cancer Res., 70:3027-3033 (2010). [cited by applicant]
Call et al., “The organizing principle in the formation of the T cell receptor-CD3 complex,” Cell, 111(7):967-979 (2002). [cited by applicant]
Call et al., “The T cell receptor: critical role of the membrane environment in receptor assembly and function,” Annu. Rev. Immunol., 23:101-125 (2005). [cited by applicant]
Cao et al., “Expression of mesothelin, fascin, and prostate stem cell antigen in primary ovarian mucinous tumors and their utility in differentiating primary ovarian mucinous tumors from metastatic pancreatic mucinous c… [cited by applicant]
Capecchi et al., “Gene targeting in mice: functional analysis of the mammalian genome for the twenty-first century,” Nat. Rev. Genet., 6:507-512 (2005). [cited by applicant]
Carpenito et al., “Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains,” Proc. Natl. Acad. Sci. U.SA., 106:3360-3365 (2009). [cited by applicant]
Chames et al., “Therapeutic antibodies: successes, limitations and hopes for the future,” Br. J. Pharmacol., 157:220-233 (2009). [cited by applicant]
Chang et al., “Emerging concepts of T cell metabolism as a target of immunotherapy,” Nat. Immunol., 17:364-368 (2016). [cited by applicant]
Chang et al., “Transgene-enforced co-stimulation of CD4+ T cells leads to enhanced and sustained anti-tumor effector functioning,” Cytotherapy, 9:771-784 (2007). [cited by applicant]
Chekmasova et al., “Adoptive T cell immunotherapy strategies for the treatment of patients with ovarian cancer,” Discov. Med., 9:62-70 (2010). [cited by applicant]
Chen et al., “Direct expansion of human allospecific FoxP3+CD4+ regulatory T cells with allogeneic B cells for therapeutic application,” J. Immunol., 183:4094-4102 (2009). [cited by applicant]
Chen et al., “Molecular mechanisms of T cell co-stimulation and co-inhibition,” Nat. Rev. Immunol., 13(4):227-242 (2013). [cited by applicant]
Chen, “Mesothelin expression in thymic epithelial tumors (TETs),” J Clin. Oncol., 32:503s, abstract 7607 (2014). [cited by applicant]
Cheung et al., “Anti-idiotypic antibody facilitates scFv chimeric immune receptor gene transduction and clonal expansion of human lymphocytes for tumor therapy,” Hybrid Hybridomics, 22:209-218 (2003). [cited by applicant]
Chinnasamy et al., “Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice,” Clin. Cancer Res., 18:1672-1683 (2012). [cited by applicant]
Chinnasamy et al., “Simultaneous targeting of tumor antigens and the tumor vasculature using T lymphocyte transfer synergize to induce regression of established tumors in mice,” Cancer Res., 73:3371-3380 (2013). [cited by applicant]
Chmielewski et al., “T cells redirected by a CD3ζ chimeric antigen receptor can establish self-antigen-specific tumour protection in the long term,” Gene Ther., 20:177-186 (2013). [cited by applicant]
Chmielewski et al., “T cells that target carcinoembryonic antigen eradicate orthotopic pancreatic carcinomas without inducing autoimmune colitis in mice.,” Gastroenterology, 143:1095-1107 (2012). [cited by applicant]
Choi et al., “Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma,” J Clin. Neurosci., 21:189-190 (2014). [cited by applicant]
Chow et al., “T cells redirected to EphA2 for the immunotherapy of glioblastoma,” Mol. Ther., 21:629-637 (2013). [cited by applicant]
Chuvpilo et al., “Multiple closely-linked NFAT/octamer and HMG I(Y) binding sites are part of the interleukin-4 promoter,” Nucleic Acids Res., 21(24):5694-5704 (1993). [cited by applicant]
Cooper et al., “Enhanced antilymphoma efficacy of CD19-redirected influenza MP1-specific CTLs by cotransfer of T cells modified to present influenza MP1,” Blood, 105(4):1622-1631 (2005). [cited by applicant]
Cornetta et al., “Gene transfer into primates and prospects for gene therapy in humans,” Prog. Nucleic Acid Res. Mol. Biol., 36:311-322 (1989). [cited by applicant]
Corthay et al., “Evaluation of the percentage of peripheral T cells with two different T cell receptor alpha-chains and of their potential role in autoimmunity,” J. Autoimmun., 16(4):423-429 (2001). [cited by applicant]
Dainty et al., “Overexpression of folate binding protein and mesothelin are associated with uterine serous carcinoma,” Gynecol. Oncol., 105:563-570 (2007). [cited by applicant]
Darcy et al., “Expression in cytotoxic T lymphocytes of a single-chain anti-carcinoembryonic antigen antibody. Redirected Fas ligand-mediated lysis of colon carcinoma,” Eur J Immunol., 28:1663-1672 (1998). [cited by applicant]
Darcy et al., “Redirected perforin-dependent lysis of colon carcinoma by ex vivo genetically engineered CTL,” J Immunol., 164:3705-3712 (2000). [cited by applicant]
Davies et al., “Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells,” Mol. Med., 18:565-576 (2012). [cited by applicant]
Davila et al., “How do CARs work?: Early insights from recent clinical studies targeting CD19,” Oncoimmunol. 1(9):1577-1583 (2012). [cited by applicant]
De Vree et al., “Targeted sequencing by proximity ligation for comprehensive variant detection and local haplotyping,” Nat. Biotechnol., 32(10):1019-1025 (2014). [cited by applicant]
Deng et al., “Adoptive T-cell therapy of prostate cancer targeting the cancer stem cell antigen EpCAM,” BMC Immunol., 16:1 (2015). [cited by applicant]
Deniger et al., “Sleeping Beauty Transposition of Chimeric Antigen Receptors Targeting Receptor Tyrosine Kinase-Like Orphan Receptor-1 (ROR1) into Diverse Memory T-Cell Populations,” PLoS One, 10:e0128151 (2015). [cited by applicant]
Dennis et al., “Markers of adenocarcinoma characteristic of the site of origin: development of a diagnostic algorithm,” Clin. Cancer Res., 11:3766-3772 (2005). [cited by applicant]
