Granted Patent
B2
US 12,291,722 · App. 15/306,729 · Granted May 6, 2025
Methods for manufacturing adoptive cell therapies
Inventors:
Richard Morgan (Center Harbor, NH); Kevin Friedman (Medford, MA); Dawn Maier (North Reading, MA)
Assignee:
2seventy bio, Inc.
C12N5/0636A61K38/177A61K39/4611A61K39/4631A61K39/464412A61K39/464417C12N7/00C12N15/86A61K2035/124C07K2319/00C12N2501/2301C12N2501/998C12N2740/10043C12N2740/15043C12N2799/021C12N2799/027C12N2810/855
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Abstract
The invention provides compositions and methods for manufacturing adoptive cell therapies. In particular embodiments, the invention provides methods of harvesting populations of cells, isolating and activating PBMCs, expanding T cells, and administering the T cell therapeutic to a subject in need thereof.
Claims (45)
1. A method for manufacturing a human T cell therapeutic for a subject comprising:
a) obtaining a population of human peripheral blood mononuclear cells (PBMCs) from the subject, wherein the PBMCs comprise CD4+ T cells, CD8+ T cells, and antigen presenting cells (APCs);
b) culturing the population of PBMCs of step a) for about 20 hours to about 24 hours prior to transduction in a cell culture medium comprising i) one or more cytokines, ii) a soluble anti-CD3 antibody or CD3-binding fragment thereof, and iii) a soluble anti-CD28 antibody or a CD28-binding fragment thereof, thereby producing activated T cells;
c) transducing the population of PBMCs of step b) comprising activated T cells with a lentiviral vector comprising a polynucleotide encoding an anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR), thereby producing transduced T cells; and
d) culturing the population of PBMCs of step c) in a cell growth medium to expand the number of the transduced T cells,
thereby manufacturing the human T cell therapeutic for the subject.
2. The method of claim 1 , wherein obtaining the population of PBMCs comprises leukapheresis.
3. The method of claim 1 , wherein obtaining the population of PBMCs of step a) comprises sedimentation.
4. The method of claim 3 , wherein the sedimentation comprises a density gradient.
5. The method of claim 3 , wherein the sedimentation is performed using a semiautomated flowthrough centrifuge or a counter-flow centrifugal elutriation device.
6. The method of claim 1 , further comprising washing the population of PBMCs of any one or more of steps (a), (b), (c), or (d), in a buffer or cell culture medium.
7. The method of claim 6 , wherein the population of PBMCs are washed in T cell growth medium (TCGM) containing one or more cytokines.
8. The method of claim 7 , wherein the one or more cytokines in the TCGM are selected from the group consisting of: IL-2, IL-7, IL-15, IL-9, and IL-21.
9. The method of claim 8 , wherein the cytokine is IL-2.
10. The method of claim 9 , wherein the concentration of IL-2 is about 250 IU/mL.
11. The method of claim 1 , wherein the population of PBMCs of step (a) is cryopreserved in a controlled rate freezer.
12. The method of claim 11 , wherein the cryopreserved population of PBMCs is thawed.
13. The method of claim 1 , wherein the population of PBMCs is seeded for culturing in step (b) in TCGM at a density of about 1×10 6 cells/mL.
14. The method of claim 13 , wherein the TCGM comprises one or more cytokines selected from the group consisting of: IL-2, IL-7, IL-15, IL-9, and IL-21.
15. The method of claim 14 , wherein the one or more cytokines are selected from the group consisting of: IL-2, IL-7, and IL-15.
16. The method of claim 14 , wherein the one or more cytokines comprise IL-2.
17. The method of claim 14 , wherein the concentration of the one or more cytokines is about 250 IU/mL.
18. The method of claim 13 , wherein about 1×10 9 transducing units (TU) to about 2×10 9 TU of the lentiviral vector are used to transduce 1×10 8 seeded cells.
19. The method of claim 1 , wherein steps (b)-(d) are in a cell culture bag or a bioreactor.
20. The method of claim 1 , wherein the concentration of the anti-CD3 antibody is about 50 ng/mL.
21. The method of claim 1 , wherein the concentration of the anti-CD28 antibody is about 50 ng/mL.
22. The method of claim 1 , wherein the lentiviral vector is diluted to 20% v/v of the total culture volume.
23. The method of claim 1 , wherein the lentiviral vector is diluted to about 40% to about 50% v/v of the total culture volume.
24. The method of claim 1 , wherein the population of PBMCs of step (c) is transduced for about 18 to about 48 hours.
25. The method of claim 1 , wherein the population of PBMCs of step (c) is transduced for about 18 to about 36 hours.
26. The method of claim 1 , wherein the population of PBMCs of step (c) is transduced for about 24 hours.
27. The method of claim 1 , wherein the number of transduced T cells is expanded at least 50-fold or at least 100-fold during the culture of step d).
28. The method of claim 1 , wherein the number of transduced T cells is expanded at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, or at least 600-fold, during the culture of step d).
29. The method of claim 1 , wherein the one or more cytokines in the cell culture medium of step (b) is IL-2.
30. The method of claim 1 , wherein the PBMCs further comprise natural killer (NK) cells, B cells, monocytes and dendritic cells.
31. A method for manufacturing a human T cell therapeutic comprising:
a) providing a population of autologous human peripheral blood mononuclear cells (PBMCs) comprising CD4+ T cells, CD8+ T cells, and antigen presenting cells (APCs);
b) culturing the population of PBMCs of step a) for about 20 hours to about 24 hours prior to transduction in a cell culture medium comprising i) one or more cytokines, ii) a soluble anti-CD3 antibody or CD3-binding fragment thereof, and iii) a soluble anti-CD28 antibody or a CD28-binding fragment thereof, thereby producing activated T cells;
c) transducing the population of PBMCs of step b) comprising activated T cells with a lentiviral vector comprising a polynucleotide encoding an anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR), thereby producing transduced T cells; and
d) culturing the population of PBMCs of step c) in a cell growth medium to expand the number of the transduced T cells,
thereby manufacturing the human T cell therapeutic.
32. The method of claim 31 , wherein the population of autologous human PBMCs is obtained from whole blood.
33. The method of claim 32 , wherein the whole blood is processed by leukapheresis to obtain the autologous human PBMCs.
34. The method of claim 31 , wherein the one or more cytokines in the cell culture medium of step (b) is IL-2.
35. The method of claim 31 , wherein the PBMCs further comprise natural killer (NK) cells, B cells, monocytes and dendritic cells.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Sep 14, 2021
From: BLUEBIRD BIO, INC.
To: 2SEVENTY BIO, INC.
Reel/Frame 057683/0099 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 16, 2018
From: MORGAN, RICHARD; FRIEDMAN, KEVIN; MAIER, DAWN
To: BLUEBIRD BIO, INC.
Reel/Frame 045257/0775 →
Continuity (2)
Provisional Application
61984558
· Apr 25, 2014
References Cited (400)
US 5585089A
· Queen et al.
· 1996
[cited by applicant]
US 5827642A
· Riddell et al.
· 1998
[cited by applicant]
US 5858358A
· June et al.
· 1999
[cited by applicant]
US 5883223A
· Gray
· 1999
[cited by applicant]
US 5994136A
· Naldini et al.
· 1999
[cited by applicant]
US 6005079A
· Casterman et al.
· 1999
[cited by applicant]
US 6013516A
· Verma et al.
· 2000
[cited by applicant]
US 6040177A
· Riddell et al.
