IP Library › Granted Patent US 12,577,285
Granted Patent B2
US 12,577,285 · App. 16/769,971 · Granted Mar 17, 2026

Process for producing a composition of engineered T cells

Inventors: Mirna Mujacic (Seattle, WA); Ayu Rahardjo (Seattle, WA); Pascal Beauchesne (Seattle, WA); Kien Khuu-Duong (Seattle, WA); Ivie Aifuwa (Seattle, WA); Calvin Chan (Seattle, WA)
Assignee: Juno Therapeutics, Inc.
C07K14/7051A61K40/11A61K40/31A61K40/4215C12N5/0636A61K2239/31A61K2239/38A61K2239/48C12N2510/00
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 12,577,285
App. No.
16/769,971
Granted
Mar 17, 2026
Kind
B2
Abstract

The present disclosure provides methods for genetically engineering T cells, such as CD4+ T cells and/or CD8+ T cells, for use in cell therapy. In some aspects, the provided methods include one or more steps for pooling enriched CD4+ and CD8+ cells, such as at a 1:1 ratio, and then incubating the cells under stimulating conditions, introducing a recombinant polypeptide to the cells through transduction or transfection, and/or cultivating the cells under conditions that promote proliferation and/or expansion. In some aspects, the provided methods are an efficient, reliable means to produce genetically engineered T cells with a high degree of success.

Claims (104)

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

(a) incubating an input composition under stimulating conditions, thereby generating a stimulated composition, wherein:

the input composition comprises between 100×10 6 and 500×10 6 total CD4+ and CD8+ T cells at a concentration of between 1×10 6 cells/mL and 5×10 6 cells/mL and a ratio of between 3:1 and 1:3 CD4+to CD8+ T cells, wherein the T cells of the input composition are primary T cells obtained from a human subject having a cancer; and

the stimulating conditions comprise the presence of a stimulatory reagent comprising a primary agent that specifically binds to CD3 and a secondary agent that specifically binds to CD28;

(b) introducing a chimeric antigen receptor (CAR) into T cells from the stimulated composition, thereby generating an engineered cell composition, wherein:

the incubation and introducing are each performed in a first serum-free medium comprising 0.5 mM to 5 mM L-glutamine, 0.5 mM to 5 mM L-alanyl-L-glutamine, between 50 IU/mL and 500 IU/mL recombinant IL-2, between 100 IU/mL and 2,000 IU/mL recombinant IL-7, and between 50 IU/mL and 500 IU/mL recombinant IL-15;

the introducing is initiated within 2 days after the initiation of the incubation under stimulating conditions;

the introducing comprises contacting between 50×10 6 T cells and 200×10 6 T cells from the stimulated composition with an agent comprising a polynucleotide encoding the CAR; and

during the introducing, the T cells from the stimulated composition are cultured at a concentration of between 0.5×10 6 cells/mL and 2×10 6 cells/mL; and

(c) cultivating the engineered composition under conditions to promote expansion of the engineered T cells, thereby producing an output composition comprising engineered T cells, wherein:

the cultivating is performed in a second serum-free medium comprising 0.5 mM to 5 mM L-glutamine, 0.5 mM to 5 mM L-alanyl-L-glutamine, between 50 IU/mL and 500 IU/mL recombinant IL-2, between 100 IU/mL and 2,000 IU/mL recombinant IL-7, and between 50 IU/mL and 500 IU/mL recombinant IL-15;

the cultivating is initiated within 3 days after the initiation of the of the incubation under stimulating conditions;

the cultivating is performed under steady rocking conditions;

at least a portion of the cultivating is performed with perfusion using the second serum-free medium; and

the cultivating is performed at least until the engineered composition comprises a threshold number of viable T cells that is at least 2,000×10 6 viable T cells, wherein the threshold number of viable T cells is achieved within 9 days of the initiation of the incubation.

2 . The method of claim 1 , wherein the input composition comprises at or about 300×10 6 total CD4+ and CD8+ T cells.

3 . The method of claim 1 , wherein the input composition comprises a concentration of between 3×10 6 cells/mL and 5×10 6 cells/mL.

4 . The method of claim 1 , wherein the input composition comprises a concentration of or of about 3×10 6 cells/mL.

5 . The method of claim 1 , wherein the input composition comprises a ratio of between 2:1 and 1:2 CD4+to CD8+cells.