Drapkin et al., “Expression of candidate tumor markers in ovarian carcinoma and benign ovary: evidence for a link between epithelial phenotype and neoplasia” Hum. Pathol., 35:1014-1021 (2004). [cited by applicant]
Duong et al., “Enhancing the specificity of T-cell cultures for adoptive immunotherapy of cancer,” Immunotherapy, 3:33-48 (2011). [cited by applicant]
Dupont et al., “Artificial antigen-presenting cells transduced with telomerase efficiently expand epitope-specific, human leukocyte antigen-restricted cytotoxic T cells,” Cancer Res., 65(12):5417-5427 (2005). [cited by applicant]
Eglitis et al., “Retroviral vectors for introduction of genes into mammalian cells,” BioTechniques, 6:608-614 (1988). [cited by applicant]
Einama et al., “Luminal membrane expression of mesothelin is a prominent poor prognostic factor for gastric cancer,” Br. J Cancer, 107:137-142 (2012). [cited by applicant]
Ellis, “Silencing and variegation of gammaretrovirus and lentivirus vectors,” Hum. Gene Ther., 316(11):1241-1246 (2005). [cited by applicant]
Emtage et al., “Second-generation anti-carcinoembryonic antigen designer T cells resist activation-induced cell death, proliferate on tumor contact, secrete cytokines, and exhibit superior antitumor activity in vivo: a … [cited by applicant]
Eyquem et al., “One Step Generation of Universal CAR T Cells,” Mol. Ther., 24(Supp 1):S109 (2016) (Published online Apr. 22, 2016, accessable online at American Society of Gene & Cell Therapy (ASGCT) Apr. 18, 2016, ASGC… [cited by applicant]
Eyquem et al., “Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection,” Nature, 543(7643):113-117 (2017). [cited by applicant]
Fantini et al., “Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25-T cells through Foxp3 induction and down-regulation of Smad7,” J. Immunol., 172(9):5149-5153 (2004). [cited by applicant]
Finney et al., “Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product,” J. Immunol., 161:2791-2797 (1998). [cited by applicant]
Frank et al., “Mesothelin expression in pancreatic mucinous cysts.,” Am. J Clin. Pathol., 142:313-319 (2014). [cited by applicant]
Friedman, “Progress toward human gene therapy,” Science, 244:1275-1281 (1989). [cited by applicant]
Frierson et al., “Large-scale molecular and tissue microarray analysis of mesothelin expression in common human carcinomas,” Hum. Pathol., 34(6):605-609 (2003). [cited by applicant]
Frigault et al., “Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells,” Cancer Immunol Res., 3(4):356-367 (2015). [cited by applicant]
Gade et al., “Targeted elimination of prostate cancer by genetically directed human T lymphocytes,” Cancer Res., 65:9080-9088 (2005). [cited by applicant]
Gaj et al., “ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering,” Trends Biotechnol., 31(7):397-405 (2013). [cited by applicant]
Gallardo et al., “The internal ribosomal entry site of the encephalomyocarditis virus enables reliable coexpression of two transgenes in human primary T lymphocytes,” Gene Ther., 4(10):1115-1119 (1997). [cited by applicant]
Galloway et al., “The use of the monoclonal antibody mesothelin in the diagnosis of malignant mesothelioma in pleural biopsies,” Histopathology, 48:767-769 (2006). [cited by applicant]
Gao et al., “Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma,” Clin. Cancer Res., 20:6418-6428 (2014). [cited by applicant]
Gattinoni et al., “A human memory T cell subset with stem cell-like properties,” Nat. Med., 17(10):1290-1297 (2011). [cited by applicant]
Geldres et al., “T lymphocytes redirected against the chondroitin sulfate proteoglycan-4 control the growth of multiple solid tumors both in vitro and in vivo,” Clin. Cancer Res., 20:962-971 (2014). [cited by applicant]
GenBank Accession No. NP_000607.1, “T-cell surface glycoprotein CD4 isoform 1 precursor [ [cited by applicant]
GenBank Accession No. NP_001139345.1, “T-cell surface glycoprotein CD8 alpha chain isoform 1 precursor [ [cited by applicant]
GenBank Accession No. NP_001181943.1, “T-cell surface glycoprotein CD4 isoform 2 [ [cited by applicant]
GenBank Accession No. NP_001181944.1, “T-cell surface glycoprotein CD4 isoform 3 [ [cited by applicant]
GenBank Accession No. NP_001181945.1, “T-cell surface glycoprotein CD4 isoform 3 [ [cited by applicant]
GenBank Accession No. NP_001181946.1, “T-cell surface glycoprotein CD4 isoform 3 [ [cited by applicant]
GenBank Accession No. NP_001552.2, “tumor necrosis factor receptor superfamily member 9 precursor [ [cited by applicant]
GenBank Accession No. NP_003318.1, “tumor necrosis factor receptor superfamily member 4 precursor [ [cited by applicant]
GenBank Accession No. NP_006130.1, “T-cell-specific surface glycoprotein CD28 isoform 1 precursor [ [cited by applicant]
GenBank Accession No. NP_036224.1, “inducible T-cell costimulator precursor [ [cited by applicant]
GenBank Accession No. NP_055081.1, “hematopoietic cell signal transducer isoform 1 precursor [ [cited by applicant]
GenBank Accession No. NP_932170.1, “T-cell surface glycoprotein CD3 zeta chain isoform 1 precursor [ [cited by applicant]
GenBank Accession No. NP_955592.1, “p46 IN [Moloney murine leukemia virus],” (Feb. 10, 2015). [cited by applicant]
GenBank Accession No. P10747.1, “T-cell-specific surface glycoprotein CD28,” (Jul. 6, 2016). [cited by applicant]
GenBank Accession No. P41273.1, “Tumor necrosis factor ligand superfamily member 9,” (Jul. 6, 2016). [cited by applicant]
GenBank Accession No. P43489.1, “Tumor necrosis factor receptor superfamily member 4,” (Jul. 6, 2016). [cited by applicant]
Gersbach et al., “Targeted plasmid integration into the human genome by an engineered zinc-finger recombinase,” Nucl. Acids Res., 39:7868-7878 (2011). [cited by applicant]