· 2000
[cited by applicant]
US 6352694B1
· June et al.
· 2002
[cited by applicant]
US 6534055B1
· June et al.
· 2003
[cited by applicant]
US 6682907B1
· Charneau et al.
· 2004
[cited by applicant]
US 6692964B1
· June et al.
· 2004
[cited by applicant]
US 6797514B2
· Berenson et al.
· 2004
[cited by applicant]
US 6867041B2
· Berenson et al.
· 2005
[cited by applicant]
US 6887466B2
· June et al.
· 2005
[cited by applicant]
US 6905680B2
· June et al.
· 2005
[cited by applicant]
US 6905681B1
· June et al.
· 2005
[cited by applicant]
US 6905874B2
· Berenson et al.
· 2005
[cited by applicant]
US 7067318B2
· June et al.
· 2006
[cited by applicant]
US 7144575B2
· June et al.
· 2006
[cited by applicant]
US 7172869B2
· June et al.
· 2007
[cited by applicant]
US 7175843B2
· June et al.
· 2007
[cited by applicant]
US 7232566B2
· June et al.
· 2007
[cited by applicant]
US 7754482B2
· Riley et al.
· 2010
[cited by applicant]
US 7977095B2
· Bonyhadi
· 2011
[cited by examiner]
US 9034324B2
· Kalled et al.
· 2015
[cited by applicant]
US 9402865B2
· Powell et al.
· 2016
[cited by applicant]
US 9499629B2
· June et al.
· 2016
[cited by applicant]
US 9765342B2
· Kochenderfer
· 2017
[cited by applicant]
US 20020177125A1
· Kamb
· 2002
[cited by examiner]
US 20030012783A1
· Kindsvogel
· 2003
[cited by applicant]
US 20080274091A1
· Slepushkin
· 2008
[cited by examiner]
US 20130280220A1
· Ahmed
· 2013
[cited by examiner]
US 20140086889A1
· Battaglia et al.
· 2014
[cited by applicant]
US 20170049819A1
· Friedman et al.
· 2017
[cited by applicant]
US 20170226216A1
· Morgan et al.
· 2017
[cited by applicant]
US 20180147271A1
· Morgan et al.
· 2018
[cited by applicant]
US 20210032658A1
· Morgan et al.
· 2021
[cited by applicant]
AU 2013204923A1
· 2014
[cited by applicant]
CN 103442768A
· 2013
[cited by applicant]
EP 0324154A2
· 1989
[cited by applicant]
EP 0404097A2
· 1990
[cited by applicant]
EP 2094837A2
· 2009
[cited by applicant]
JP 2012501180
· 2012
[cited by applicant]
JP 2013522286
· 2013
[cited by applicant]
JP 2015513399A
· 2015
[cited by applicant]
JP 2017513891A
· 2017
[cited by applicant]
JP 2020015767A
· 2020
[cited by applicant]
JP 6671370B2
· 2020
[cited by applicant]
RU 2477728C1
· 2013
[cited by applicant]
WO WO1993001161A1
· 1993
[cited by applicant]
WO WO1994004678A1
· 1994
[cited by applicant]
WO WO1994025591A1
· 1994
[cited by applicant]
WO WO1995028407
· 1995
[cited by applicant]
WO WO1997032970A1
· 1997
[cited by applicant]
WO WO2003057171A2
· 2003
[cited by applicant]
WO WO2004035768A1
· 2004
[cited by applicant]
WO WO2004104185A1
· 2004
[cited by applicant]
WO WO2006010834A1
· 2006
[cited by applicant]
WO WO2006090291A2
· 2006
[cited by applicant]
WO WO2007018318A1
· 2007
[cited by applicant]
WO WO2008153742A2
· 2008
[cited by applicant]
WO WO2009058564A2
· 2009
[cited by applicant]
WO WO2009091826A2
· 2009
[cited by applicant]
WO WO2010104949A2
· 2010
[cited by applicant]
WO WO2011041093A1
· 2011
[cited by applicant]
WO WO2011057124A1
· 2011
[cited by applicant]
WO WO2011114275A1
· 2011
[cited by applicant]
WO WO2012079000A1
· 2012
[cited by applicant]
WO WO2012099973A2
· 2012
[cited by applicant]
WO WO2012129514A1
· 2012
[cited by applicant]
WO WO2012140130A1
· 2012
[cited by applicant]
WO WO2012163805A1
· 2012
[cited by applicant]
WO WO2012170911A2
· 2012
[cited by applicant]
WO WO2013070468A1
· 2013
[cited by applicant]
WO WO2013126712A1
· 2013
[cited by applicant]
WO WO2013154760A1
· 2013
[cited by examiner]
WO WO2014011996A1
· 2014
[cited by applicant]
WO WO2014031687A1
· 2014
[cited by applicant]
WO WO2014039523A1
· 2014
[cited by applicant]
WO WO2014048920A1
· 2014
[cited by applicant]
WO WO2014055442A1
· 2014
[cited by applicant]
WO WO2014055668A1
· 2014
[cited by applicant]
WO WO2014055771A1
· 2014
[cited by applicant]
WO WO2014059173A2
· 2014
[cited by applicant]
WO WO2014089335A2
· 2014
[cited by applicant]
WO WO2014099671A1
· 2014
[cited by applicant]
WO WO2014100385A1
· 2014
[cited by applicant]
WO WO2014130635A1
· 2014
[cited by applicant]
WO WO2015120096A2
· 2015
[cited by applicant]
WO WO2015123527A1
· 2015
[cited by applicant]
WO WO2015158671A1
· 2015
[cited by applicant]
WO WO2015164739A1
· 2015
[cited by applicant]
WO WO2015164745A1
· 2015
[cited by applicant]
WO WO2015164759A2
· 2015
[cited by applicant]
WO WO2015188119A1
· 2015
[cited by applicant]
WO WO2016014789A2
· 2016
[cited by applicant]
WO WO2016094304A2
· 2016
[cited by applicant]
WO WO2016164429A1
· 2016
[cited by applicant]
WO WO2017099712A1
· 2017
[cited by applicant]
WO WO2021109977A1
· 2021
[cited by applicant]
“Proleukin For Injection (Chiron)” 2000. 14 pages, downloaded from https://theodora.com/drugs/proleukin_for_injection_chiron.html on Apr. 28, 2018.
[cited by examiner]
Mallone et al. Isolation and Preservation of Peripheral Blood Mononuclear Cells for Analysis of Islet Antigen-Reactive T Cell Responses: Position Statement of the T-Cell Workshop Committee of the Immunology of Diabetes …
[cited by examiner]
Ledbetter et al. CD28 Ligation in T-Cell Activation: Evidence for Two Signal Transduction Pathways. Blood, 1990. 7(1):1531-1539.
[cited by examiner]
Vidan et al. Functional Integrity of the CD28 Co-Stimulatory Pathway in T Lymphocytes from Elderly Subjects. Age and Ageing, 1999. 28: 221-227.
[cited by examiner]
Wikipedia entry for White Blood Cell. Retrieved from the internet Sep. 26, 2023. https://en.wikipedia.org/wiki/White_blood_cell.
[cited by examiner]
The Reprocell Blog. Protocol for buffy coat preparation from whole blood. Retrieved from the internet Sep. 26, 2023. https://www.reprocell.com/blog/biopta/buffy-coat-preparation-from-whole-blood.
[cited by examiner]
The Reprocell Blog. Protocol for PBMC isolation from buffy coat samples. Retrieved from the internet Sep. 26, 2023. https://www.reprocell.com/blog/biopta/pbmc-isolation-from-buffy-coat-samples.
