IP Library › Granted Patent US 12,215,348
Granted Patent B2
US 12,215,348 · App. 18/506,851 · Granted Feb 4, 2025

Methods for producing genetically engineered cell compositions and related compositions

Inventors: Mirna Mujacic (Seattle, WA); Ayu Rahardjo (Kirkland, WA)
Assignee: Juno Therapeutics, Inc.
C12N5/0636A61K39/4611A61K39/4631A61K39/464417C12N7/00C12N15/86G01N33/56972A61K2239/48C12N2502/1114C12N2740/13043C12N2740/15043G01N2333/70514G01N2333/70517
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 12,215,348
App. No.
18/506,851
Granted
Feb 4, 2025
Kind
B2
Abstract

Provided herein are methods and compositions for generating engineered cells, such as cells expressing a recombinant receptor, including methods involving stimulation and/or engineering of an input composition having a defined ratio of naïve-like CD4+ T cells to naïve-like CD8+ T cells. In particular, the methods can be used to engineer T cells with genetically engineered receptors, such as genetically engineered antigen receptors such as engineered (recombinant) TCRs and chimeric antigen receptors (CARs), or other recombinant chimeric receptors. Features of the methods include producing a more consistent and/or predictable T cell product and/or a product with lower toxicity compared with other methods.

Claims (34)

1. A method of generating a composition of engineered cells, the method comprising:

contacting an input cell composition comprising naïve-like CD4+ T cells and naïve-like CD8+ T cells from a biological sample from a subject with an agent comprising a nucleic acid molecule encoding a recombinant receptor under conditions to introduce the nucleic acid encoding the recombinant receptor into cells in the composition;

wherein the naïve-like CD4+ T cells and the naïve-like CD8+ T cells are surface positive for CD45RA, CD27 and/or CCR7 and are surface negative for CD45RO and/or CD62L;

wherein the ratio of naïve-like CD4+ T cells to naïve-like CD8+ T cells present in the input cell composition is between 10:1 and 0.05:1, inclusive; and

wherein the method produces recombinant receptor expressing T cells.

2. The method of claim 1 , further comprising stimulating the cells, prior to, during and/or subsequent to said contacting, wherein stimulating comprises incubating the cells in the presence of one or more stimulating agents, wherein stimulating results in activation and/or proliferation of the cells.

3. A method of generating a composition of engineered cells, the method comprising:

(i) stimulating an input cell composition comprising naïve-like CD4+ T cells and naïve-like CD8+ T cells from a biological sample from a subject in the presence of one or more stimulating agents, wherein the naïve-like CD4+ T cells and the naïve-like CD8+ T cells are surface positive for CD45RA, CD27 and/or CCR7 and are surface negative for CD45RO and/or CD62L, wherein the ratio of naïve-like CD4+ T cells to naïve-like CD8+ T cells present in the input cell composition is between 10:1 and 0.05:1, inclusive; and wherein stimulating results in activation of the cells;

(ii) contacting the input cell composition with an agent comprising a nucleic acid molecule encoding a recombinant receptor under conditions to introduce the nucleic acid encoding the recombinant receptor into cells in the composition; and

(iii) stimulating the cells subsequent to said contacting, wherein stimulating comprises incubating the cells in the presence of one or more stimulating agents and wherein stimulating results in proliferation of the cells,

wherein the method produces recombinant receptor expressing T cells.

4. The method of claim 1 , wherein the naïve-like CD4+ T cells and the naïve-like CD8+ T cells are surface positive for CD45RA and CCR7.

5. The method of claim 1 , wherein the naïve-like CD4+ T cells and the naïve-like CD8+ T cells are surface positive for CD27 and CCR7.

6. The method of claim 1 , wherein the naïve-like CD4+ T cells and the naïve-like CD8+ T cells are surface positive for CCR7 and surface negative for CD62L.

7. The method of claim 1 , wherein the input cell composition comprises a ratio of naïve-like CD4+ T cells to naïve-like CD8+ T cells of between 0.8:1 and 2.2:1, each inclusive.

8. The method of claim 4 , wherein the input cell composition comprises a ratio of CCR7+CD45RA+CD4+ cells to CCR7+CD45RA+CD8+ cells of between 0.8:1 and 2.2:1, each inclusive.

9. The method of claim 4 , wherein the input cell composition comprises a ratio of CCR7+CD45RA+CD4+ cells to CCR7+CD45RA+CD8+ cells of or about 1.4:1, 1.1:1, or 1.0:1.

10. The method of claim 5 , wherein the input cell composition comprises a ratio of CD27+CCR7+CD4+ cells to CD27+CCR7+CD8+ cells of between 1.2:1 and 2.4:1, each inclusive.

11. The method of claim 5 , wherein the input cell composition comprises a ratio of CD27+CCR7+CD4+ cells to CD27+CCR7+CD8+ cells of or about 2.7:1.

12. The method of claim 5 , wherein the input cell composition comprises a ratio of CD27+CCR7+CD4+ cells to CD27+CCR7+CD8+ cells of or about 1.69:1.

13. The method of claim 6 , wherein the input cell composition comprises a ratio of CD62L-CCR7+CD4+ cells to CD62L-CCR7+CD8+ cells of between 0.8:1 and 2.2:1, each inclusive.

14. The method of claim 6 , wherein the input cell composition comprises a ratio of CD62L-CCR7+CD4+ cells to CD62L-CCR7+CD8+ cells of or about 2.2:1, 2:1, 1.6:1, or 1.66:1.

15. The method of claim 1 , wherein the composition of engineered cells comprises at least 50%, at least 70%, at least 90%, or 100% of cells that express the recombinant receptor.