6 . The method of claim 1 , wherein the input composition comprises a ratio of or of about 1:1 CD4+to CD8+cells.

7 . The method of claim 1 , wherein the contacting is by transduction with a viral vector.

8 . The method of claim 7 , wherein the viral vector is a retroviral vector.

9 . The method of claim 1 , wherein at least about 100×10 6 T cells and up to about 200×10 6 T cells of the stimulated composition are contacted with the agent comprising the polynucleotide.

10 . The method of claim 1 , wherein during the introducing, the T cells from the stimulated composition are cultured at a concentration of or of about 1×10 6 cells/mL.

11 . The method of claim 1 , wherein the primary agent comprises an anti-CD3 antibody or an antigen-binding fragment thereof, and the secondary agent comprises an anti-CD28 antibody or an antigen-binding fragment thereof.

12 . The method of claim 11 , wherein the primary agent and secondary agent are present on the surface of a solid support.

13 . The method of claim 12 , wherein the solid support is a bead.

14 . The method of claim 13 , wherein the ratio of beads to cells is from or from about 2:1 to 0.5:1.

15 . The method of claim 13 , wherein the ratio of beads to cells is or is about 1:1.

16 . The method of claim 1 , wherein the input composition is incubated under stimulating conditions for between 12 hours and 36 hours, inclusive.

17 . The method of claim 1 , wherein the contacting is carried out for between 12 hours and 36 hours, inclusive.

18 . The method of claim 1 , wherein at least a portion of the cultivating is performed with perfusion at a rate of at least 500 mL/day.

19 . The method of claim 1 , wherein at least a first portion of the cultivating is performed with a perfusion rate of or of about 750 mL/day, and at least a second portion of the cultivating is performed with a perfusion rate of or of about 1,500 mL/day.

20 . The method of claim 1 , wherein:

the perfusion is initiated at a rate of or of about 750 mL/day when the cells reach a density of or of about 0.6×10 6 cells/mL; and

the perfusion is increased to a rate of or of about 1500 mL/day when the cells reach a density of or of about 2.0×10 6 cells/mL.

21 . The method of claim 1 , wherein the threshold number of viable T cells is achieved between about 5 days and about 9 days from the initiation of the incubation.

22 . The method of claim 1 , further comprising formulating cells of the output composition for cryopreservation or administration to a subject.

23 . The method of claim 1 , further comprising isolating the CD4+ and the CD8+ T cells from a biological sample from the subject prior to the incubation.

24 . The method of claim 1 , wherein the CAR is capable of binding to a target antigen that is associated with, specific to, or expressed on a cell or tissue of a disease, disorder or condition.

25 . The method of claim 1 , wherein the recombinant receptor is an anti-B cell maturation antigen (BCMA) CAR.

26 . The method of claim 1 , wherein during at least a portion of the cultivating, the cells are monitored for cell viability, concentration, density, number, or a combination thereof, wherein the monitoring is carried out by differential digital holography microscopy (DDHM).

27 . The method of claim 1 , wherein the input composition comprises at least 80% cells that are CD4+ T cells and CD8+ T cells.

28 . The method of claim 1 , wherein the input composition comprises at least 90% cells that are CD4+ T cells and CD8+ T cells.

29 . The method of claim 1 , wherein the threshold number of viable T cells is achieved within 8 days of the initiation of the incubation.

30 . The method of claim 1 , wherein the threshold number of viable T cells is achieved between about 5 days and about 8 days from the initiation of the incubation.

31 . The method of claim 1 , wherein the cancer is a multiple myeloma.

32 . The method of claim 1 , wherein at least 30% of the cells in the output composition are CCR7+/CD45RA− or CCR7+/CD45RO+.

33 . The method of claim 1 , wherein for a plurality of output compositions produced by the method for a plurality of different human subjects having the cancer, the mean percentage of cells that are CCR7+/CD45RA− or CCR7+/CD45RO+in the plurality of the output compositions is between about 40% and about 65%.

34 . The method of claim 1 , wherein the contacting is effected by spinoculation.

35 . The method of claim 1 , wherein each of the first serum-free medium and the second serum-free medium do not comprise phenol red.

36 . The method of claim 1 , wherein each of the first serum-free medium and the second serum-free medium comprise a serum-substitute protein.

37 . The method of claim 1 , wherein the concentration of at least one of the cytokines in the first serum-free medium and second serum-free medium is different.