Gierasch, “Signal sequences,” Biochem., 28:923-930 (1989). [cited by applicant]
Gilham et al., “Primary polyclonal human T lymphocytes targeted to carcino-embryonic antigens and neural cell adhesion molecule tumor antigens by CD3zeta-based chimeric immune receptors,” J Immunother., 25:139-151 (2002… [cited by applicant]
Gong et al., “Cancer patient T cells genetically targeted to prostate-specific membrane antigen specifically lyse prostate cancer cells and release cytokines in response to prostate-specific membrane antigen,” Neoplasia… [cited by applicant]
Guedan et al., “ICOS-based chimeric antigen receptors program bipolar TH17/THI cells,” Blood, 124:1070-1080 (2014). [cited by applicant]
Guillonneau et al., “CD8+ regulatory T cells in solid organ transplantation,” Curr. Opin. Organ Transplant., 15:751-756 (2010). [cited by applicant]
Gyobu et al., “Generation and targeting of human tumor-specific Tc1 and Th1 cells transduced with a lentivirus containing a chimeric immunoglobulin T-cell receptor,” Cancer Res., 64:1490-1495 (2004). [cited by applicant]
Haney et al., “Isolation of viable antigen-specific CD8+ T cells based on membrane-bound tumor necrosis factor (TNF)-α expression,” J. Immunol. Methods, 369:33-41 (2011). [cited by applicant]
Hassan et al., “Localization of mesothelin in epithelial ovarian cancer,” Appl. Immunohistochem. Mol. Morphol. 13:243-247 (2005). [cited by applicant]
Hassan et al., “Mesothelin is overexpressed in pancreaticobiliary adenocarcinomas but not in normal pancreas and chronic pancreatitis,” Am. J. Clin. Pathol., 124:838-845 (2005). [cited by applicant]
Haynes et al., “Fas-ligand-mediated lysis of erbB-2-expressing tumour cells by redirected cytotoxic T lymphocytes,” Cancer Immunol. Immunother., 47:278-286 (1999). [cited by applicant]
Haynes et al., “Rejection of syngeneic colon carcinoma by CTLs expressing single-chain antibody receptors codelivering CD28 costimulation,” J Immunol., 169:5780-5786 (2002). [cited by applicant]
Haynes et al., 2001, “Redirecting Mouse CTL Against Colon Carcinoma: Superior Signaling Efficacy of Single-Chain Variable Domain Chimeras Containing TCR-zeta vs Fc Epsilon RI-gamma,” J. Immunol., 166:182-187. [cited by applicant]
Hegde et al., “Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma,” Mol. Ther., 21:2087-2101 (2013). [cited by applicant]
Hillerdal et al., “Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice,” BMC Cancer, 14:30 (2014). [cited by applicant]
Hollyman et al., “Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy,” J. Immunother., 32:169-180 (2009). [cited by applicant]
Hombach et al., “A chimeric receptor that selectively targets membrane-bound carcinoembryonic antigen (mCEA) in the presence of soluble CEA,” Gene Ther., 6:300-304 (1999). [cited by applicant]
Hombach et al., “T cell targeting of TAG72+ tumor cells by a chimeric receptor with antibody-like specificity for a carbohydrate epitope,” Gastroenterology, 113:1163-1170 (1997). [cited by applicant]
Honey et al., “Understanding why T-cell receptors remain single,” Nat. Rev. Immunol., 5:95 (2005). [cited by applicant]
Hong et al., “Diverse solid tumors expressing a restricted epitope of L1-CAM can be targeted by chimeric antigen receptor redirected T lymphocytes,” J Immunother., 37:93-104 (2014). [cited by applicant]
Huang et al., “Genetically modified T cells targeting interleukin-11 receptor α-chain kill human osteosarcoma cells and induce the regression of established osteosarcoma lung metastases,” Cancer Res., 72:271-281 (2012). [cited by applicant]
Hubbard et al., “Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome,” Blood, 127(21):2513-2522 (2016). [cited by applicant]
Hudecek et al., “Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells,” Clin. Cancer Res., 19:3153-3164 (2013). [cited by applicant]
Huse et al., “Generation of a large combinatorial library of the immunoglobulin repertoire in phage lambda,” Science, 246:1275-1281 (1989). [cited by applicant]
Huston et al., “Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in [cited by applicant]
Imai et al., “Genetic modification of T cells for cancer therapy,” J. Biol. Regul. Homeost. Agents, 18(1):62-71 (2004). [cited by applicant]
Inami et al., “Secretion of N-ERC/mesothelin and expression of C-ERC/mesothelin in human pancreatic ductal carcinoma,” Oncol. Rep., 20:1375-1380 (2008). [cited by applicant]
International Search Report for International Application No. PCT/US2017/027601 dated Nov. 14, 2017. [cited by applicant]
Ito et al., “ERC/mesothelin is expressed in human gastric cancer tissues and cell lines,” Oncol. Rep., 31:27-33 (2014). [cited by applicant]
Iyer et al., “Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease,” Crit. Rev. Immunol., 32(1):23-63 (2012). [cited by applicant]
Jain et al., “Transcriptional regulation of the IL-2 gene,” Curr. Opin. Immunol., 7(3):333-342 (1995). [cited by applicant]
Jensen et al., “Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells,” Immunol. Rev., 257:127-133 (2014). [cited by applicant]
Jensen et al., “Designing chimeric antigen receptors to effectively and safely target tumors,” Curr. Opin. Immunol., 33:9-15 (2015). [cited by applicant]
Johnson et al., “Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma,” Sci. Transl. Med., 7:275ra22 (2015). [cited by applicant]
Johnson, “Gene therapy for cystic fibrosis,” Chest, 107:77S-83S (1995). [cited by applicant]
Juillerat et al., “Design of chimeric antigen receptors with integrated controllable transient functions,” Sci. Rep., 18950 (2016). [cited by applicant]