[cited by examiner]
Parel, et a. CD4+ CD8+ Double Positive (DP) T Cells in Health and Disease. Autoimmunity Reviews, 2004. (3)215-220.
[cited by examiner]
Alt and Caselmann. “Liver-directed gene therapy: molecular tools and current preclinical and clinical studies”, Journal of Hepatology (1995); 23: 746-758.
[cited by applicant]
Asheuer, M. et al., “Human CD34+Cells Differentiate into Microglia and Express Recombinant Therapeutic Protein”, Proceedings of the National Academy of Sciences USA (2004); 101.10: 3557-3562.
[cited by applicant]
Avery, Danielle T., et al. “BAFF selectively enhances the survival of plasmablasts generated from human memory B cells.” The Journal of Clinical Investigation (2003); 112.2: 286-297.
[cited by applicant]
Battaglia et al., “Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells”, Blood (2005); 105(12): 4743-4748.
[cited by applicant]
Bellucci, Roberto, et al. “Graft-versus-tumor response in patients with multiple myeloma is associated with antibody response to BCMA, a plasma-cell membrane receptor.” Blood (2005); 105.10: 3945-3950.
[cited by applicant]
Bird, Robert E., et al. “Single-chain antigen-binding proteins.” Science (1988); 242.4877: 423-427.
[cited by applicant]
Borden and Kabat, “Nucleotide sequence of the cDNAs encoding the variable region heavy and light chains of a myeloma protein specific for the terminal nonreducing end of alpha(1----6)dextran”, Proc Natl Acad Sci U S A (…
[cited by applicant]
Brody and Crystal, “Adenovirus-mediated in vivo gene transfer”, Ann. N. Y. Acad. Sci. (1994); 716: 90-101; discussion 101-3.
[cited by applicant]
Carell, Thomas, et al. “A novel procedure for the synthesis of libraries containing small organic molecules.” Angewandte Chemie International Edition in English (1994); 33.20: 2059-2061.
[cited by applicant]
Carell, Thomas, et al. “A Solution-Phase Screening Procedure for the Isolation of Active Compounds from a Library of Molecules.” Angewandte Chemie International Edition in English (1994); 33.20: 2061-2064.
[cited by applicant]
Carpenito, Carmine, et al. “Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains.” Proceedings of the National Academy of Sciences USA (2009); 106.9:…
[cited by applicant]
Carpenter, Robert O., et al. “B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma.” Clinical Cancer Research (2013); 19.8: 2048-2060.
[cited by applicant]
Challita, P. et al., “Multiple modifications in cis elements of the long terminal repeat of retroviral vectors lead to increased expression and decreased DNA methylation in embryonic carcinoma cells.” J Virol. (1995); 6…
[cited by applicant]
Chan, W.K., et al. “Chimeric antigen receptor-redirected CD45RA-negative T cells have potent antileukemia and pathogen memory response without graft-versus-host activity.” Leukemia (2015); 29(2): 387-395 (2015).
[cited by applicant]
Chaudhary, Vuay K., et al. “A rapid method of cloning functional variable-region antibody genes in
[cited by applicant]
Chiu, April, et al. “Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to Baff and April.” Blood (2007); 109.2: 729-739.
[cited by applicant]
Cho, Charles Y., et al. “An unnatural biopolymer.” Science (1993); 261: 1303-1304.
[cited by applicant]
Chothia and Lesk, “Canonical structures for the hypervariable regions of immunoglobulins”, J Mol Biol (1987); 196(4): 901-917.
[cited by applicant]
Chothia, C. et al., “Conformations of immunoglobulin hypervariable regions”, Nature (1989); 342(6252):877-883.
[cited by applicant]
Clever, J. et al., “RNA Secondary Structure and Binding Sites for gag Gene Products in the 5′ Packaging Signal of Human Immunodeficiency Virus Type 1.” J. of Virology (1995); 69(4): 2101-2109.
[cited by applicant]
Cooper, Laurence JN, et al. “T-cell clones can be rendered specific for CD19: Toward the selective augmentation of the graft-versus-B-lineage leukemia effect.” Blood (2003); 101.4: 1637-1644.
[cited by applicant]
Cribbs, A.P., et al., “Simplified production and concentration of lentiviral vectors to achieve high transduction in primary human T cells.” BMC Biotechnology (2013); 13(1): 98.
[cited by applicant]
Cullen and Greene, “Regulatory Pathways Governing HIV-1 Replication”, Cell (1989); 58: 423-426.
[cited by applicant]
Cullen, B.R., “Human Immunodeficiency Virus as a Prototypic Complex Retrovirus”, Journal of Virology (1991); 65(3): 1053-1056.
[cited by applicant]
De Felipe, Pablo, and Ryan, Martin D. “Targeting of proteins derived from self-processing polyproteins containing multiple signal sequences.” Traffic (2004); 5.8: 616-626.
[cited by applicant]
De Oliveira, S.N., et al. “Modification of Hematopoietic Stem/Progenitor Cells with CD19-Specific Chimeric Antigen Receptors as a Novel Approach for Cancer Immunotherapy.” Human Gene Therapy (2013); 24(10): 824-839.
[cited by applicant]
De-Gang, S., 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 Research (2011), 71(13): 4617-4627.
[cited by applicant]
Desjarlais, John R., and Berg, Jeremy M. “Length-encoded multiplex binding site determination: application to zinc finger proteins.” Proceedings of the National Academy of Sciences (1994); 91.23: 11099-11103.
[cited by applicant]
Desjarlais, John R., and Berg, Jeremy M. “Use of a zinc-finger consensus sequence framework and specificity rules to design specific DNA binding proteins.” Proceedings of the National Academy of Sciences (1993); 90.6: 2…
[cited by applicant]
DeWitt, S. Hobbs, et al. “Diversomers”: An approach to nonpeptide, nonoligomeric chemical diversity. Proceedings of the National Academy of Sciences USA (1993); 90.15: 6909-6913.
[cited by applicant]
Donnelly, M. et al., “The ‘cleavage’ activities of foot-and-mouth disease virus 2A site-directed mutants and naturally occurring ‘2A-like’ sequences.” J Gen Virol. (2001); 82 (Pt 5): 1027-1041.
[cited by applicant]
Dull et al., “A third-generation lentivirus vector with a conditional packaging system”, Journal of Virology (1998); 72(11): 8463-8671.
[cited by applicant]
European Application No. EP 15783117.3, Extended European Search Report dated Aug. 22, 2017, 8 pages.
[cited by applicant]
European Application No. EP 15783862.4, Extended European Search Report dated Sep. 22, 2017, 7 pages.
[cited by applicant]
European Application No. EP 15802488.5, Third Party Observation dated Oct. 17, 2017, 3 pages.
[cited by applicant]
European Application No. EP 15782739.5, Extended European Search Report dated Nov. 9, 2017, 11 pages.
[cited by applicant]
Ferry and Heard, “Liver-directed gene transfer vectors”, Hum Gene Ther. (1998); 9(14): 1975-1981.
[cited by applicant]
Gallop, Mark A., et al. “Applications of combinatorial technologies to drug discovery. 1. Background and peptide combinatorial libraries.” Journal of Medicinal Chemistry (1994); 37.9: 1233-1251.
[cited by applicant]
Garland, R. J., et al. “The use of Teflon cell culture bags to expand functionally active CD8+ cytotoxic T lymphocytes.” Journal of Immunological Methods (1999); 227.1: 53-63.