38 . The method of claim 1 , wherein the concentrations of recombinant IL-2, IL-7, and IL-15 in the second serum-free medium are twice the concentrations of recombinant IL-2, IL-7, and IL-15 in the first serum-free medium.

39 . The method of claim 1 , wherein:

the first serum-free medium comprises between at or about 100 IU/mL and at or about 300 IU/mL recombinant IL-2, between at or about 500 IU/mL and at or about 1,500 IU/mL recombinant IL-7, and between at or about 100 IU/mL and at or about 300 IU/mL recombinant IL-15; and/or

the second serum-free medium comprises between at or about 100 IU/mL and at or about 300 IU/mL recombinant IL-2, between at or about 500 IU/mL and at or about 1,500 IU/mL recombinant IL-7, and between at or about 100 IU/mL and at or about 300 IU/mL recombinant IL-15.

40 . The method of claim 1 , wherein the first and/or second serum-free medium comprises between at or about 50 IU/mL and at or about 150 IU/mL recombinant IL-2, between at or about 500 IU/mL and at or about 1,000 IU/mL recombinant IL-7, and between at or about 50 IU/mL and at or about 150 IU/mL recombinant IL-15.

41 . The method of claim 1 , wherein the first serum-free medium comprises between at or about 50 IU/mL and at or about 150 IU/mL recombinant IL-2, between at or about 500 IU/mL and at or about 1,000 IU/mL recombinant IL-7, and between at or about 50 IU/mL and at or about 150 IU/mL recombinant IL-15.

42 . The method of claim 41 , wherein the second serum-free medium comprises between at or about 150 IU/mL and at or about 250 IU/mL recombinant IL-2, between at or about 1000 IU/mL and at or about 1,500 IU/mL recombinant IL-7, and between at or about 150 IU/mL and at or about 250 IU/mL recombinant IL-15.

43 . The method of claim 1 , wherein the second serum-free medium comprises between at or about 150 IU/mL and at or about 250 IU/mL recombinant IL-2, between at or about 1000 IU/mL and at or about 1,500 IU/mL recombinant IL-7, and between at or about 150 IU/mL and at or about 250 IU/mL recombinant IL-15.

44 . The method of claim 1 , wherein at least a portion of the cultivating is performed with perfusion using the second serum-free medium at a rate of between 500 mL/day and 800 mL/day.

45 . The method of claim 1 , wherein at least a portion of the cultivating is performed with perfusion using the second serum-free medium at a rate of between 900 mL/day and 1,500 mL/day.

46 . The method of claim 1 , wherein:

at least a first portion of the cultivating is performed with perfusion using the second serum-free medium at a rate of between 500 mL/day and 800 mL/day; and

at least a second portion of the cultivating is performed with perfusion using the second serum-free medium at a rate of between 900 mL/day and 1,500 mL/day.

47 . The method of claim 1 , wherein the perfusion using the second serum-free medium is performed at a rate of between 500 mL/day and 800 mL/day when the cells reach a density of between or between about 0.4×10 6 cells/mL and 0.8×10 6 cells/mL.

48 . The method of claim 1 , wherein the perfusion using the second serum-free medium is performed at a rate of between 900 mL/day and 1,500 mL/day when the cells reach a density of between or between about 1.0×10 6 cells/mL and 1.4×10 6 cells/mL.

49 . The method of claim 1 , wherein:

the perfusion using the second serum-free medium is performed at a rate of between 500 mL/day and 800 mL/day when the cells reach a density of between or between about 0.4×10 6 cells/mL and 0.8×10 6 cells/mL; and

the perfusion using the second serum-free medium is performed at a rate of between 900 mL/day and 1,500 mL/day when the cells reach a density of between or between about 1.0×10 6 cells/mL and 1.4×10 6 cells/mL.

50 . The method of claim 1 , wherein the threshold number of viable T cells that is at least 2400×10 6 viable T cells.

51 . The method of claim 1 , wherein the second serum-free medium comprises between 600 IU/mL and 2,000 IU/mL recombinant IL-7.