Kachala et al., “Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma,” Clin. Cancer Res., 20(4):1020-1028 … [cited by applicant]
Kailayangiri et al., “The ganglioside antigen G(D2) is surface-expressed in Ewing sarcoma and allows for MHC-independent immune targeting,” Br. J Cancer, 106:1123-1133 (2012). [cited by applicant]
Kaiser et al., “Towards a commercial process for the manufacture of genetically modified T cells for therapy,” Cancer Gene Therapy, 22:72-78 (2015). [cited by applicant]
Kakarla et al., “Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma,” Mol. Ther., 21:1611-1620 (2013). [cited by applicant]
Kanagawa et al., “Tumor vessel-injuring ability improves antitumor effect of cytotoxic T lymphocytes in adoptive immunotherapy,” Cancer Gene Ther., 20:57-64 (2013). [cited by applicant]
Kandalaft et al., “A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer,” J Transl. Med., 10:157 (2012). [cited by applicant]
Katz et al., “Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor-Modified T-cell Therapy for CEA+ Liver Metastases,” Clin. Cancer Res., 21:3149-3159 (2015). [cited by applicant]
Kawamata et al., “C-ERC/mesothelin provokes lymphatic invasion of colorectal adenocarcinoma,” J Gastroenterol., 49:81-92 (2014). [cited by applicant]
Kawamata et al., “Intracellular localization of mesothelin predicts patient prognosis of extrahepatic bile duct cancer,” Int. J Oncol., 41:2109-2118 (2012). [cited by applicant]
Kershaw et al., “A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer,” Clin. Cancer Res., 12:6106-6115 (2006). [cited by applicant]
Kershaw et al., “Gene-engineered T cells as a superior adjuvant therapy for metastatic cancer,” J. Immunol., 173:2143-2150 (2004). [cited by applicant]
Kim et al., “The basis for TCR-mediated regulation of the IL-2 receptor alpha chain gene: role of widely separated regulatory elements,” EMBO J, 21(12):3051-3059 (2002). [cited by applicant]
Kobayashi et al., “A chimeric antigen receptor for TRAIL-receptor 1 induces apoptosis in various types of tumor cells,” Biochem. Biophys. Res. Commun. 453:798-803 (2014). [cited by applicant]
Koenen et al., “CD27/CFSE-Based Ex Vivo Selection of Highly Suppressive Alloantigen-Specific Human Regulatory T Cells,” J. Immunol., 174:7573-7583 (2005). [cited by applicant]
Koneru et al., “IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo,” Oncoimmunology, 4:e994446 (2015). [cited by applicant]
Kong et al., “Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T cells,” Clin. Cancer Res., 18:5949-5960 (2012). [cited by applicant]
Krause et al., “Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes,” J Exp. Med., 188:619-626 (1998). [cited by applicant]
Krebs et al., “T cells redirected to interleukin-13Rα2 with interleukin-13 mutein—chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Rα1,” Cytotherapy, 16:1121-1131 (2014). [cited by applicant]
Krishnamurthy et al., “Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma,” Clin. Cancer Res., 21:3241-3251 (2015). [cited by applicant]
Kushitani et al., “Immunohistochemical marker panels for distinguishing between epithelioid mesothelioma and lung adenocarcinomam,” Pathol. Int., 57:190-199 (2007). [cited by applicant]
Lamers et al., “Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells,” Blood, 117(1):72-82 (2011). [cited by applicant]
Lamers et al., “Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity,” Mol Ther., 21:904-912 (2013). [cited by applicant]
Lan et al., “Induced Foxp3+ regulatory T cells: a potential new weapon to treat autoimmune and inflammatory diseases?,” J. Mol. Cell. Biol., 4:22-28 (2012). [cited by applicant]
Lanitis et al., “Primary human ovarian epithelial cancer cells broadly express HER2 at immunologically-detectable levels,” PLoS One, 7:e49829 (2012). [cited by applicant]
Lanitis et al., “Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor,” Mol. Ther., 20:633-643 (2012). [cited by applicant]
Latouche et al., “Induction of human cytotoxic T lymphocytes by artificial antigen-presenting cells,” Nat. Biotechnol., 18:405-409 (2000). [cited by applicant]
Lazovic et al., “Imaging immune response in vivo: cytolytic action of genetically altered T cells directed to glioblastoma multiforme” Clin. Cancer Res., 14:3832-3839 (2008). [cited by applicant]
Le Gal La Salle et al., “An adenovirus vector for gene transfer into neurons and glia in the brain,” Science, 259:988-990 (1993). [cited by applicant]
Lee et al., “A distal cis-regulatory element, CNS-9, controls NFAT1 and IRF4-mediated IL-10 gene activation in T helper cells,” Mol. Immunol., 46(4):613-621 (2009). [cited by applicant]
Lee et al., “In vivo inhibition of human CD19 targeted effector T cells by natural T regulatory cells in a xenotransplant murine model of B cell malignancy,” Cancer Res., 71:2871-2881 (2011). [cited by applicant]
Li et al., “Genetically engineered T cells expressing a HER2-specific chimeric receptor mediate antigen-specific tumor regression,” Cancer Gene Ther., 15:382-392 (2008). [cited by applicant]
Li et al., “Mesothelin expression is associated with poor outcomes in breast cancer,” Breast Cancer Res. Treat., 147:675-684 (2014). [cited by applicant]
Liebig et al., “Forced expression of deltaN-TCF-1B in colon cancer derived cell lines is accompanied by the induction of CEACAM5/6 and mesothelin,” Cancer Lett., 223:159-167 (2005). [cited by applicant]
Lim et al., “CCR5: no longer a “good for nothing” gene—chemokine control of West Nile virus infection,” Trends Immunol., 27(7):308-312 (2006). [cited by applicant]
Liu et al., “CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells,” J. Exp. Med., 203:1701-1711 (2006). [cited by applicant]