[cited by applicant]
Gattinoni, L., et al., “Adoptive immunotherapy for cancer: building on success.” Nat Rev Immunol (2006); 6(5): 383-393, 25 pages.
[cited by applicant]
GenBank Accession Reference # L09137.2, “Cloning vector pUC19c”, Apr. 27, 1993, 3 pages.
[cited by applicant]
Giannoni, F., et al., “Allelic Exclusion and Peripheral Reconstitution by TCR Transgenic T Cells Arising From Transduced Human Hematopoietic Stem/Progenitor Cells.” Molecular Therapy (2013); 21(5): 1044-1054.
[cited by applicant]
Guertin, David A., and Sabatini, David M. “Defining the role of mTOR in cancer.” Cancer Cell (2007); 12.1: 9-22.
[cited by applicant]
Haanen, John B.A.G., et al. “Selective expansion of cross-reactive CD8+ memory T cells by viral variants.” Journal of Experimental Medicine (1999); 190.9: 1319-1328.
[cited by applicant]
Holliger, Philipp, et al. “Diabodies”: small bivalent and bispecific antibody fragments. Proceedings of the National Academy of Sciences (1993); 90.14: 6444-6448.
[cited by applicant]
Holt, L. et al., “Domain antibodies: proteins for therapy”, Trends in Biotechnology (2003); 21(11): 484-490.
[cited by applicant]
Huang and Yen, “Role of the hepatitis B virus posttranscriptional regulatory element in export of intronless transcripts”, Molecular and Cellular Biology (1995); 15(7): 3864-3869.
[cited by applicant]
Hudson, Peter J., and Souriau, Christelle. “Engineered antibodies.” Nature medicine 9.1 (2003): 129-134.
[cited by applicant]
Imren, S. et al., “High-level beta-globin expression and preferred intragenic integration after lentiviral transduction of human cord blood stem cells”, J Clin Invest (2004); 114(7): 953-962.
[cited by applicant]
International Application No. PCT/US2015/041722, International Preliminary Report on Patentability dated Jan. 24, 2017, 7 pages.
[cited by applicant]
International Preliminary Report on Patentability for International Application No. PCT/US2015/027510, dated Oct. 25, 2016, 6 pages.
[cited by applicant]
International Preliminary Report on Patentability for International Application No. PCT/US2015/027518, dated Oct. 25, 2016, 6 pages.
[cited by applicant]
International Preliminary Report on Patentability for International Application No. PCT/US2015/027539, dated Oct. 25, 2016, 6 pages.
[cited by applicant]
International Preliminary Report on Patentability for International Application No. PCT/US2015/034515, dated Dec. 5, 2016, 10 pages.
[cited by applicant]
International Preliminary Report on Patentability for International Application No. PCT/US2015/064269, dated Jun. 22, 2017, 6 pages.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2015/027510, dated Jul. 30, 2015, 10 pages.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2015/027518, dated Jul. 30, 2015, 9 pages.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2015/027539, dated Nov. 2, 2015, 6 pages.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2015/034515, dated Sep. 14, 2015, 12 pages.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2015/041722, dated Jan. 6, 2016, 11 pages.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2015/064269, dated Feb. 23, 2016, 9 pages.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2015/064270, dated Feb. 11, 2016, 11 pages.
[cited by applicant]
Irion, Stefan, et al. “Identification and targeting of the ROSA26 locus in human embryonic stem cells.” Nature Biotechnology (2007); 25.12: 1477-1482.
[cited by applicant]
Kalled, Susan L. “The role of BAFF in immune function and implications for autoimmunity.” Immunological Reviews (2005); 204.1: 43-54.
[cited by applicant]
Kay, M. A., “Adenoviral Vectors for Hepatic Gene Transfer in Animals.” Chest (1997); 111: 138S-142S.
[cited by applicant]
Kim, Yang-Gyun, et al. “Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain.” Proceedings of the National Academy of Sciences (1996); 93.3: 1156-1160.
[cited by applicant]
Kochenderfer, J.N., et al. “Adoptive Transfer Of Syngeneic T Cells Transduced With A Chimeric Antigen Receptor That Recognizes Murine CD19 Can Eradicate Lymphoma And Normal B Cells.” Blood (2010); 16(19): 3875-3886; Gen…
[cited by applicant]
Koch-Nolte, F., “Single domain antibodies from llama effectively and specifically block T cell ecto-ADP-ribosyltransferase ART2.2 in vivo”, Faseb J (2007); 21(13):3490-3498.
[cited by applicant]
Koldej, R.M., et al., “Comparison of Insulators and Promoters for Expression of the Wiskott-Aldrich Syndrome Protein Using Lentiviral Vectors” Human Gene Therapy Clinical Development (2013); 24: 77-85.
[cited by applicant]
Kozak, M., “An analysis of 5′-noncoding sequences from 699 vertebrate messenger RNAs”, Nucleic Acids Res. (1987); 15(20): 8125-8148.
[cited by applicant]
Kozak, M., “Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes”, Cell (1986); 44(2): 283-292.
[cited by applicant]
Kutner et al., “Production, concentration and titration of pseudotyped HIV-1-based lentiviral vectors”, Nature Protocols (2009); 4: 495-505.
[cited by applicant]
Laabi, Y., et al. “A new gene, BCM, on chromosome 16 is fused to the interleukin 2 gene by at (4; 16)(q26; p13) translocation in a malignant T cell lymphoma.” The EMBO Journal (1992); 11.11: 3897-3904.
[cited by applicant]
Laabi, Yacine, et al. “The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectionally transcribed.” Nucleic Acids Research (1994); 22.7: 1147-1154.
[cited by applicant]
Landau and Littman. “Packaging system for rapid production of murine leukemia virus vectors with variable tropism.” Journal of Virology (1992); 66.8: 5110-5113.
[cited by applicant]
Larson, S.M., et al. “Anti-CD19 chimeric antigen receptor controlled by the suicide gene HSVsr39TK in hematopoietic stem cells for immunotherapy of B-lineage malignancies.” Blood (2013); 122(21): 1659.
[cited by applicant]
Lee, H. C. et al., “Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue”, Nature (2000); 408(6811): 483-488.
[cited by applicant]
Levitt, “Definition of an efficient synthetic poly(A) site”, Genes & Development (1989); 3: 1019-1025.
[cited by applicant]
Liu, Lin, et al., “Adoptive T-cell therapy of B-cell malignancies: Conventional and physiological chimeric antigen receptors.” Cancer Letters (2012); 316(1): 1-5.
[cited by applicant]
Liu and Mertz, “HnRNP L binds a cis-acting RNA sequence element that enables intron-dependent gene expression.” Genes & Dev. (1995); 9: 1766-1780.
[cited by applicant]
Liu, Pixu, et al. “Targeting the phosphoinositide 3-kinase pathway in cancer.” Nature Reviews Drug Discovery (2009); 8.8: 627-644.
[cited by applicant]
Liu, Qiang, et al. “Design of polydactyl zinc-finger proteins for unique addressing within complex genomes.” Proceedings of the National Academy of Sciences (1997);94.11: 5525-5530.
[cited by applicant]
Lovelock and Bishop, “Prevention of freezing damage to living cells by dimethyl sulphoxide”, Nature (1959); 183(4672): 1394-1395.
[cited by applicant]
Mackay, Fabienne, et al. “BAFF and APRIL: a tutorial on B cell survival.” Annual Review of Immunology (2003); 21.1: 231-264.