52 . A method for producing a composition of engineered cells, the method comprising:

(a) combining a composition of CD4+ T cells and a composition of CD8+ T cells at a ratio of between 2:1 and 1:2 CD4+to CD8+ T cells, thereby generating an input composition, wherein:

the input composition comprises between 100×10 6 and 500×10 6 total CD4+ and CD8+ T cells at a concentration of between 1×10 6 cells/mL and 5×10 6 cells/mL; and

the T cells of the input composition are primary T cells obtained from a human subject having a cancer;

(b) incubating the input composition under stimulating conditions, thereby generating a stimulated composition, wherein the stimulating conditions comprise a primary agent that specifically binds to CD3 and a secondary agent that specifically binds to CD28;

(c) introducing a chimeric antigen receptor (CAR) into T cells from the stimulated composition, thereby generating an engineered cell composition, wherein:

the incubation and introducing are each performed in a first serum-free medium comprising 0.5 mM to 5 mM L-glutamine, 0.5 mM to 5 mM L-alanyl-L-glutamine, between 50 IU/mL and 500 IU/mL recombinant IL-2, between 100 IU/mL and 2,000 IU/mL recombinant IL-7, and between 50 IU/mL and 500 IU/mL recombinant IL-15;

the introducing is initiated within 2 days after the initiation of the incubation under stimulating conditions;

the introducing comprises contacting between 50×10 6 T cells and 200×10 6 T cells from the stimulated composition with an agent comprising a polynucleotide encoding the CAR; and

during the introducing, the T cells from the stimulated composition are cultured at a concentration of between 0.5×10 6 cells/mL and 2×10 6 cells/mL; and

(c) cultivating the engineered composition under conditions to promote expansion of the engineered T cells, thereby producing an output composition comprising engineered T cells, wherein:

the cultivating is performed in a second serum-free medium comprising 0.5 mM to 5 mM L-glutamine, 0.5 mM to 5 mM L-alanyl-L-glutamine, between 50 IU/mL and 500 IU/mL recombinant IL-2, between 100 IU/mL and 2,000 IU/mL recombinant IL-7, and between 50 IU/mL and 500 IU/mL recombinant IL-15;

the cultivating is initiated within 3 days after the initiation of the incubation under stimulating conditions;

the cultivating is performed under steady rocking conditions;

at least a portion of the cultivating is performed with perfusion using the second serum-free medium; and

the cultivating is performed at least until the engineered composition comprises a threshold number of viable T cells that is at least 2,000×10 6 viable T cells, wherein the threshold number of viable T cells is achieved within 9 days of the initiation of the incubation.

53 . A method for producing a composition of engineered cells, the method comprising:

(a) incubating an input composition under stimulating conditions, thereby generating a stimulated composition, wherein:

the input composition comprises between 100×10 6 and 500×10 6 total CD4+ and CD8+ T cells at a concentration of between 1×10 6 cells/mL and 5×10 6 cells/mL and a ratio of between 3:1 and 1:3 CD4+to CD8+ T cells, wherein the T cells of the input composition are primary T cells obtained from a human subject having a cancer; and

the stimulating conditions comprise the presence of a stimulatory reagent comprising a primary agent that specifically binds to CD3 and a secondary agent that specifically binds to CD28;

(b) introducing a chimeric antigen receptor (CAR) into T cells from the stimulated composition, thereby generating an engineered cell composition, wherein:

the incubation and introducing are each performed in a first serum-free medium comprising 0.5 mM to 5 mM L-glutamine, 0.5 mM to 5 mM L-alanyl-L-glutamine, between 50 IU/mL and 500 IU/mL recombinant IL-2, between 100 IU/mL and 2,000 IU/mL recombinant IL-7, and between 50 IU/mL and 500 IU/mL recombinant IL-15;

the introducing is initiated within 2 days after the initiation of the incubation under stimulating conditions;

the introducing comprises contacting between 50×10 6 T cells and 200×10 6 T cells from the stimulated composition with an agent comprising a polynucleotide encoding the CAR; and

during the introducing, the T cells from the stimulated composition are cultured at a concentration of between 0.5×10 6 cells/mL and 2×10 6 cells/mL; and