Liu et al., “On the dynamics of TCR:CD3 complex cell surface expression and downmodulation,” Immunity, 13(5):665-675 (2000). [cited by applicant]
Lo et al., “Anti-GD3 chimeric sFv-CD28/T-cell receptor zeta designer T cells for treatment of metastatic melanoma and other neuroectodermal tumors,” Clin. Cancer Res., 16:2769-2780 (2010). [cited by applicant]
Lombardo et al., “Site-specific integration and tailoring of cassette design for sustainable gene transfer,” Nat. Methods, 8(10):861-869 (2011). [cited by applicant]
Louis et al., “Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma,” Blood, 118:6050-6056 (2011). [cited by applicant]
Luria, 1987, “Promoter and enhancer elements in the rearranged alpha chain gene of the human T cell receptor”, EMBO J, 6(11):3307-3312. [cited by applicant]
Ma et al., “Anti-prostate specific membrane antigen designer T cells for prostate cancer therapy,” Prostate, 61:12-25 (2004). [cited by applicant]
Ma et al., “Serine Is an Essential Metabolite for Effector T Cell Expansion,” Cell Metab., 25(2):345-357 (2017). [cited by applicant]
Macdonald et al., “Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor,” J. Clin. Invest., 126:1413-1424 (2016). [cited by applicant]
Macian, “NFAT proteins: key regulators of T-cell development and function,” Nat. Rev. Immunol., 5(6):472-484 (2005). [cited by applicant]
Macleod et al., “Antigen-based immunotherapy (AIT) for autoimmune and allergic disease,” Curr. Opin. Pharmacol., 23:11-16 (2015). [cited by applicant]
Macleod et al., “Integration of a CD19 CAR into the TCR Alpha Chain Locus Streamlines Production of Allogeneic Gene-Edited CAR T Cells,” Mol. Ther., 25(4):949-961 (2017). [cited by applicant]
Maher et al., “Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor,” Nat. Biotechnol., 20:70-75 (2002). [cited by applicant]
Mahnke et al., “The who's who of T-cell differentiation: human memory T-cell subsets,” Eur. J. Immunol., 43(11):2797-2809 (2013). [cited by applicant]
Maliar et al., “Redirected T cells that target pancreatic adenocarcinoma antigens eliminate tumors and metastases in mice,” Gastroenterology, 143:1375-1384 (2012). [cited by applicant]
Mcguinness et al., “Anti-tumor activity of human T cells expressing the CC49-zeta chimeric immune receptor,” Hum Gene Ther., 10:165-173 (1999). [cited by applicant]
Mcnamee et al., “Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function,” Immunol. Res., 55(1-3):58-70 (2013). [cited by applicant]
Mehta et al., “NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression,” Proc. Natl. Acad. Sci. USA, 102(6):2016-2021 (2005). [cited by applicant]
Miao et al., “EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma,” PLoS One, 9:e94281 (2014). [cited by applicant]
Miettinen et al., “Expression of calretinin, thrombomodulin, keratin 5, and mesothelin in lung carcinomas of different types: an immunohistochemical analysis of 596 tumors in comparison with epithelioid mesotheliomas of… [cited by applicant]
Miller et al., “Improved Retroviral Vectors for Gene Transfer and Expression,” Biotechniques, 7:980-990 (1989). [cited by applicant]
Miller et al., “The journey from discoveries in fundamental immunology to cancer immunotherapy,” Cancer Cell, 27(4):439-449 (2015). [cited by applicant]
Miller, “Retrovirus packaging cells,” Hum. Gene Ther., 1(1):5-14 (1990). [cited by applicant]
Miyara et al., “TREG-cell therapies for autoimmune rheumatic diseases,” Nat. Rev. Rheumatol., 10:543-551 (2014). [cited by applicant]
Moen, “Directions in gene therapy,” Blood Cells, 17:407-416 (1991). [cited by applicant]
Montes et al., “Optimum in vitro expansion of human antigen-specific CD8 T cells for adoptive transfer therapy,” Clin. Exp. Immunol. 142:292-302 (2005). [cited by applicant]
Moon et al., “Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors,” Clin. Cancer Res., 20(16):4262-4273 (2014). [cited by applicant]
Morgan et al., “Cancer regression in patients after transfer of genetically engineered lymphocytes,” Science, 314(5796):126-129 (2006). [cited by applicant]
Morgan et al., “Recognition of glioma stem cells by genetically modified T cells targeting EGFRVIII and development of adoptive cell therapy for glioma,” Hum. Gene Ther., 23:1043-1053 (2012). [cited by applicant]
Morgenroth et al., “Targeting of tumor cells expressing the prostate stem cell antigen (PSCA) using genetically engineered T-cells,” Prostate, 67:1121-1131 (2007). [cited by applicant]
Moritz et al., “Cytotoxic T lymphocytes with a grafted recognition specificity for ERBB2-expressing tumor cells,” Proc. Natl. Acad. Sci. U.S.A., 91:4318-4322 (1994). [cited by applicant]
Movassagh et al., “Retrovirus-mediated gene transfer into T cells: 95% transduction efficiency without further in vitro selection,” Hum. Gene Ther., 11:1189-1200 (2000). [cited by applicant]
Neeson et al., “Ex vivo culture of chimeric antigen receptor T cells generates functional CD8+ T cells with effector and central memory-like phenotype” Gene Ther., 17:1105-1116 (2010). [cited by applicant]
Nolan et al., “Bypassing immunization: optimized design of “designer T cells” against carcinoembryonic antigen (CEA)-expressing tumors, and lack of suppression by soluble CEA,” Clin Cancer Res., 5:3928-3941 (1999). [cited by applicant]
Nomura et al., “Mesothelin expression is a prognostic factor in cholangiocellular carcinoma,” Int. Surg., 98:164-169 (2013). [cited by applicant]
Noyan et al., “Isolation of human antigen-specific regulatory T cells with high suppressive function,” Eur. J. Immunol., 44:2592-2602 (2014). [cited by applicant]
Obulhasim et al., “Mesothelin gene expression and promoter methylation/hypomethylation in gynecological tumors,” Eur. J Gynaecol. Oncol., 31:63-71 (2010). [cited by applicant]