16. The method of claim 1 , wherein the ratio of recombinant receptor expressing CD4+ T cells to recombinant receptor expressing CD8+ T cells is or is about 8.6:1, 7.6:1, 2.6:1, 2.0:1, 1.6:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, or 1.0:1.

17. The method of claim 1 , wherein the ratio of recombinant receptor expressing CD4+ T cells to recombinant receptor expressing CD8+ T cells is or is about 2.6:1 or 2.0:1.

18. The method of claim 1 , wherein the ratio of recombinant receptor expressing CD27+CCR7+CD4+ T cells to recombinant receptor expressing CD27+CCR7+CD8+ T cells is or is about 8.6:1, 7.6:1, 2.6:1, 2.0:1, 1.6:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, or 1.0:1.

19. The method of claim 1 , wherein the ratio of recombinant receptor expressing CCR7+CD45RA+CD4+ T cells to recombinant receptor expressing CCR7+CD45RA+CD8+ T cells is or is about 8.6:1, 7.6:1, 2.6:1, 2.0:1, 1.6:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, or 1.0:1.

20. The method of claim 1 , wherein the ratio of recombinant receptor expressing CD62L-CCR7+CD4+ T cells to recombinant receptor expressing CD62L-CCR7+CD8+ T cells is or is about 8.6:1, 7.6:1, 2.6:1, 2.0:1, 1.6:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, or 1.0:1.

21. The method of claim 1 , wherein the recombinant receptor is a chimeric antigen receptor (CAR).

22. The method of claim 1 , wherein the biological sample is or comprises a whole blood sample, a buffy coat sample, a peripheral blood mononuclear cells (PBMC) sample, an unfractionated T cell sample, a lymphocyte sample, a white blood cell sample, an apheresis product, or a leukapheresis product.

23. The method of claim 1 , wherein the subject is a human subject.

24. The method of claim 1 , wherein the input cell composition comprises from or from about 1×10 7 to 5×10 9 total cells or total T cells, or of viable populations of any of the foregoing.

25. The method of claim 3 , wherein the one or more one stimulating agents is selected from the group consisting of CD3-binding molecules; CD28-binding molecules; recombinant IL-2; recombinant IL-15; and recombinant IL-7, a vaccine comprising an antigen specifically recognized by the antigen receptor, and an anti-idiotype antibody that specifically binds the antigen receptor or combinations thereof.