(c) cultivating the engineered composition under conditions to promote expansion of the engineered T cells, thereby producing an output composition comprising engineered T cells, wherein:

the cultivating is performed in a second serum-free medium comprising 0.5 mM to 5 mM L-glutamine, 0.5 mM to 5 mM L-alanyl-L-glutamine, between 50 IU/mL and 500 IU/mL recombinant IL-2, between 100 IU/mL and 2,000 IU/mL recombinant IL-7, and between 50 IU/mL and 500 IU/mL recombinant IL-15;

the cultivating is initiated within 3 days after the initiation of the incubation under stimulating conditions;

the cultivating is performed under steady rocking conditions;

at least a portion of the cultivating is performed with perfusion using the second serum-free medium; and

the cultivating is performed at least until the engineered composition comprises a threshold number of viable T cells that is at least 2,400×10 6 viable T cells, wherein the threshold number of viable T cells is achieved between 5 days and 9 days from the initiation of the incubation.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 6, 2020
From: MUJACIC, MIRNA; RAHARDJO, AYU; BEAUCHESNE, PASCAL; AIFUWA, IVIE; CHAN, CALVIN; KHUU-DUONG, KIEN
To: JUNO THERAPEUTICS, INC.
Reel/Frame 053127/0863 →
Continuity (9)
Provisional Application 62774855 · Dec 3, 2018
Provisional Application 62774165 · Nov 30, 2018
Provisional Application 62754564 · Nov 1, 2018
Provisional Application 62740903 · Oct 3, 2018
Provisional Application 62721604 · Aug 22, 2018
Provisional Application 62716971 · Aug 9, 2018
Provisional Application 62614965 · Jan 8, 2018
Provisional Application 62596774 · Dec 8, 2017
Related Publication 20200384025A1 · Dec 10, 2020
References Cited (400)
US 1631788A · Bennett · 1927 [cited by applicant]
US 4452773A · Molday · 1984 [cited by applicant]
US 4690915A · Rosenberg · 1987 [cited by applicant]
US 4795698A · Owen · 1989 [cited by applicant]
US 5087616A · Myers · 1992 [cited by applicant]
US 5168049A · Meade et al. · 1992 [cited by applicant]
US 5200084A · Liberti · 1993 [cited by applicant]
US 5219740A · Miller · 1993 [cited by applicant]
US 5506121A · Skerra et al. · 1996 [cited by applicant]
US 5773224A · Grandics et al. · 1998 [cited by applicant]
US 6022951A · Sano et al. · 2000 [cited by applicant]
US 6040177A · Riddell et al. · 2000 [cited by applicant]
US 6060273A · Dirks et al. · 2000 [cited by applicant]
US 6103493A · Skerra et al. · 2000 [cited by applicant]
US 6123655A · Fell · 2000 [cited by applicant]
US 6156493A · Stayton · 2000 [cited by applicant]
US 6165750A · Stayton et al. · 2000 [cited by applicant]
US 6207453B1 · Maass · 2001 [cited by applicant]
US 6368813B1 · Reznik et al. · 2002 [cited by applicant]
US 6410319B1 · Raubitschek · 2002 [cited by applicant]
US 6451995B1 · Cheung · 2002 [cited by applicant]
US 6733433B1 · Fell · 2004 [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 7362449B2 · Dubois et al. · 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 7776562B2 · Busch et al. · 2010 [cited by applicant]
US 7981632B2 · Schmidt · 2011 [cited by applicant]
US 8008450B2 · Williams et al. · 2011 [cited by applicant]
US 8153765B2 · Park et al. · 2012 [cited by applicant]
US 8298782B2 · Busch et al. · 2012 [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 8603477B2 · Afar et al. · 2013 [cited by applicant]
US 8735540B2 · Schmidt et al. · 2014 [cited by applicant]
US 8802374B2 · Jensen · 2014 [cited by applicant]
US 8822647B2 · Jensen · 2014 [cited by applicant]
US 8911993B2 · June et al. · 2014 [cited by applicant]
US 9023604B2 · Schmidt et al. · 2015 [cited by applicant]
US 9684281B2 · Mathuis et al. · 2017 [cited by applicant]
US 9904248B2 · Mathuis et al. · 2018 [cited by applicant]
US 10131882B2 · Matthew et al. · 2018 [cited by applicant]
US 11066475B2 · Sather et al. · 2021 [cited by applicant]