Oestreich et al., “NFATc1 regulates PD-1 expression upon T cell activation,” J. Immunol., 181(7):4832-4839 (2008). [cited by applicant]
Ohno et al., “Expression of miR-17-92 enhances anti-tumor activity of T-cells transduced with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts,” J Immunother. Cancer, 1:21 (2013). [cited by applicant]
Ohno et al., “Retrovirally engineered T-cell-based immunotherapy targeting type III variant epidermal growth factor receptor, a glioma-associated antigen,” Cancer Sci., 101:2518-2524 (2010). [cited by applicant]
Ordonez et al., “Diagnostic utility of immunohistochemistry in distinguishing between epithelioid pleural mesotheliomas and breast carcinomas: a comparative study,” Hum. Pathol., 45:1529-1540 (2014). [cited by applicant]
Ordonez, “Application of mesothelin immunostaining in tumor diagnosis,” Am. J Surg. Pathol., 27:1418-1428 (2003). [cited by applicant]
Ordonez, “The diagnostic utility of immunohistochemistry in distinguishing between epithelioid mesotheliomas and squamous carcinomas of the lung: a comparative study,” Mod. Pathol., 19:417-428 (2006). [cited by applicant]
Ordonez, “The diagnostic utility of immunohistochemistry in distinguishing between mesothelioma and renal cell carcinoma: a comparative study,” Hum. Pathol., 35:697-710 (2004). [cited by applicant]
Ordonez, “The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma,” Am. J Surg. Pathol., 27:1031-1051 (2003). [cited by applicant]
Ordonez, “Value of mesothelin immunostaining in the diagnosis of mesothelioma,” Mod. Pathol., 16:192-197 (2003). [cited by applicant]
Osborn et al., “Evaluation of TCR Gene Editing Achieved by TALENs, CRISPR/Cas9, and megaTAL Nucleases,” Mol. Ther., 24(3):570-581 (2016). [cited by applicant]
Pan et al., “Expression of calretinin and other mesothelioma-related markers in thymic carcinoma and thymoma,” Hum. Pathol., 34:1155-1162 (2003). [cited by applicant]
Panelli et al., “A tumor-infiltrating lymphocyte from a melanoma metastasis with decreased expression of melanoma differentiation antigens recognizes MAGE-12,” J. Immunol., 164(8):4382-4392 (2000). [cited by applicant]
Panelli et al., “Expansion of tumor-T cell pairs from fine needle aspirates of melanoma metastases,” J. Immunol., 164:495-504 (2000). [cited by applicant]
Papa et al., “Clinical Evaluation of ErbB-Targeted CAR T-Cells, Following Intracavity Delivery in Patients with ErbB-Expressing Solid Tumors,” Methods Mol. Biol., 1317:365-382 (2015). [cited by applicant]
Papanicolaou et al., “Rapid expansion of cytomegalovirus-specific cytotoxic T lymphocytes by artificial antigen-presenting cells expressing a single HLA allele,” Blood, 102(7):2498-2505 (2003). [cited by applicant]
Parente-Pereira et al., “Use of retroviral-mediated gene transfer to deliver and test function of chimeric antigen receptors in human T-cells,” J. Biol. Methods, 1(2):e7 (2014). [cited by applicant]
Parinyanitikul et al., “Mesothelin expression and survival outcomes in triple receptor negative breast cancer,” Clin. Breast Cancer, 13(5): doi:10.1016/j.clbc.2013.05.001 (2013). [cited by applicant]
Park et al., “Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma,” Mol. Ther., 15:825-833 (2007). [cited by applicant]
Parker et al., “Expansion and characterization of T cells transduced with a chimeric receptor against ovarian cancer,” Hum. Gene Ther., 11:2377-2387 (2000). [cited by applicant]
Patel et al., “T-cell killing of heterogenous tumor or viral targets with bispecific chimeric immune receptors,” Cancer Gene Ther. 7:1127-1134 (2000). [cited by applicant]
Petrausch et al., “Re-directed T cells for the treatment of fibroblast activation protein (FAP)-positive malignant pleural mesothelioma (FAPME-1),” BMC Cancer, 12:615 (2012). [cited by applicant]
Pinthus et al., “Immuno-gene therapy of established prostate tumors using chimeric receptor-redirected human lymphocytes,” Cancer Res., 63:2470-2476 (2003). [cited by applicant]
Poirot et al., “Multiplex Genome-Edited T-cell Manufacturing Platform for “Off-the-Shelf” Adoptive T-cell Immunotherapies,” Cancer Res., 75(18):3853-3864 (2015). [cited by applicant]
Pollok et al., “Costimulation of transduced T lymphocytes via T cell receptor-CD3 complex and CD28 leads to increased transcription of integrated retrovirus,” Hum. Gene Ther., 10:2221-2236 (1999). [cited by applicant]
Ponomarev et al., “Imaging TCR-dependent NFAT-mediated T-cell activation with positron emission tomography in vivo,” Neoplasia, 3(6):480-488 (2001). [cited by applicant]
Provasi et al., “Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer,” Nat. Med., 18(5):807-815 (2012). [cited by applicant]
Pu et al., “Utility of WT-1, p63, MOC31, mesothelin, and cytokeratin (K903 and CK5/6) immunostains in differentiating adenocarcinoma, squamous cell carcinoma, and malignant mesothelioma in effusions,” Diagn. Cytopathol.… [cited by applicant]
Pule et al., “Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma,” Nat. Med., 14:1264-1270 (2008). [cited by applicant]
Putnam et al., “Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation,” Am. J. Transplant., 13(11):3010-3020 (2013). [cited by applicant]
Putnam et al., “Expansion of Human Regulatory T-Cells From Patients With Type 1 Diabetes,” Diabetes, 58:652-662 (2009). [cited by applicant]
Quinn et al., “T cell activation modulates retrovirus-mediated gene expression,” Hum. Gene Ther., 9:1457-1467 (1998). [cited by applicant]
Rader, “DARTs take aim at BiTEs,” Blood, 117(17):4403-4404 (2011). [cited by applicant]
Rainusso et al., “Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma,” Cancer Gene Ther., 19:212-217 (2012). [cited by applicant]