[cited by applicant]
Maier, Dawn, et al., “Development of a Simple and Robust Closed System Manufacturing Platform for T Cells Engineered With Chimeric Antigen Receptor (CAR) for Adoptive Immunotherapy.” Molecular Therapy (2014); Supplement…
[cited by applicant]
Maldarelli et al., “Identification of posttranscriptionally active inhibitory sequences in human immunodeficiency virus type 1 RNA: novel level of gene regulation”, Journal of Virology (1991); 65(11): 5732-5743.
[cited by applicant]
Malim et al., “Immunodeficiency virus rev trans-activator modulates the expression of the viral regulatory genes”, Nature (1988); 335: 181-183.
[cited by applicant]
Meuer, Stefan C., et al. “An alternative pathway of T-cell activation: a functional role for the 50 kd T11 sheep erythrocyte receptor protein.” Cell (1984); 36.4: 897-906.
[cited by applicant]
Miller, A.D., “Human gene therapy comes of age.” Nature (1992); 357: 455-460.
[cited by applicant]
Milone, M. et al., “Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo”, Molecular Therapy (2009); 17(8):1453-1464.
[cited by applicant]
Moreaux, Jérôme, et al. “BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone.” Blood (2004); 103.8: 3148-3157.
[cited by applicant]
Naldini L. et al., “Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector”, Proc Natl Acad Sci USA (1996); 93(21): 11382-11388.
[cited by applicant]
Naldini, L. et al., “In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector”, Science (1996); 272(5259): 263-267.
[cited by applicant]
Naldini, L., “Lentiviruses as gene transfer agents for delivery to non-dividing cells”, Curr Opin Biotechnol. (1998); 5: 457-63.
[cited by applicant]
Neri, Paola, et al. “Neutralizing B-Cell-Activating Factor Antibody Improves Survival and Inhibits Osteoclastogenesis in a Severe Combined Immunodeficient Human Multiple Myeloma Model.” Clinical Cancer Research (2007); …
[cited by applicant]
Ng et al., “B Cell-Activating Factor Belonging to the TNF Family (BAFF)-R Is the Principal BAFF Receptor Facilitating BAFF Costimulation of Circulating T and B Cells.” Journal of Immunology (2004); 173(2): 807-817.
[cited by applicant]
Novak, Anne J., et al. “Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival.” Blood (2004); 103.2: 689-694.
[cited by applicant]
O'Connor, Brian P., et al. “BCMA is essential for the survival of long-lived bone marrow plasma cells.” Journal of Experimental Medicine (2004); 199.1: 91-98.
[cited by applicant]
Oka, K. et al., “Recent advances in liver-directed gene therapy: implications for the treatment of dyslipidemia”, Curr Opin Lipidol. (2000); 11(2): 179-186.
[cited by applicant]
Orlandi, R. et al., “Cloning immunoglobulin variable domains for expression by the polymerase chain reaction”, Proc Natl Acad Sci USA (1989); 86(10):3833-3737.
[cited by applicant]
Patel, S. et al., “Impact of chimeric immune receptor extracellular protein domains on T cell function.” Gene Ther (1999); 6(3): 412-419.
[cited by applicant]
Plückthun, A. “Antibodies from
[cited by applicant]
Pomerantz, Joel L., et al. “Structure-based design of transcription factors.” Science (1995); 267.5194: 93-96.
[cited by applicant]
Riechmann and Muyldermans, “Single domain antibodies: comparison of camel VH and camelised human VH domains”, J Immunol Methods (1999); 231(1-2):25-38.
[cited by applicant]
Ruella, M. and Kalos, M. “Adoptive immunotherapy for cancer.” Immunological Reviews (2014); 257(1): 14-38.
[cited by applicant]
Ryan, M. et al., “Virus-encoded proteinases of the picornavirus super-group.” J Gen Virol. (1997); 78 (Pt 4): 699-723.
[cited by applicant]
Sanchez, Eric, et al. “Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival.” British Journal of Haematology (2012); 158.6: 727-738.
[cited by applicant]
Schiemann, Barbara, et al. “An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway.” Science (2001); 293.5537: 2111-2114.
[cited by applicant]
Sather, B.B., et al. “Development of B-lineage Predominant Lentiviral Vectors for Use in Genetic Therapies for B Cell Disorders.” Molecular Therapy (2011); 19(3): 515-525.
[cited by applicant]
Shiratori, Y. et al., “Strategy of liver-directed gene therapy: present status and future prospects”, Liver (1999); 19(4): 265-274.
[cited by applicant]
Singh et al., “HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development”, British Journal of Cancer (2014); 111: 1888-1898.
[cited by applicant]
Smith-Arica and Bartlett, “Gene Therapy: Recombinant Adeno-associated Virus Vectors”, Curr. Cardiol. Rep. (2001); 3: 43-49.
[cited by applicant]
Somerville and Dudley, “Bioreactors get personal.” OncoImmunology (2012); 1(9): 1-3.
[cited by applicant]
Soneoka, Yuko, et al. “A transient three-plasmid expression system for the production of high titer retroviral vectors.” Nucleic Acids Research (1995); 23.4: 628-633.
[cited by applicant]
Strayer, D.S., “Viral gene delivery”, Expert Opinion on Investigational Drugs (1999); 8(12): 2159-2172.
[cited by applicant]
Szymczak, Andrea L., et al. “Correction of multi-gene deficiency in vivo using a single‘self-cleaving’2A peptide-based retroviral vector.” Nature Biotechnology (2004); 22.5: 589-594.
[cited by applicant]
Ten Berge, I. J. M., et al. “Selective expansion of a peripheral blood CD8+ memory T cell subset expressing both granzyme B and I-selectin during primary viral infection in renal allograft recipients.” Transplantation P…
[cited by applicant]
Thompson, Jeffrey S., et al. “BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population.” Journal of Experimental Medicine…
[cited by applicant]
Thulé and Liu, “Regulated hepatic insulin gene therapy of STZ-diabetic rats”, Gene Therapy (2000); 7: 1744-1752.
[cited by applicant]
Tumaini, B., et al., “Simplified process for the production of anti-CD19-CAR-engineered T cells.” Cytotherapy (2013); 15: 1406-1415.
[cited by applicant]
Van Der Waart, A.B., et al., “Akt Signalling Inhibition Promotes The Ex Vivo generation Of Minor Histocompatibility Antigen-Specific CD8+ Memory Stem T Cells.” Blood (2013); 122(21): 3269. (Abstract, 2 pages).
[cited by applicant]
Vera, Juan, et al. “T lymphocytes redirected against the K light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells.” Blood (2006); 108.12: 3890-3897.
[cited by applicant]
Wu and Kabat, “An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity”, J Exp Med. (1970); 132(2): 211-250.
[cited by applicant]
Xu, Shengli, and Lam, Kong-Peng. “B-cell maturation protein, which binds the tumor necrosis factor family members BAFF and APRIL, is dispensable for humoral immune responses.” Molecular and Cellular Biology (2001); 21.1…
[cited by applicant]
Yang, N.S., “Gene Transfer into Mammalian Somatic Cells in Vivo”, Critical Reviews in Biotechnology (1992); 12(4): 335-356.
[cited by applicant]
Yang, Soo Young, et al. “A common pathway for T lymphocyte activation involving both the CD3-Ti complex and CD2 sheep erythrocyte receptor determinants.” The Journal of Immunology (1986); 137.4: 1097-1100.