26. The method of claim 25 , wherein the one or more one stimulating agents comprises CD3-binding molecules and CD28-binding molecules.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 20, 2024
From: MUJACIC, MIRNA; RAHARDJO, AYU
To: JUNO THERAPEUTICS, INC.
Reel/Frame 066504/0516 →
Continuity (4)
Continuation 16637709
Provisional Application 62596770 · Dec 8, 2017
Provisional Application 62543363 · Aug 9, 2017
Related Publication 20240076617A1 · Mar 7, 2024
References Cited (276)
US 4452773A · Molday · 1984 [cited by applicant]
US 4690915A · Rosenberg · 1987 [cited by applicant]
US 4795698A · Owen · 1989 [cited by applicant]
US 5168062A · Stinski · 1992 [cited by applicant]
US 5200084A · Liberti · 1993 [cited by applicant]
US 5219740A · Miller · 1993 [cited by applicant]
US 5385839A · Stinski · 1995 [cited by applicant]
US 5773224A · Grandics et al. · 1998 [cited by applicant]
US 5994136A · Naldini 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 6207453B1 · Maass · 2001 [cited by applicant]
US 6410319B1 · Raubitschek · 2002 [cited by applicant]
US 6451995B1 · Cheung · 2002 [cited by applicant]
US 7070995B2 · Jensen · 2006 [cited by applicant]
US 7265209B2 · Jensen · 2007 [cited by applicant]
US 7354762B2 · Jensen · 2008 [cited by applicant]
US 7446179B2 · Jensen · 2008 [cited by applicant]
US 7446190B2 · Sadelain · 2008 [cited by applicant]
US 7446191B2 · Jensen · 2008 [cited by applicant]
US 8324353B2 · Jensen · 2012 [cited by applicant]
US 8339645B2 · Nakawaki · 2012 [cited by applicant]
US 8389282B2 · Sadelain et al. · 2013 [cited by applicant]
US 8479118B2 · Lyndersay et al. · 2013 [cited by applicant]
US 8802374B2 · Jensen · 2014 [cited by applicant]
US 8911993B2 · June et al. · 2014 [cited by applicant]
US 11400115B2 · Ramsborg et al. · 2022 [cited by applicant]
US 11851678B2 · Mujacic et al. · 2023 [cited by applicant]
US 20020131960A1 · Sadelain · 2002 [cited by applicant]
US 20020150914A1 · Anderson et al. · 2002 [cited by applicant]
US 20030170238A1 · Gruenberg · 2003 [cited by applicant]
US 20030223994A1 · Hoogenboom et al. · 2003 [cited by applicant]
US 20030235908A1 · Berenson et al. · 2003 [cited by applicant]
US 20040191260A1 · Reiter et al. · 2004 [cited by applicant]
US 20060034850A1 · Weidanz et al. · 2006 [cited by applicant]
US 20060074008A1 · Senter et al. · 2006 [cited by applicant]
US 20070099253A1 · Erkhov et al. · 2007 [cited by applicant]
US 20070116690A1 · Yang et al. · 2007 [cited by applicant]
US 20080085532A1 · Gorlach et al. · 2008 [cited by applicant]
US 20090226474A1 · Weidanz et al. · 2009 [cited by applicant]
US 20090304679A1 · Weidanz · 2009 [cited by applicant]
US 20110003380A1 · Miltenyi · 2011 [cited by applicant]
US 20110070581A1 · Gupta · 2011 [cited by applicant]
US 20130149337A1 · Cooper et al. · 2013 [cited by applicant]
US 20130287748A1 · June · 2013 [cited by applicant]
US 20140255993A1 · Follstad et al. · 2014 [cited by applicant]
US 20140294841A1 · Scheinberg et al. · 2014 [cited by applicant]
US 20150283178A1 · June et al. · 2015 [cited by applicant]
US 20160152723A1 · Chen et al. · 2016 [cited by applicant]
US 20160362472A1 · Bitter et al. · 2016 [cited by applicant]
US 20170037369A1 · Ramsborg et al. · 2017 [cited by applicant]
US 20170051035A1 · Payne et al. · 2017 [cited by applicant]
US 20170051252A1 · Morgan et al. · 2017 [cited by applicant]
US 20170209492A1 · June et al. · 2017 [cited by applicant]
US 20170356902A1 · Ukekawa et al. · 2017 [cited by applicant]
US 20180296602A1 · Riddell et al. · 2018 [cited by applicant]
US 20200239910A1 · Bonyhadi et al. · 2020 [cited by applicant]
US 20200384025A1 · Mujacic et al. · 2020 [cited by applicant]
US 20210128616A1 · Himanshu et al. · 2021 [cited by applicant]
US 20230090176A1 · Ramsborg et al. · 2023 [cited by applicant]
US 20230190814A1 · Ramsborg et al. · 2023 [cited by applicant]
CN 103305464 · 2013 [cited by applicant]
CN 103502438 · 2014 [cited by applicant]
EP 0452342 · 1991 [cited by applicant]
EP 2537416 · 2012 [cited by applicant]
JP 2006525013 · 2006 [cited by applicant]
JP 201075191 · 2010 [cited by applicant]
WO WO1992008796 · 1992 [cited by applicant]
WO WO1994028143 · 1994 [cited by applicant]
WO WO1996013593 · 1996 [cited by applicant]
WO WO1996018105 · 1996 [cited by applicant]
WO WO1999018129 · 1999 [cited by applicant]
WO WO1999060120 · 1999 [cited by applicant]
WO WO2000014257 · 2000 [cited by applicant]
WO WO2000043551 · 2000 [cited by applicant]
WO WO2003020763 · 2003 [cited by applicant]
WO WO2003068201 · 2003 [cited by applicant]
WO WO2004029221 · 2004 [cited by applicant]
WO WO2004033685 · 2004 [cited by applicant]
WO WO2004096975 · 2004 [cited by applicant]
WO WO2006000830 · 2006 [cited by applicant]
WO WO2007117602 · 2007 [cited by applicant]
WO WO2009003493 · 2009 [cited by applicant]
WO WO2009072003 · 2009 [cited by applicant]
WO WO2009072006 · 2009 [cited by applicant]
WO WO2009076524 · 2009 [cited by applicant]
WO WO2010033140 · 2010 [cited by applicant]
WO WO2011044186 · 2011 [cited by applicant]
WO WO2012099973 · 2012 [cited by applicant]
WO WO2012129514 · 2012 [cited by applicant]
WO WO2013011011 · 2013 [cited by applicant]
WO WO2013038272 · 2013 [cited by applicant]
WO WO2013062365 · 2013 [cited by applicant]
WO WO2013071154 · 2013 [cited by applicant]
WO WO2013123061 · 2013 [cited by applicant]
WO WO2013124474 · 2013 [cited by applicant]
WO WO2013126726 · 2013 [cited by applicant]
WO WO2013166321 · 2013 [cited by applicant]
WO WO2014011996 · 2014 [cited by applicant]