Rettig et al., “Transduction and selection of human T cells with novel CD34/thymidine kinase chimeric suicide genes for the treatment of graft-versus-host disease,” Mol. Ther., 8:29-41 (2003). [cited by applicant]
Riese et al., “Enhanced effector responses in activated CD8+ T cells deficient in diacylglycerol kinases,” Cancer Res., 73:3566-3577 (2013). [cited by applicant]
Riley et al., “Human T regulatory cell therapy: take a billion or so and call me in the morning,” Immunity, 30:656-665 (2009). [cited by applicant]
Riviere et al., “Effects of retroviral vector design on expression of human adenosine deaminase in murine bone marrow transplant recipients engrafted with genetically modified cells,” Proc. Natl. Acad. Sci. USA, 92:6733… [cited by applicant]
Riviere et al., “Hematopoietic stem cell engineering at a crossroads,” Blood, 119(5):1107-1116 (2012). [cited by applicant]
Rizk et al., “Tissue and serum mesothelin are potential markers of neoplastic progression in Barrett's associated esophageal adenocarcinoma,” Cancer Epidemiol. Biomarkers Prev., 21(3):482-486 (2012). [cited by applicant]
Roe et al., “Mesothelin-related predictive and prognostic factors in malignant mesothelioma: a nested case-control study,” Lung Cancer, 61:235-243 (2008). [cited by applicant]
Rosen et al., “Potential markers that complement expression of CA125 in epithelial ovarian cancer,” Gynecol. Oncol. 99:267-277 (2005). [cited by applicant]
Rosenberg et al., “Gene transfer into humans—immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction,” N. Engl. J. Med., 323:570-578 (1990). [cited by applicant]
Rossig et al., “Targeting of G(D2)-positive tumor cells by human T lymphocytes engineered to express chimeric T-cell receptor genes,” Int. J Cancer, 94:228-236 (2001). [cited by applicant]
Roybal et al., “Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors,” Cell, 167(2):419-432 (2016). [cited by applicant]
Sabatos-Peyton et al., “Antigen-specific immunotherapy of autoimmune and allergic diseases,” Curr. Opin. Immunol., 22(5):609-615 (2010). [cited by applicant]
Sadelain et al., “Efficient retroviral-mediated gene transfer into murine primary lymphocytes,” 8th International Congress of Immunology, Budapest, Hungary, Aug. 23-28, 1992, W-88:542, Absract 34. [cited by applicant]
Sadelain et al., “Targeting Tumours with Genetically Enhanced T Lymphocytes,” Nat. Rev. Cancer, 3:35-45 (2003). [cited by applicant]
Sadelain et al., “The basic principles of chimeric antigen receptor design,” Cancer Discov., 3(4):388-398 (2013). [cited by applicant]
Sadelain et al., “The promise and potential pitfalls of chimeric antigen receptors,” Curr. Opin. Immunol., 21(2):215-223 (2009). [cited by applicant]
Sadelain, “CAR therapy: the CD19 paradigm,” J. Clin. Invest., 125(9):3392-3400 (2015). [cited by applicant]
Sage et al., “PD-1 controls Lymph Node and Blood T Follicular Regulatory Cells,” Nat. Immunol., 14(2):152-161 (2013). [cited by applicant]
Sakuma et al., “Homologous Recombination-Independent Large Gene Cassette Knock-in in CHO Cells Using TALEN and MMEJ-Directed Donor Plasmids,” Int. J. Mol. Sci., 16(10):23849-23866 (2015). [cited by applicant]
Sampson et al., “EGFRVIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss,” Clin. Cancer Res., 20:972-984 (2014). [cited by applicant]
Sanchez et al., “Combining T-cell immunotherapy and anti-androgen therapy for prostate cancer,” Prostate Cancer Prostatic Dis., 16:123-131 (2013). [cited by applicant]
Sather et al., “Efficient modification of CCR5 in primary human hematopoietic cells using a megaTAL nuclease and AAV donor template,” Sci. Transl. Med., 7(307):307ra156 (2015). [cited by applicant]
Scales et al., “An antimesothelin-monomethyl auristatin e conjugate with potent antitumor activity in ovarian, pancreatic, and mesothelioma models,” Mol. Cancer Ther., 13:2630-2640 (2014). [cited by applicant]
Schietinger et al., “Tolerance and exhaustion: defining mechanisms of T cell dysfunction,” Trends Immunol., 35(2):51-60 (2014). [cited by applicant]
Schirrmann et al., “Human natural killer cell line modified with a chimeric immunoglobulin T-cell receptor gene leads to tumor growth inhibition in vivo,” Cancer Gene Ther., 9:390-398 (2002). [cited by applicant]
Schmidt et al., “Eradication of melanomas by targeted elimination of a minor subset of tumor cells,” Proc. Natl. Acad. Sci. U.S.A., 108:2474-2479 (2011). [cited by applicant]
Scholler et al., “Decade-Long Safety and Function of Retroviral-Modified Chimeric Antigen Receptor T-cells,” Sci. Transl. Med., 4:132ra53 (2012). [cited by applicant]
Schroder et al., “HIV-1 integration in the human genome favors active genes and local hotspots,” Cell, 110(4):521-529 (2002). [cited by applicant]
Schrum et al., “Surface T-cell antigen receptor expression and availability for long-term antigenic signaling,” Immunol. Rev., 196:7-24 (2003). [cited by applicant]
Schuberth et al., “Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells,” J. Transl. Med., 11:187 (2013). [cited by applicant]
Seddiki et al., “Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells,” J. Exp. Med., 203:1693-1700 (2006). [cited by applicant]
Servais et al., “Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients,” Clin. Cancer Res., 18(9):2478-2489 (2012… [cited by applicant]
Sharifzadeh et al., “Genetically engineered T cells bearing chimeric nanoconstructed receptors harboring TAG-72-specific camelid single domain antibodies as targeting agents,” Cancer Lett., 334:237-244 (2013). [cited by applicant]
Sharp, “Gene Therapy,” Lancet, 337:1277-1278 (1991). [cited by applicant]