[cited by applicant]
Yee, Jiing-Kuan, et al. “A general method for the generation of high-titer, pantropic retroviral vectors: highly efficient infection of primary hepatocytes.” Proceedings of the National Academy of Sciences USA. (1994); …
[cited by applicant]
Zennou, V. et al., “HIV-1 genome nuclear import is mediated by a central DNA flap.” Cell (2000); 101(2): 173-185.
[cited by applicant]
Zhong, Shi, et al. “Retroviral transduction of T-cell receptors in mouse T-cells.” JoVE (Journal of Visualized Experiments) (2010); 44: e2307, 4 pages.
[cited by applicant]
Zuckermann, Ronald N., et al. “Discovery of nanomolar ligands for 7-transmembrane G-protein-coupled receptors from a diverse N-(substituted) glycine peptoid library.” Journal of Medicinal Chemistry (1994); 37.17: 2678-2…
[cited by applicant]
Zufferey et al., “Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo”, Nat Biotechnol. (1997), 15(9): 871-875.
[cited by applicant]
Zufferey, R. et al., “Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transgenes delivered by retroviral vectors.” J Virol. (1999); 73(4): 2886-2892.
[cited by applicant]
Zufferey, R. et al., “Self-Inactivating Lentivirus Vector for Safe and Efficient In Vivo Gene Delivery”, J Virol (1998); 72(12): 9873-9880.
[cited by applicant]
Esser, et al., “NK cells engineered to express a GD2-specific antigen receptor display built-in ADCC-like activity against tumor cells of neuroectodermal origin.” Journal of Cellular and Molecular Medicine (2012); 16(3)…
[cited by applicant]
European Application No. EP 15802488.5, Extended European Search Report dated Dec. 19, 2017, 11 pages.
[cited by applicant]
European Application No. EP 15824299.0, Extended European Search Report dated Dec. 13, 2017, 11 pages.
[cited by applicant]
Garfall, A.L., “Immunotherapy with Chimeric Antigen Receptors for Multiple Myeloma.” Discovery Medicine: Discovery Class of Medicine, Research Technology, and T. Solariz, Inc., (2014); 17(91): 37-46.
[cited by applicant]
Hirai, et al., “MK-2206, an Allosteric Aid Inhibitor, Enhances Antitumor Efficacy by Standard Chemotherapeutic Agents or Molecular Targeted Drugs In vitro and In vivo.” Molecular Cancer Therapeutics (2010); 9(7): 1956-1…
[cited by applicant]
Kim, et al., “Role of PI3K/Akt signaling in memory CD8 T cell differentiation.” Frontiers in Immunology (2013); 4: 20, 11 pages.
[cited by applicant]
Lanitis, et al., “Chimeric Antigen Receptor T Cells with Dissociated Signaling Domains Exhibit Focused Antitumor Activity with Reduced Potential for Toxicity In Vivo.” Cancer Immunology Research (2013); 1(1): 43-53, pub…
[cited by applicant]
Li, Qun, “Recent progress in the discovery of Akt inhibitors as anticancer agents.” Expert Opinion on Therapeutic Patents (2007); 17(9): 1077-1130.
[cited by applicant]
Movassagh, et al., “Retrovirus-Mediated Gene Transfer into T cells: 95% transduction efficiency without Further in Vitro Selection.” Human Gene Therapy (2000); 11: 1189-1200.
[cited by applicant]
Perkins, et al., “Manufacturing an Enhanced CAR T Cell Product By Inhibition of the PI3K/Akt Pathway During T Cell Expansion Results in Improved In Vivo Efficacy of Anti-BCMA CAR T Cells.” Blood (2015); 126(3): 1893.
[cited by applicant]
Third Party Submission filed in U.S. Appl. No. 15/316,792, filed Feb. 23, 2018, 6 pages.
[cited by applicant]
Urak, et al., “Ex vivo Akt inhibition promotes the generation of potent CD19CAR T cells for adoptive immunotherapy.” Journal for Immuno Therapy of Cancer (2017); 5(1): 26, 13 pages.
[cited by applicant]
Van Der Waart, A.B., et al., “Akt Signalling Inhibition Promotes The Ex Vivo generation Of Minor Histocompatibility Antigen-Specific CD8+ Memory Stem T Cells.” Blood (2013); 122(21): 3269.
[cited by applicant]
Van Der Waart, A.B., et al., “Inhibition of Akt signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy.” Blood (2014); 124(23): 3490-3500.
[cited by applicant]
Van Der Waart, A.B., et al., “Time to Akt Superior tumor-reactive T cells for adoptive immunotherapy.” OncoImmunology (2015); 4(5): e1003016, 3 pages.
[cited by applicant]
Weigelt, et al., “Genomic determinants of the PI3K pathway inhibitor response in cancer.” Frontiers in Oncology (2012), 2: Article V 109, pp. 1-16.
[cited by applicant]
Wu, et al., “Over-expressing Akt in T cells to resist tumor immunosuppression and increase anti-tumor activity.” BMC Cancer (2015); 15(1): 603, 10 pages.
[cited by applicant]
Yap, et al., “Preclinical Pharmacology, Antitumor Activity, and Development of Pharmacodynamic Markers for the Novel, Potent AKT Inhibitor CCT128930.” Molecular Cancer Therapeutics (2011); 10(2): 360-371, (Published on-…
[cited by applicant]
Zhang, et al., “An NKp30-Based Chimeric Antigen Receptor Promotes T cell Effector Functions and Antitumor Efficacy In Vivo.” The Journal of Immunology (2012); 189: 2290-2299 (prepublished online Jul. 30, 2012).
[cited by applicant]
European Application No. EP 15868392.0, Extended European Search Report dated Jun. 25, 2018, 5 pages.
[cited by applicant]
Halene, et al., “Improved Expression in Hematopoietic and Lymphoid Cells in Mice After Transplantation of Bone Marrow Transduced With a Modified Retroviral Vector.” Blood (1999); 94(10): 3349-3357.
[cited by applicant]
International Preliminary Report on Patentability for International Application No. PCT/US2015/064270, dated Jun. 12, 2018, 12 pages.
[cited by applicant]
Li, et al., “Optimal promoter usage for lentiviral vector-mediated transduction of cultured central nervous system cells.” Journal of Neuroscience Methods (2010); 189 (1): 56-64.
[cited by applicant]
Kochenderfer, J.N., et al., “Construction and Pre-clinical Evaluation of an Anti-CD19 Chimeric Antigen Receptor.” J Immunother. (2009); 32 (7): 689-702.
[cited by applicant]
Shirasu and Kuroki, “Functional Design of Chimeric T-Cell Antigen Receptors for Adoptive Immunotherapy of Cancer: Architecture and Outcomes.” Anticancer Research (2012); 32 (6): 2377-2383.
[cited by applicant]
Uchibori, et al., “CD269 (BCMA)-Specific CAR-Expressing T Cells Dramatically Eradicate Myeloma Cells from Bone Marrow of an Orthotopic Multiple Myeloma Mouse Model.” Molecular Therapy (2016); Abstract 400, 24 (Supplemen…
[cited by applicant]
Wang, et al., “CS-1 Re-Directed Central Memory T Cell Therapy for Multiple Myeloma.” Blood (2014); 124 (21): 1114.