WO WO2014031687 · 2014 [cited by applicant]
WO WO2014055668 · 2014 [cited by applicant]
WO WO2014130657 · 2014 [cited by applicant]
WO WO2015157252 · 2015 [cited by applicant]
WO WO2015164675 · 2015 [cited by applicant]
WO WO2015164745 · 2015 [cited by applicant]
WO WO2016019300 · 2016 [cited by applicant]
WO WO2016090190 · 2016 [cited by applicant]
WO WO2016090312 · 2016 [cited by applicant]
WO WO2016090320 · 2016 [cited by applicant]
WO WO2016090327 · 2016 [cited by applicant]
WO WO2016090329 · 2016 [cited by applicant]
WO WO2016164580 · 2016 [cited by applicant]
WO WO2017068421 · 2017 [cited by applicant]
WO WO2017075389 · 2017 [cited by applicant]
WO WO2018157171 · 2018 [cited by applicant]
WO WO2019032929 · 2019 [cited by applicant]
WO WO2019113557 · 2019 [cited by applicant]
WO WO2019113559 · 2019 [cited by applicant]
US 8,252,592 B2, 08/2012, Sadelain (withdrawn) [cited by applicant]
Abate-Daga et al., “CAR models: next-generation CAR modifications for enhanced T cell function,” Mol Ther Oncolytics (May 2016) 3:16014. [cited by applicant]
Ali et al., “T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma,” Blood (Sep. 2016) 128(13):1688-1700. [cited by applicant]
Alonso-Camino et al., “CARbodies: Human Antibodies Against Cell Surface Tumor Antigens Selected From Repertoires Displayed on T Cell Chimeric Antigen Receptors,” Mol Ther Nucl Acids (2013) 2: e93. [cited by applicant]
Alvarez-Fernandez et al., “A short CD3/CD28 costimulation combined with IL-21 enhance the generation of human memory stem T cells for adoptive immunotherapy,” J Transl Med. (Jul. 2016) 14(1):214. [cited by applicant]
Applikon Biotechnology/BioPharma-Reporter (2016) How automation has changed the way we count cells BioPharma-Reporter.com; 1-4 (Year: 2016). [cited by applicant]
Barrett et al., “Chimeric Antigen Receptor Therapy for Cancer,” Annual Review of Medicine (2014) 65:333-347. [cited by applicant]
Berdeja et al., “First-in-human multicenter study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: Updated results,” J Clin Oncol (Jun. 2017) 35(15)-suppl.; 3010. [cited by applicant]
Bersenev, “Crude versus defined CAR T-cell therapy product,” dated May 1, 2016. Retrieved from the Internet: https://stemcellassays.com/2016/05/crude-versus-defined-car-t-cell-therapy-product/. [cited by applicant]
Berthois et al., “Phenol red in tissue culture media is a weak estrogen: Implications concerning the study of estrogen-responsive cells in culture,” Proc. Natl. Acad. Sci (1986) 83: 2496-2500. [cited by applicant]
Boris-Lawrie et al., “Recent advances in retrovirus vector technology,” Cur. Opin. Genet. Develop. (1993) 3:102-109. [cited by applicant]
Brash et al., “Strontium phosphate transfection of human cells in primary culture: stable expression of the simian virus 40 large-T-antigen gene in primary human bronchial epithelial cells,” Mol. Cell Biol. (1987) 7: 20… [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. (2013) 5(177):177ra38. [cited by applicant]
Brentjens et al., “Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias,” Blood (2011) 118(18):4817-4828. [cited by applicant]
Brown et al., “Structure-Based Mutagenesis of the Human Immunodeficiency Virus Type 1 DNA Attachment Site: Effects on Integration and cDNA Synthesis,” J Viral (1999) 73(11):9011-9020. [cited by applicant]
Burns et al., “Vesicular stomatitis virus G glycoprotein pseudotyped retroviral vectors: concentration to very high titer and efficient gene transfer into mammalian and nonmammalian cells,” Proc. Natl. Acad. Sci. USA (1… [cited by applicant]
Carlens et al., “Ex vivo T lymphocyte expansion for retroviral transduction: influence of serum-free media on variations in cell expansion rates and lymphocyte subset distribution,” Exp Hematol (2000) 28(10): 1137-1146. [cited by applicant]
Carrillo et al., “The Multiple Sequence Alignment Problem in Biology,” SIAM Journal on Applied Mathematics (1988) 48(5):1073-1082. [cited by applicant]
Casati et al., “Clinical-scale selection and viral transduction of human naïve and central memory CD8+ T cells for adoptive cell therapy of cancer patients,” Cancer Immunology (2013) 62(10): 1563-1573. [cited by applicant]
Cavalieri et al., “Human T lymphocytes transduced by lentiviral vectors in the absence of TCR activation maintain an intact immune competence,” Blood (2003) 102(2): 497-505. [cited by applicant]
Cheadle et al., “Chimeric antigen receptors for T-cell based therapy,” Methods Mol Biol (2012) 907:645-666. [cited by applicant]
Chervin et al., “Engineering higher affinity T cell receptors using a T cell display system,” J Immunol Methods. (2008) 339(2): 175-84. [cited by applicant]
Chicaybam et al., “An efficient low cost method for gene transfer to T lymphocytes,” PLoS ONE (2013) 8(3): e60298. [cited by applicant]
Cho et al., “Human mammalian cell sorting using a highly integrated micro-fabricated fluorescence-activated cell sorter (microFACS),” Lab Chip (2010) 10: 1567-1573. [cited by applicant]
Chothia et al.,. “The outline structure of the T-cell alpha beta receptor,” EMBO J. (1988) 7(12): 3745-55. [cited by applicant]
Church et al., “Tumor-specific CD4+ T cells maintain effector and memory tumor-specific CD8+ T cells,” Eur J Immunol (2013) 44(1):69-79. [cited by applicant]
Clackson et al., “Making antibody fragments using phage display libraries,” Nature (1991) 352(6336):624-628. [cited by applicant]