Sharpe et al., “Genetically modified T cells in cancer therapy: opportunities and challenges,” Dis. Model Mech., 8(4):337-350 (2015). [cited by applicant]
Shen et al., “Chimeric antigen receptor containing ICOS signaling domain mediates specific and efficient antitumor effect of T cells against EGFRvIII expressing glioma,” J Hematol. Oncol., 6:33 (2013). [cited by applicant]
Shibaguchi et al., “A fully human chimeric immune receptor for retargeting T-cells to CEA-expressing tumor cells,” Anticancer Res., 26:4067-4072 (2006). [cited by applicant]
Shirasu et al., “Molecular characterization of a fully human chimeric T-cell antigen receptor for tumor-associated antigen EpCAM.,” J Biomed. Biotechnol., 2012:ID853879 (2012). [cited by applicant]
Singh et al., “Nature of tumor control by permanently and transiently modified GD2 chimeric antigen receptor T cells in xenograft models of neuroblastoma,” Cancer Immunol. Res., 2:1059-1070 (2014). [cited by applicant]
Sommermeyer et al., “Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo,” Leukemia, 30(2):492-500 (2016). [cited by applicant]
Song et al., “A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity,” Oncotarget, 6(25):21533-21546 (2015). [cited by applicant]
Song et al., Chimeric NKG2D CAR-expressing T cell-mediated attack of human ovarian cancer is enhanced by histone deacetylase inhibition Hum. Gene Ther., 24:295-305 (2013). [cited by applicant]
Song et al., “In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB),” Cancer Res., 71:4617-4627 (2011). [cited by applicant]
Sontheimer, “The Bacterial Origins of the CRISPR Genome-Editing Revolution,” Hum. Gene Ther., 26(7):413-424 (2015). [cited by applicant]
Stancovski et al., “Targeting of T lymphocytes to Neu/HER2-expressing cells using chimeric single chain Fv receptors,” J Immunol., 151:6577-6582 (1993). [cited by applicant]
Stastny et al., “Medulloblastomas expressing IL13Ralpha2 are targets for IL 13-zetakine+ cytolytic T cells,” J Pediatr. Hematol. Oncol., 29:669-677 (2007). [cited by applicant]
Su et al., “Human CD4+CD25 high CD127 low/neg Regulatory T Cells,” Methods Mol. Biol., 806:287-299 (2012). [cited by applicant]
Sun et al., “Construction and evaluation of a novel humanized HER2-specific chimeric receptor,” Breast Cancer Res., 16:R61 (2014). [cited by applicant]
Swierczynski et al., “Analysis of novel tumor markers in pancreatic and biliary carcinomas using tissue microarrays,” Hum. Pathol., 35:357-366 (2004). [cited by applicant]
Szymczak et al., “Development of 2A peptide-based strategies in the design of multicistronic vectors,” Expert Opin. Biol. Therapy, 5(5):627-638 (2005). [cited by applicant]
Tan et al., “Mesothelin (MSLN) promoter is hypomethylated in malignant mesothelioma, but its expression is not associated with methylation status of the promoter,” Hum. Pathol.,41:1330-1338 (2010). [cited by applicant]
Tang et al., “T cells expressing a LMP1-specific chimeric antigen receptor mediate antitumor effects against LMP1-positive nasopharyngeal carcinoma cells in vitro and in vivo,” J Biomed. Res., 28:468-475 (2014). [cited by applicant]
Tchou et al., “Mesothelin, a novel immunotherapy target for triple negative breast cancer,” Breast Cancer Res. Treat., 133:799-804 (2012). [cited by applicant]
Tey, “Adoptive T-cell therapy: adverse events and safety switches,” Clin. Transl. Immunology, 3(6):e17 (2014). [cited by applicant]
Themeli et al., “Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy,” Nat. Biotechnol., 31(10):928-933 (2013). [cited by applicant]
Tollefson et al., “Inhibition of TRAIL-Induced Apoptosis and Forced Internalization of TRAIL Receptor 1 by Adenovirus Proteins,” J. Virol., 75(19):8875-8887 (2001). [cited by applicant]
Tolstoshev et al., “Gene expression using retroviral vectors,” Current Opin. Biotechnol., 1:55-61 (1990). [cited by applicant]
Torikai et al., “A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR,” Blood, 119(24):5697-5705 (2012… [cited by applicant]
Torikai et al., “Toward eliminating HLA class I expression to generate universal cells from allogeneic donors,” Blood, 122(8):1341-1349 (2013). [cited by applicant]
Tozbikian et al., “Mesothelin expression in triple negative breast carcinomas correlates significantly with basal-like phenotype, distant metastases and decreased survival,” PLoS One, 9(12):e114900 (2014). [cited by applicant]
Tsai et al., “Defining and improving the genome-wide specificities of CRISPR-Cas9 nucleases,” Nat. Rev. Genet., 17(5):300-312 (2016). [cited by applicant]
Ukena et al., “Isolation strategies of regulatory T cells for clinical trials: Phenotype, function, stability, and expansion capacity,” Exp. HEmatol., 39:1152-1160 (2011). [cited by applicant]
Van Lent et al., “Functional human antigen-specific T cells produced in vitro using retroviral T cell receptor transfer into hematopoietic progenitors,” J. Immunol., 179:4959-4968 (2007). [cited by applicant]
Vasileva et al., “Genome-editing tools for stem cell biology,” Cell Death Dis., 6:e1831 (2015). [cited by applicant]
Von Heijne, “Signal sequences. The limits of variation,” J. Mol. Biol., 184(1):99-105 (1985). [cited by applicant]
Von Kalle et al., “Vector integration and tumorigenesis,” Hum. Gene Ther., 25(6):475-481 (2014). [cited by applicant]
Wang et al., “Clinical manufacturing of CAR T cells: foundation of a promising therapy,” Mol. Ther. Oncolytics, 3:16015 (2016). [cited by applicant]
Wang et al., “Clinicopathological significance of mesothelin expression in invasive breast cancer,” J Int. Med. Res., 40:909-916 (2012). [cited by applicant]
Wang et al., “Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors,” Cancer Immunol. Res., 3:815-826 (2015). [cited by applicant]