US 11400115B2 · Ramsbourg et al. · 2022 [cited by applicant]
US 11458167B2 · Jensen · 2022 [cited by applicant]
US 20020131960A1 · Sadelain · 2002 [cited by applicant]
US 20020150914A1 · Anderse et al. · 2002 [cited by applicant]
US 20030170238A1 · Gruenberg et al. · 2003 [cited by applicant]
US 20030223994A1 · Hoogenboom 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 20070092530A1 · Weidanz 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 20080171951A1 · Fell · 2008 [cited by applicant]
US 20090226474A1 · Weidanz et al. · 2009 [cited by applicant]
US 20090304679A1 · Weidanz · 2009 [cited by applicant]
US 20100260748A1 · Elkins et al. · 2010 [cited by applicant]
US 20110003380A1 · Miltenyi · 2011 [cited by applicant]
US 20110070581A1 · Gupta · 2011 [cited by applicant]
US 20110293667A1 · Baksh et al. · 2011 [cited by applicant]
US 20120189622A1 · Tesar et al. · 2012 [cited by applicant]
US 20130029418A1 · Angel et al. · 2013 [cited by applicant]
US 20130149337A1 · Cooper et al. · 2013 [cited by applicant]
US 20130287748A1 · June · 2013 [cited by applicant]
US 20140234893A1 · Enenkel · 2014 [cited by applicant]
US 20140255993A1 · Follstad · 2014 [cited by examiner]
US 20140271635A1 · Brogdon et al. · 2014 [cited by applicant]
US 20140294841A1 · Scheinberg et al. · 2014 [cited by applicant]
US 20150051266A1 · Kochenderfer · 2015 [cited by applicant]
US 20150283178A1 · June et al. · 2015 [cited by applicant]
US 20160046724A1 · Brogdon et al. · 2016 [cited by applicant]
US 20160152723A1 · Chen et al. · 2016 [cited by applicant]
US 20160237139A1 · Puléet al. · 2016 [cited by applicant]
US 20160297884A1 · Kuo et al. · 2016 [cited by applicant]
US 20160346326A1 · Bot 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 20170226216A1 · Morgan et al. · 2017 [cited by applicant]
US 20170281766A1 · Wiltzius · 2017 [cited by applicant]
US 20170283504A1 · Wiltzius · 2017 [cited by applicant]
US 20180085444A1 · Morgan et al. · 2018 [cited by applicant]
US 20180296602A1 · Riddell et al. · 2018 [cited by applicant]
US 20180334653A1 · O'Neill · 2018 [cited by applicant]
US 20190161553A1 · Blythe et al. · 2019 [cited by applicant]
US 20200354677A1 · Lee et al. · 2020 [cited by applicant]
US 20210163893A1 · Westoby et al. · 2021 [cited by applicant]
US 20210207080A1 · Beauchesne et al. · 2021 [cited by applicant]
US 20210324100A1 · Blythe et al. · 2021 [cited by applicant]
US 20210393690A1 · Sather et al. · 2021 [cited by applicant]
US 20220096651A1 · Costa et al. · 2022 [cited by applicant]
US 20230087953A1 · Westoby et al. · 2023 [cited by applicant]
US 20230090176A1 · Ramsborg et al. · 2023 [cited by applicant]
US 20230149462A1 · Stirner et al. · 2023 [cited by applicant]
US 20230190814A1 · Ramsborg et al. · 2023 [cited by applicant]
US 20230346734A1 · Hudecek et al. · 2023 [cited by applicant]
CN 103305464 · 2013 [cited by applicant]
CN 103502438 · 2014 [cited by applicant]
CN 104450614 · 2015 [cited by applicant]
CN 105777911 · 2016 [cited by applicant]
CN 105837693 · 2016 [cited by applicant]
CN 106635955A · 2017 [cited by applicant]
CN 106754670 · 2017 [cited by applicant]
CN 106834218 · 2017 [cited by applicant]
CN 106801032 · 2017 [cited by applicant]
CN 107827989 · 2018 [cited by applicant]
EP 0452342 · 1991 [cited by applicant]
EP 2537416 · 2012 [cited by applicant]
EP 3372670 · 2018 [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 WO199624606 · 1996 [cited by applicant]
WO WO1998040396 · 1998 [cited by applicant]
WO WO1998040510 · 1998 [cited by applicant]
WO WO1999018129 · 1999 [cited by applicant]
WO WO1999025817 · 1999 [cited by applicant]
WO WO1999060120 · 1999 [cited by applicant]
WO WO2000014257 · 2000 [cited by applicant]
WO WO2000038762 · 2000 [cited by applicant]
WO WO2000043551 · 2000 [cited by applicant]