[cited by applicant]
Ward, et al., “Binding activities of a repertoire of single immunoglobulin variable domains secreted from
[cited by applicant]
Friedman et al., “Effective Targeting of Multiple B-Cell Maturation Antigen-Expressing Hematological Malignances by Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T Cells,” Human Gene Therapy, vol. 29, No. 5, …
[cited by applicant]
Huye L.E. et al. “Combining mTor inhibitors with rapamycin-resistant T cells: a two-pronged approach to tumor elimination”. Molecular Therapy, 2011, 19(12): 2239-2248.
[cited by applicant]
Kulemzin et al., “Engineering Chimeric Antigen Receptors,” Acta Naturae, vol. 9, No. 1 (32) 2017, 6-14.
[cited by applicant]
Muyldermans, et al., “Nanobodies: Natural Single-Domain Antibodies,” Annual Review of Biochemistry vol. 82:775-797 (vol. publication date Jun. 2013) First published online as a Review in Advance on Mar. 13, 2013 https:/…
[cited by applicant]
Xu et al., “The development of CAR design for tumor CAR-T cell therapy,” Oncotarget, 2018, vol. 9, No. 17, pp. 13991-14004.
[cited by applicant]
Xue L. et al., “The role of the PI3K-AKT kinase pathway in T-cell development beyond the beta checkpoint”. Eur J Immunol., 2008, 38(11):3200-7.
[cited by applicant]
Allan et al., “Generation of Potent and Stable Human CD4+ T Regulatory Cells by Activation-independent Expression of FOXP3,” www.moleculartherapy.org vol. 16 No. 1, 194-202 Jan. 2008.
[cited by applicant]
European Application No. EP 19193858.8, Extended European Search Report dated Feb. 21, 2020, 10 pages.
[cited by applicant]
European Application No. EP 19210785.2, Extended European Search Report dated Feb. 21, 2020, 9 pages.
[cited by applicant]
European Application No. EP 19218258.2, Extended European Search Report dated Jun. 26, 2020, 7 pages.
[cited by applicant]
Fedorov VD et al., “PD-1- and CTLA-4-Based Inhibitory Chimeric Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses”, Sci Transl Med, 2013, vol. 5, No. 215, pp. 1-25.
[cited by applicant]
Mallone et al., “Isolation and preservation of peripheral blood mononuclear cells for analysis of islet antigen-reactive T cell responses: position statement of the T-Cell Workshop Committee of the Immunology of Diabete…
[cited by applicant]
Sadelain M et al., “The basic principles of chimeric antigen receptor (CAR) design”, Cancer Discov, 2013, vol. 3, No. 4, pp. 388-398.
[cited by applicant]
Xu et al., “Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15,” Blood, Jun. 12, 2014, vol. 123, No. 24.
[cited by applicant]
Zhong, X. et al., “Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+T cell-mediated tumor eradication”, Mol Ther (2010);18(2):413-20.
[cited by applicant]
Astrakhan et al., “Ubiquitous high-level gene expression in hematopoietic lineages provides effective lentiviral gene therapy of murine Wiskott-Aldrich syndrome,” Blood. May 10, 2012; 119(19): 4395-4407.
[cited by applicant]
Aviles Mendoza et al., “Comparison of Five Retrovirus Vectors Containing the Human IL-2 Receptor g Chain Gene for Their Ability to Restore T and B Lymphocytes in the X-Linked Severe Combined Immunodeficiency Mouse Model…
[cited by applicant]
Dienstmann et al., “Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors,” Molecular Cancer Therapeutics, 13(5):1021-1031, Apr. 18, 2014.
[cited by applicant]
European Application No. EP 15782739.5, Notice of Opposition dated Oct. 2, 2020, 9 pages.
[cited by applicant]
European Application No. EP 20205511.7, Extended European Search Report dated May 6, 2021, 13 pages.
[cited by applicant]
European Application No. EP 20170239.6, Extended European Search Report dated Sep. 18, 2020, 11 pages.
[cited by applicant]
Gattinoni, L., et al., “Moving T memory stem cells to the clinic,” Blood, Jan. 24, 2013, vol. 121, No. 4, pp. 567-568.
[cited by applicant]
Han et al., “Chimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges,” Journal of Hematology & Oncology, Jul. 8, 2013, 6:47, 7 pages.
[cited by applicant]
Oh et al., “Lentiviral vector design using alternative RNA export elements,” Retrovirology, 2007, 4:38, 10 pages.
[cited by applicant]
Ryan et al., Antibody targeting of B-cell maturation antigen on malignant plasma cells, Mol Cancer Ther, Nov. 2007, vol. 6, No. 11, pp. 3009-3018.
[cited by applicant]
Sigma-Aldrich, “Cryopreservation”, Biofiles, vol. 5, No. 4, pp. 1-22, published 2010.
[cited by applicant]
Adler and Dimitrov, Therapeutic Antibodies Against Cancer, 26 Hematology/Oncology Clinics ofNorth America 447-481 (2012) (“Adler”).
[cited by applicant]
Ahmad et al., “scFv Antibody: Principles and Clinical Application,” Clinical and Developmental Immunology, vol. 2012, Article ID 980250, 15 pages.
[cited by applicant]
Almagro et al., “Humanization of antibodies,” Frontiers in Bioscience, 13, Jan. 1, 2008, pp. 1619-1633.
[cited by applicant]
Atanackovic, D., et al., “CD4+CD25+FOXP3+ T Regulatory Cells Reconstitute and Accumulate In The Bone Marrow of Patients With Multiple Myeloma Following Allogeneic Stem Cell Transplantation,” Haematol 93(3):423-430 (2008…
[cited by applicant]
Barthelemy et al., “Comprehensive Analysis of the Factors Contributing to the Stability and Solubility of Autonomous Human VH Domains,” The Journal of Biological Chemistry, Feb. 8, 2008, vol. 283, No. 6, pp. 3639-3654.
[cited by applicant]
Bausch-Fluck, et al., “A Mass Spectrometric-Derived Cell Surface Protein Atlas,” PLoS One 10(4):e0121314, pp. 1-22 (2015).
[cited by applicant]
Bausch-Fluck, et al., “The In Silico Human Surfaceome,” PNAS 115(46): E10988-E10997 (2018).
[cited by applicant]
Beck, A., et al., “Strategies and Challenges for the Next Generation of Therapeutic Antibodies,” Immunol 10:345-352 (2010).
[cited by applicant]
Beiboer et al., “Guided Selection of a Pan Carcinoma Specific Antibody Reveals Similar Binding Characteristics yet Structural Divergence Between the Original Murine Antibody and its Human Equivalent,” J. Mol. Biol. (200…
[cited by applicant]
Berger et al., “CD28 costimulation and immunoaffinity-based selection efficiently generat primary gene-modified T cells for adoptive immunotherapy,” Blood, Jan. 15, 2003, vol. 101, No. 2, pp. 476-484.
[cited by applicant]
Biagi et al., “Chimeric T-cell receptors: new challenges for targeted immunotherapy in hematologic malignancies,” Haematologica 2007; 92:381-388.
[cited by applicant]
Bleumer, I., et al., “A Phase II Trial of Chimeric Monoclonal Antibody G250 for Advanced Renal Cell Carcinoma Patients,” Br J Cancer 90:985-990 (2004).
[cited by applicant]
Bobisse et al., “Reprogramming T Lymphocytes for Melanoma Adoptive Immunotherapy by T-Cell Receptor Gene Transfer with Lentiviral Vectors,” Cancer Research, Dec. 15, 2009; 69(24), pp. 9385-9394.