Clarke and Davies in: Methods in Molecular Medicine, vol. 58: Metastasis Research Protocols, vol. 2: Cell Behavior In Vitro and In Vivo, Edited by: S. A. Brooks and U. Schumacher © Humana Press Inc., Totowa, NJ (2001) p… [cited by applicant]
Cohen et al., “Recombinant antibodies with MHC-restricted, peptide-specific, T-cell receptor-like specificity: new tools to study antigen presentation and TCR-peptide-MHC interactions,” J Mol Recognit. (2003) 16(5): 324… [cited by applicant]
Cooper 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) 101:1637-1644. [cited by applicant]
Dai et al., “Chimeric Antigen Receptors Modified T-Cells for Cancer Therapy.” J Natl Cancer Inst. (Jul. 2016) 108(7); djv349. [cited by applicant]
Davila et al., “CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia,” PLoS ONE (2013) 8(4): e61338. [cited by applicant]
Davis et al., “Assessment of a positive selection technique using an avidin column to isolate human peripheral blood T cell subsets,” J Immunol Methods. (1994) 175(2):247-57. [cited by applicant]
De Felipe et al., “Targeting of proteins derived from self-processing polyproteins containing multiple signal sequences,” Trafic (2004) 5(8):616-626. [cited by applicant]
De Felipe, “Skipping the co-expression problem: the new 2A “CHYSEL” technology,” Genetics Vaccines and Therapy (2004) 2:13. [cited by applicant]
Dirks et al., “Genome-wide epigenomic profiling for biomarker discovery,” Clin Epigenetics (Nov. 2016) 8:122. [cited by applicant]
Dull, T. et al. (Nov. 1998) “A Third-Generation Lentivirus Vector with a Conditional Packaging System,” J. Viral. 72:8463-8471. [cited by applicant]
Eaker et al., “Concise review: guidance in developing commercializable autologous/patient-specific cell therapy manufacturing,” Stem Cells Transl Med. (2013) 2(11): 871-83. [cited by applicant]
Engelman et al., “Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication,” J Viral (1995) 69(5):2729-2736. [cited by applicant]
Fan et al., “Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma,” J Clin Oncol (Jun. 2017) 35(18 suppl.):LBA3001. [cited by applicant]
Fedorov et al., “PD-1- and CTLA-4-Based Inhibitory Chimeric Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses,” Sci Transl Medicine (2013) 5(215):215ra172. [cited by applicant]
Fernandes et al., “Kinetics of class II MHC expression on cytotoxic T cells generated by skin allograft,” Tissue Antigens. (1990) 36(3):93-9. [cited by applicant]
Fraietta et al., “Biomarkers of Response to Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with Chronic Lymphocytic Leukemia,” Blood (Dec. 2016) 128(22):57. [cited by applicant]
Fraietta et al., “Identification of functional determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T-cell therapy if chronic lymphocytic leukemia,” Blood (Dec. 2017) 130:3181. [cited by applicant]
Frayer et al., “Mean Body Weight, Height, Waist Circumference, and Body Mass Index Among Adults: United States, 1999-2000 Through 2015-2016,” Natl Health Stat Report. (2018) (122):1-16. [cited by applicant]
Gantke et al., “AFM26 is a novel, highly potential BCMA/CD16A-directed bispecific antibody for high affinity NK-cell engagement in multiple myeoma,” J Clin Oncol (May 2017) 35(15_suppl.); Abstract 8045. [cited by applicant]
Gardner et al., “Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults,” Blood (Jun. 2017) 129(25):3322-3331. [cited by applicant]
Gattinoni et al., “T memory stem cells in health and disease,” Nat Med. (Jan. 2017) 23(1):18-27. [cited by applicant]
Ghassemi et al., “203. Shortened T Cell Culture with IL-7 and IL-15 Provides the Most Potent Chimeric Antigen Receptor (CAR)-Modified T Cells for Adoptive Immunotherapy,” Molecular Therapy, May 2016, vol. 24, Supplement… [cited by applicant]
Godin et al., “Microfluidics and photonics for Bio-System-on-a-Chip: a review of advancements in technology towards a microfluidic flow cytometry chip,” J Biophoton. (2008) 1(5):355-376. [cited by applicant]
Gunzer et al,, “Two-step negative enrichment of CD4+ and CD8+ T cells from murine spleen via nylon wool adherence and an optimized antibody cocktail,” J Immunol Methods. (2001) 258(1-2): 55-63. [cited by applicant]
Harrington et al., “Development of JCARH125: Optimization of a Fully Human Anti-BCMA CAR for Use in the Treatment of Multiple Myeloma,” ASH 2017. Abstract. Blood (Dec. 2017) 130:1813. [cited by applicant]
Harrington et al., “JCARH125: Development of an Optimized Fully Human Anti-BCMA CAR for the Treatment of Multiple Myeloma,” ASH 2017. Poster 1813. Presented on Dec. 9-12 . . . . [cited by applicant]
Henning et al., “Epigenetic control of CD8+ T cell differentiation,” Nat Rev Immunol (2018) 18(5): 340-356. [cited by applicant]
Hermans et al., “The VITAL assay: a versatile fluorometric technique for assessing CTL- and NKT-mediated cytotoxicity against multiple targets in vitro and in vivo,” J. Immunological Methods (2004) 285(1): 25-40. [cited by applicant]
Hinrichs et al., “Human effector CD8+ T cells derived from naïve rather than memory subsets possess superior traits for adoptive immunotherapy,” Blood (2011) 117(3): 808-814. [cited by applicant]
Hirakawa et al., “IL-2, IL-7, IL-15 and IL-6 Induce Differential Activation of Naive and Memory T Cell Subsets,” Blood (Dec. 2015) 126(23):3425, 4 pages. [cited by applicant]
Hoffmann et al., “Differences in expansion Potential of naive chimeric antigen receptor T cells from healthy Donors and Untreated chronic lymphocytic leukemia Patients,” Front. Immunol. (2018) 8:1956. [cited by applicant]