[cited by applicant]
Braendstrup, P., et al., “The Long Road to The First FDA Approved Gene Therapy: Chimeric Antigen Receptor T Cells Targeting CD19,” Cytotherapy 22(2):57-69 (2020).
[cited by applicant]
Braga, W.M.T., et al., “The Role of Regulatory T Cells and TH17 Cells in Multiple Myeloma,” Clin Dev Immunol 2012(293479):1-4, (2012).
[cited by applicant]
Brenner, M. K. and Heslop, H.E., “Adoptive T Cell Therapy of Cancer,” Curr Opin Immunol 22:251-257 (2010).
[cited by applicant]
Brentjens, R.J., et al., “Genetically Targeted T Cells Eradicate Systemic Acute Lymphoblastic Leukemia Xenografts,” Clin Cancer Res 13(18):5426-5435 (2007).
[cited by applicant]
Brentjens, R., et al., “Treatment of Chronic Lymphocytic Leukemia With Genetically Targeted Autologous T Cells: Case Report of an unforeseen Adverse Event in a Phase I Clinical Trial,” Molecular Therapy 18(4):666-668 (2…
[cited by applicant]
Brimnes, M.K. et al., “Increased Level of Both CD4+FOXP3+Regulatory T Cells and CH14+HLA-DR-/low Myeloid-Derived Suppressor Cells and Decreased Level of Dendritic Cells in Patients with Multiple Myeloma,” Clin Immunol 7…
[cited by applicant]
Bross et al., “Approval Summary: Gemtuzumab Ozogamicin in Relapsed Acute Myeloid Leukemia,” Clinical Cancer Research, Jun. 2001, vol. 7, 1490-1496.
[cited by applicant]
Caers et al., “Multiple myeloma—an update on diagnosis and treatment,” European Journal of Haematology, 2008 81 (329-343).
[cited by applicant]
Cartellieri, M., et al., “Chimeric Antigen Receptor-Engineered T Cells for Immunotherapy of Cancer,” J Biomed and Biotech 2010(956304):1-13 (2010).
[cited by applicant]
Ch'en et al., “Characterisation of monoclonal antibodies to the TNF and TNF receptor families,” Cellular Immunology 236 (2005) 78-85.
[cited by applicant]
Chauhan, A.K., “Human CD4+ T-Cells: A Role for Low-Affinity Fc Receptors,” Front. Immunol. (2016) 7:215, 8 pages.
[cited by applicant]
Chinnasamy et al., “Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice,” J Clin Invest. 2010;120(11):3953-3968.
[cited by applicant]
Cho et al., “Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy,” Front. Immunol. (2018) 9:1821.
[cited by applicant]
Choi et al., “Predicting antibody complementarity determining region structures without classification,” Molecular BiosSystems, 2011, 7, pp. 3327-3334.
[cited by applicant]
Clarke et al., “Improved Post-Thaw Recovery of Peripheral Blood Stem/Progenitor Cells Using a Novel Intracellular-like Cryopreservation Solution,” Cytotherapy, 2009, 11(4): 472-479.
[cited by applicant]
Extract from ThermoFisher Website page, Dynabeads cell isolation and expansion support—getting started, 1 page.
[cited by applicant]
Dai et al., “Human Immunodeficiency Virus Integrates Directly into Naïve Resting CD4+ T Cells but Enters Naïve Cells Less Efficiently than Memory Cells,” Journal of Virology, May 2009, pp. 4528-4537.
[cited by applicant]
De Claro, “U.S. Food and Drug Administration Approval Summary: Brentuximab Vedotin for the Treatment of Relapsed Hodgkin Lymphoma or Relapsed Systemic Anaplastic Large-Cell Lymphoma,” Clin Cancer Res; 2012; 18(21); 5845…
[cited by applicant]
De Genst et al., “Antibody repertoire development in camelids,” Developmental and Comparative Immunology, 30 (2006), pp. 187-198.
[cited by applicant]
Demko et al., “FDA Drug Approval Summary: Alemtuzumab as Single-Agent Treatment for B-Cell Chronic Lymphocytic Leukemia,” The Oncologist 2008;13:167-174.
[cited by applicant]
Di Bernardo, A., et al., “Humoral Immunotherapy of Multiple Myeloma: Perspectives and Perplexities,” Expert Opin. Biol. Ther. 10(6):863-873 (2010).
[cited by applicant]
Di Ianni et al., “Immunomagnetic isoloation of CD4+CD25+FoxP3+ natural T regulatory lymphocytes for clinical applications,” Jan. 9, 2009, British Society for Immunology, Clinical and Experimental Immunology, 156: pp. 24…
[cited by applicant]
Di Stassi et al., “T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model,” Blood, Jun. 18, 2009, vol. 113, No. 25, 6392-6402.
[cited by applicant]
Dimopoulos and Terpos, “Multiple myeloma,” Annals of Oncology 21 (Supplement 7): vii143-vii150, 2010.
[cited by applicant]
Dimopoulos et al., “Current treatment landscape for relapsed and/or refractory multiple myeloma,” Nat. Rev. Clin. Oncol. 12, 42-54 (2015) published online Nov. 25, 2014.
[cited by applicant]
Edwards et al., “The Remarkable Flexibility of the Human Antibody Repertoire; Isolation of Over One Thousand Different Antibodies to a Single Protein, BLyS,” J. Mol. Biol. (2003) 334, pp. 103-118.
[cited by applicant]
Eshhar et al., “Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the γ or ζ subunits of the immunoglobulin and T-cell receptors,” PNAS …
[cited by applicant]
European Application No. EP 15783117.3, Notice of Opposition dated Jan. 19, 2021, 37 pages.
[cited by applicant]
European Application No. EP 15783117.3, Notice of Opposition dated Jan. 21, 2021, 28 pages.
[cited by applicant]
European Application No. EP 15783117.3, Notice of Opposition dated Jan. 22, 2021, 41 pages.
[cited by applicant]
Extract from Signal Peptide Database, Jun. 10, 2010, 3 pages.
[cited by applicant]
Feyler, S., et al., “CD4+CD35+FoxP3+ Regulatory T Cells are Increase Whilst CD3+CD4-CD8-αβTCR+ Double Negative T Cells are Decreased the Peripheral Blood of Patients with Multiple Myeloma Which Correlates With Disease B…
[cited by applicant]
Ficoll-Paque manual, GE Healthcare Life Sciences, Isolation of mononuclear cells, Methodology and applications, Aug. 2014, 20 pages.
[cited by applicant]
Finney et al., “Activation of resting human primary T cells with chimeric receptors: costimulationfrom CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCRζ chain,” J Immunol 2004; 172:104-…
[cited by applicant]
Finney et al., “Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product,” J Immunol 1998; 161:2791-2797.
[cited by applicant]
Geffen and Man, “New Drugs for the Treatment of Cancer, 1990-2001,” IMAJ 2002;4:1124-1131.
[cited by applicant]
Gentile, M., et al., “Emerging Biological Insights and Novel Treatment Strategies in Multiple Myeloma,” Expert Opin Emerg Drugs 17(3):407-438 (2012).
[cited by applicant]
Giannopoulos, K., et al., “The Frequency of T Regulatory Cells Modulates the Survival of Multiple Myeloma Patients: Detailed Characterisation of Immune Status in Multiple Myeloma,” Br J Cancer 106:546-552 (2012).
[cited by applicant]
Griffiths et al., “Human anti-self antibodies with high specificity from phage display libraries,” The EMBO Journal, vol. 12, No. 2, 1993, pp. 725-734.
[cited by applicant]
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