Holler et al., “In vitro evolution of a T cell receptor with high affinity for peptide/MHC,” Proc Natl Acad Sci U S A. (2000) 97(10): 5387-5392. [cited by applicant]
Holler et al., “TCRs with high affinity for foreign pMHC show self-reactivity,” Nat Immunol. Jan. 2003;4(1):55-62. [cited by applicant]
Hou et al., Tutorial on Animal Cell Culture Techniques, Gansu Science and Technology Press, Sep. 2009: p. 105 (Article in Chinese; English translation provided). [cited by applicant]
Huang et al., “DNA transposons for modification of human primary T lymphocytes,” Methods Mol Biol (2009) 506: 115-126. [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 (2013) 19(12):3153-3164. [cited by applicant]
Hunziker et al., “Exhaustion of cytotoxic T cells during adoptive immunotherapy of virus carrier mice can be prevented by B cells or CD4+ T cells,” Eur J Immunol (2002) 32(2):374-382. [cited by applicant]
Imadome, “The clinical condition and diagnosis of EBV-T/NK-LPD (CAEBV, EBV-HLH etc.),” [Rinsho Ketsueki] Japanese J Clin Hematol (2013) 54(10):1992-98. (Reference in Japanese) English translation provided. [cited by applicant]
Irving et al., “Engineering Chimeric Antigen Receptor T-Cells for Racing in Solid Tumors: Don't Forget the Fuel,” Front Immunol (Apr. 2017) 8:267. [cited by applicant]
Janas et al., “Perfusion's role in maintenance of high-density T-cell cultures,” BioProcesses International. (2015) pp. 1-12. [cited by applicant]
Janeway et al., Immunobiology: The Immune System in Health and Disease, 3rd ED., Current Biology Publications (1997), p. 4:33. [cited by applicant]
Jethwa et al., “Use of gene-modified regulatory T-cells to control autoimmune and alloimmune pathology: is now the right time?,” Clin Immunol. (2014) 150(1):51-63. [cited by applicant]
Joao et al., “Immunologic autograft engineering by manipulation of apheresis machine collection settings,” Am. Soc. Transplantation and Cellular Therapy 12(2): Suppl 1, p. 105, Abstract 298, Feb. 2006. [cited by applicant]
Johnston, et al., “Biolistic transformation: microbes to mice,” Nature (1990) 346: 776-777. [cited by applicant]
Jores et al., “Resolution of hypervariable regions in T-cell receptor beta chains by a modified Wu-Kabat index of amino acid diversity.,” PNAS (1990) 87(23):9138-9142. [cited by applicant]
Kaartinen et al., “Low interleukin-2 concentration favors generation of early memory T cells over effector phenotypes during chimeric antigen receptor T-cell expansion,” Cytotherapy. (Jun. 2017) 19(6):689-702. [cited by applicant]
Kaech et al., “Effector and memory T-cell differentiation: implications for vaccine development,” Nat Rev Immunol (2002) 2(4):251-62. [cited by applicant]
Kahn et al., “Optimization of retroviral vector-mediated gene transfer into endothelial cells in vitro,” Circ Res. (1992) 71(6): 1508-17. [cited by applicant]
Katz et al., “Therapeutic targeting of CD19 in hematological malignancies: past, present, future and beyond.” Leuk Lymphoma. (2014) 55(5):999-1006. [cited by applicant]
Kindt et al., “Antigens and Antibodies,” in Chapter 4 of Kuby Immunology, 6th ed., W.H. Freeman and Co., N.Y, (2007) pp. 91, 14 pages. [cited by applicant]
Klaver et al., “T Cell Maturation Stage Prior to and During GMP Processing Informs on CAR T Cell Expansion in Patients,” Front Immunol. (Dec. 2016) 7:648. [cited by applicant]
Klebanoff et al., “Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy?,” J Immunother. (2012) 35(9): 651-660. [cited by applicant]
Kochenderfer et al., “Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor,” J. Immunotherapy (2009) 32(7): 689-702. [cited by applicant]
Kochenderfer et al., “Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors,” Nature Reviews Clinical Oncology (2013) 10:267-276. [cited by applicant]
Koste et al., “T-cell receptor transfer into human T cells with ecotropic retroviral vectors,” Gene Therapy (2014) 21: 533-538. [cited by applicant]
Kotb, “Bacterial pyrogenic exotoxins as superantigens,” Clin Microbiol Rev. (1995) 8(3):411-426. [cited by applicant]
Kueberuwa et al., “CCR7+ selected gene-modified T cells maintain a central memory phenotype and display enhanced persistence in peripheral blood in vivo,” J Immunother Cancer. (Feb. 2017) 5: 14. [cited by applicant]
Kugler, “Analytical Characterization Studies for CAR-T Cell Therapy,” presentation presented at Immuno-Oncology Summit Europe, Adoptive T Cell Therapy on Mar. 19, 2018. [cited by applicant]
Kurucz et al., “A bacterially expressed single-chain Fv construct from the 2B4 T-cell receptor,” Proc Natl Acad Sci U S A. (1993) 90(9): 3830-3834. [cited by applicant]
Lefranc et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev Comp Immunol (2003) 27(1):55-77. [cited by applicant]
Levine et al., “Global manufacturing of CAR T cell therapy” Mol. Ther. Methods & Clin. Dev. (Dec. 2016) 4: 92-101. [cited by applicant]
Levine et al: “Global Manufacturing of CART Cell Therapy”, Molecular Therapy—Mthods & Clinical Develop, vol. 4, Mar. 4, 2017 (Mar. 4, 2017), pp. 92-101, XP055510414. [cited by applicant]
Li et al., “Comparison of inlet geomery in microfluidic cell affinity chromatography,” Analytical chemistry (2011) 83(3):774-781. [cited by applicant]
Li et al., “Directed evolution of human T-cell receptors with picomolar affinities by phage display,” Nat Biotechnol. (2005) 23:349-354. [cited by applicant]
Li et al., “Negative enrichment of target cells by microfluidic affinity chromatography,” Analytical Chemistry (2011) 83(20):7863-7869. [cited by applicant]
Li et al., “Multiparameter cell affinity chromatography: Separation and analysis in a single microfluidic channel,” Anal Chem (2012) 84(19):8140-8148. [cited by applicant]
Life Technologies Corporation (2013) OpTmizer™CTS™ T-cell Expansion SFM Technical information; pp. 1-2 (Year: 2013). [cited by applicant]
Ling et al., “B-cell and plasma cell antigens: new and previously defined clusters,” Leucocyte typing III. (1987) 302-355. [cited by applicant]
Liu et al., “Inclusion of Strep-tag II in design of antigen receptors for T-cell immunotherapy,” Nature Biotechnology (Apr. 2016) 34(4):430-434. [cited by applicant]
Lu et al., “A Rapid Cell Expansion Process for Production of Engineered Autologous CAR-T Cell Therapies,” Human Gene Therapy Methods (Dec. 2016) 27(6):209-218. [cited by applicant]
Lupton et al., “Dominant positive and negative selection using a hygromycin phosphotransferase-thymidine kinase fusion gene,” Mol. and Cell Biol. (1991) 11:6: 3374-3378. [cited by applicant]
Manuri et al., “piggyBac transposon/transposase system to generate CD19-specific T cells for the treatment of B-lineage malignancies,” Hum Gene Ther (2010) 21(4): 427-437. [cited by applicant]
Matsuki et al., “CD45RA-Foxp3(high) activated/effector regulatory T cells in the CCR7 + CD45RA-CD27 + CD28+central memory subset are decreased in peripheral blood from patients with rheumatoid arthritis,” Biochem Biophy… [cited by applicant]
Maus et al., “Chimeric antigen receptor T-cell therapy for the community oncologist,” Oncologist (May 2016) 21(5):608-617. [cited by applicant]
Mcwilliams et al., “Mutations in the 5′ end of the human immunodeficiency virus type 1 polypurine tract affect RNase H cleavage specificity and virus titer,” J Viral (2003) 77(20):11150-11157. [cited by applicant]
Mei et al., “Rationale of anti-CD19 immunotherapy: an option to target autoreactive plasma cells in autoimmunity,” Arthritis Res Ther. (2012) 14 Suppl 5(Suppl 5):S1. [cited by applicant]
Miller et al., “Improved retroviral vectors for gene transfer and expression,” Bio Techniques (1989) 7:980-990. [cited by applicant]
Miller et al., “Retrovirus packaging cells,” Human Gene Therapy (1990) 1:5-14. [cited by applicant]
Milone et al., “Chimeric Receptors Containing CD137 Signal Transduction Domains Mediate Enhanced Survival of T Cells and Increased Antileukemic Efficacy In Vivo,” Mol Ther (2009) 17(8):1453-64. [cited by applicant]
Miyoshi et al. “Development of a self-inactivating lentivirus vector,” J Viral (1998) 72(10):8150-8157. [cited by applicant]
Mock et al., “Automated manufacturing of chimeric antigen receptor T cells for adoptive immunotherapy using CliniMACS Prodify,” Cytotherapy (Aug. 2016) 18(8):1002-1011. [cited by applicant]
Moeller et al., “Adoptive transfer of gene-engineered CD4+ helper T cells induces potent primary and secondary tumor rejection,” Blood (2005) 106(9):2995-3003. [cited by applicant]
Naldini 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 U S A. (1996) 93(21):11382-8. [cited by applicant]
Naldini et al., “In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector,” Science. Apr. 12, 1996;272(5259):263-7. [cited by applicant]
Naldini et al., “Lentiviruses as gene transfer agents for delivery to non-dividing cells”, Curr Opin Biotechnol., Oct. 9, 1998; 5:457-63. [cited by applicant]
Nascimbeni et al., “Peripheral CD4+CD8+ T cells are differentiated effector memory cells with antiviral functions,” Blood (2004) 104(2):478-86. [cited by applicant]
Navarro et al., “Estrogen Stimulation Differentially Impacts Human Male and Female Antigen-specific T cell Anti-Tumor Function and Polyfunctionality,” Gender and the Genome (Dec. 2017) 1(4); 167-179. [cited by applicant]
Okern et al., “CTS™ immune cell SR for serum free culture and expansion of human T cells,” Journal for Immuno Therapy of Cancer (2015) 3(suppl 2): P1. [cited by applicant]
Park et al., “Treating cancer with genetically engineered T cells,” Trends Biotechnol. (2011) 29(11): 550-557. [cited by applicant]
Philpott et al., “Use of Nonintegrating Lentiviral Vectors for Gene Therapy,” Human Gene Therapy (2007) 18:483. [cited by applicant]
Portolano et al., “Lack of promiscuity in autoantigen-specific H and L chain combinations as revealed by human H and L chain “roulette”,” J Immunol (1993) 150(3):880-887. [cited by applicant]
Powell et al., “Sequence and structural determinants required for priming of plus-strand DNA synthesis by the human immunodeficiency virus type 1 polypurine tract,” J Viral (1996) 70(8):5288-5296. [cited by applicant]
Pullagurla et al., “Parallel affinity-based isolation of leukocyte subsets using microfluidics: application for stroke diagnosis,” Analytical chemistry (2014) 86(8):4058-4065. [cited by applicant]
Riddell et al., “Phase I study of cellular adoptive immunotherapy using genetically modified CD8+ HIV-specific T cells for HIV seropositive patients undergoing allogeneic bone marrow transplant,” Human Gene Therapy (199… [cited by applicant]
Rosenberg, et al., “Cell transfer immunotherapy for metastatic solid cancer—what clinicians need to know,” Nat Rev Clin Oncol. (2011) 8(10):577-85. [cited by applicant]
Sabatino et al., “Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies,” Blood. (Jul. 2016) 128(4): 519-528. [cited by applicant]
Sadelain et al., “The basic principles of chimeric antigen receptor design,” Cancer Discov. (2013) 3(4): 388-398. [cited by applicant]
Scarpa et al., “Characterization of recombinant helper retroviruses from Moloney-based vectors in ecotropic and amphotropic packaging cell lines,” Virology (1991) 180:849-852. [cited by applicant]
Schlueter et al., “Specificity and binding properties of a single-chain T cell receptor,” J Mol Biol. (1996) 256(5): 859-69. [cited by applicant]
Schuler et al., SYFPEITHI, Database for Searching and T-Cell Epitope Prediction. in Immunoinformatics Methods in Molecular Biology, (2007) 409(1): 75-93. [cited by applicant]
Sharma et al., “Efficient sleeping beauty DNA transposition from DNA minicircles,” Molec Ther Nucl Acids (2013) 2, e74. [cited by applicant]
Singh et al., “ProPred: prediction of HLA-DR binding sites,” Bioinformatics. (2001) 17(12): 1236-1237. [cited by applicant]
Skea et al., “The selective expansion of functional T cell subsets,” J Hematother Stem Cell Res. (1999) 8(5): 525-38. [cited by applicant]
Smith et al., “Development and evaluation of a human single chain variable fragment (scFv) derived BCMA targeted CAR T cell vector leads to a high objective response rate in patients with advanced MM,” Blood (Dec. 2017)… [cited by applicant]
Smith, “Development and evaluation of human anti-BCMA CAR T cell therapy from concept to clinic: Outline,” Oral presentation presented at ASH Dec. 2017. [cited by applicant]
Soo Hoo et al., “Characterization of a single-chain T-cell receptor expressed in [cited by applicant]
Stemberger et al., “Novel Serial Positive Enrichment Technology Enables Clinical Multiparameter Cell Sorting,” PLoS One (2012) 7(4): e35798. [cited by applicant]
Sun et al., “Early transduction produces highly functional chimeric antigen receptor-modified virus-specific T-cells with central memory markers: a Production Assistant for Cell Therapy (PACT) translational application,… [cited by applicant]
Tang et al., “Third-generation CD28/4-1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukaemia: a non-randomised, open-label phase I trial protocol,” BMJ Open. (Nov. 20… [cited by applicant]
Terakura et al., “Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells,” Blood (2012) 1:72-82. [cited by applicant]
Themeli et al., “Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy,” Nat Biotechnol. (2013) 31(10): 928-933. [cited by applicant]
ThermoFisher Scientific, DynabeadsTM M-450 product description, Catalog No. 14011; https://www.thermofisher.com/order/catalog/product/14011; last visited Oct. 6, 2022. [cited by applicant]
Tsukahara et al., “CD19 target-engineered T-cells accumulate at tumor lesions in human B-cell lymphoma xenograft mouse models,” Biochem Biophys Res Commun (2013) 438(1): 84-89. [cited by applicant]
Turtle et al., “Anti-CD19 Chimeric Antigen Receptor-Modified T Cell Therapy for B Cell Non-Hodgkin Lyphoma and Chronic Lyphocytic Leukemia: Fludarabine and Cyclophosphamide Lyphodepletion Improves In Vivo Expansion and … [cited by applicant]
Turtle et al., “CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients,” J. Clin. Invest. (Jun. 2016) 126(6):2123-38. [cited by applicant]
Turtle et al., “Engineered T cells for anti-cancer therapy,” Curr. Opin. Immunol. (2012) 24(5): 633-39. [cited by applicant]
Upparahalli et al., “GPRC5D is a cell surface plasma cell marker whose expression is high in myeloma cells and reduced following coculture with osteoclasts,” Blood (2013) 122(21):3099. [cited by applicant]
Van Tendeloo et al., “High-level transgene expression in primary human T lymphocytes and adult bone marrow CD34+ cells via electroporation-mediated gene delivery,” Gene Therapy (2000) 7(16): 1431-1437). [cited by applicant]
Verhoeyen et al., “Lentiviral vector gene transfer into human T cells,” Methods Mol Biol. (2009) 506: 97-114. [cited by applicant]
Wang et al., “Clinical manufacturing of CAR T cells: foundation of a promising therapy,” Molecular Therapy—Oncolytics (Jun. 2016) 3:16015. [cited by applicant]
Wang et al., “Current advances in T-cell-based cancer immunotherapy,” Immunotherapy (2014) 6(12): 1265-1278. [cited by applicant]
Wang et al., “Phenotypic and functional attributes of lentivirus-modified CD19-specific human CD8+ central memory T cells manufactured at clinical scale,” J Immunother. (2012) 35(9):689-701. [cited by applicant]
Wang et al., “Open-tubular capillary cell affinity chromatography: single and tandem blood cell separation,” Anal Chem (2008) 80(6):2118-2124. [cited by applicant]
Weng et al., “The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation,” Nat Rev Immunology (2012) 12(4): 306-315. [cited by applicant]
Wu et al., “Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: current status and future outlook,” Cancer (2012) 18(2): 160-175. [cited by applicant]
Wulfing et al., “Correctly folded T-cell receptor fragments in the periplasm of [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 (2014) 123(24):3750-3759. [cited by applicant]
Xu et al., “Multiparameter comparative analysis reveals differential impacts of various cytokines on CART cell phenotypes and function ex vivo and in vivo,” Oncotarget (Dec. 2016) 7(50):82354-82368. [cited by applicant]
Yarilin, “Immunology principles,” M. Medicine (1999) 184-195, 339-347 (English Translation included). [cited by applicant]
Zufferey et al. “Self-Inactivating Lentivirus Vector for Safe and Efficient In Vivo Gene Delivery,” J. Viral (1998) 72(12):9873-9880. [cited by applicant]
Zufferey et al., “Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo,” Nat Biotechnol. Sep. 1997;15(9):871-875. [cited by applicant]