WO WO2002077018 · 2002 [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 WO2006099875 · 2006 [cited by applicant]
WO WO2007117602 · 2007 [cited by applicant]
WO WO2008035631 · 2008 [cited by applicant]
WO WO2009003493 · 2009 [cited by applicant]
WO WO2009072003 · 2009 [cited by applicant]
WO WO2009072006 · 2009 [cited by applicant]
WO WO2009080829 · 2009 [cited by applicant]
WO WO2010033140 · 2010 [cited by applicant]
WO WO2010104949 · 2010 [cited by applicant]
WO WO2011044186 · 2011 [cited by applicant]
WO WO2012081650 · 2012 [cited by applicant]
WO WO2012092612 · 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 WO2013166321 · 2013 [cited by applicant]
WO WO2014011996 · 2014 [cited by applicant]
WO WO2014031687 · 2014 [cited by applicant]
WO WO2014055668 · 2014 [cited by applicant]
WO WO2014076277 · 2014 [cited by applicant]
WO WO2014100385 · 2014 [cited by applicant]
WO WO2014144039 · 2014 [cited by applicant]
WO WO2014210064 · 2014 [cited by applicant]
WO WO2015095895 · 2015 [cited by applicant]
WO WO2015157252 · 2015 [cited by applicant]
WO WO2015157384 · 2015 [cited by applicant]
WO WO2015157391 · 2015 [cited by applicant]
WO WO2015158671 · 2015 [cited by applicant]
WO WO2015158868 · 2015 [cited by applicant]
WO WO2015164675 · 2015 [cited by applicant]
WO WO2015164745A1 · 2015 [cited by examiner]
WO WO2015181253 · 2015 [cited by applicant]
WO WO2016014565 · 2016 [cited by applicant]
WO WO2016014789 · 2016 [cited by applicant]
WO WO2016019300A1 · 2016 [cited by examiner]
WO WO2016073602 · 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 WO2016090369 · 2016 [cited by applicant]
WO WO2016094304 · 2016 [cited by applicant]
WO WO2016109410 · 2016 [cited by applicant]
WO WO2016130598 · 2016 [cited by applicant]
WO WO2016154628 · 2016 [cited by applicant]
WO WO2016164580 · 2016 [cited by applicant]
WO WO2017015427 · 2017 [cited by applicant]
WO WO2017015490 · 2017 [cited by applicant]
WO WO2017023803 · 2017 [cited by applicant]
WO WO2017027291 · 2017 [cited by applicant]
WO WO2017041143 · 2017 [cited by applicant]
WO WO2017064084 · 2017 [cited by applicant]
WO WO2017068421 · 2017 [cited by applicant]
WO WO2017087547 · 2017 [cited by applicant]
WO WO2015164745 · 2017 [cited by applicant]
WO WO2017096329 · 2017 [cited by applicant]
WO WO2017130223 · 2017 [cited by applicant]
WO WO2017156479 · 2017 [cited by applicant]
WO WO2017157505 · 2017 [cited by applicant]
WO WO2017161353 · 2017 [cited by applicant]
WO WO2017173256 · 2017 [cited by applicant]
WO WO2017177137 · 2017 [cited by applicant]
WO WO2017180993 · 2017 [cited by applicant]
WO WO2018085690 · 2018 [cited by applicant]
WO WO2018106732 · 2018 [cited by applicant]
WO WO2018162352 · 2018 [cited by applicant]
WO WO2018170188 · 2018 [cited by applicant]
WO WO2018175988 · 2018 [cited by applicant]
WO WO2018191723 · 2018 [cited by applicant]
WO WO2018197675 · 2018 [cited by applicant]
WO WO2018197949 · 2018 [cited by applicant]
WO WO2018204427 · 2018 [cited by applicant]
WO WO2019089855 · 2019 [cited by applicant]
WO WO2019090003 · 2019 [cited by applicant]
WO WO2019113556 · 2019 [cited by applicant]
WO WO2019113557 · 2019 [cited by applicant]
WO WO2020033927 · 2020 [cited by applicant]
WO WO2020092848 · 2020 [cited by applicant]
Kahn, M.L., et al (1992) Optimization of Retroviral Vector-Mediated Gene Transfer into Endothelial Cells in Vitro Circulation Research 71(6); 1508-1517 (Year: 1992). [cited by examiner]
Janas, M., et al (2015) Perfusion's Role in Maintenance of High-Density T-cell Cultures BioProcesses International pp. 1-12 (Year: 2015). [cited by examiner]
Sun, J., et al (2015) 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 app… [cited by examiner]
Klaver, Y., et al (2016) T cell Maturation Stage Prior to and During GMP Processing Informs on CAR T Cell Expansion in Patients Frontiers in Immunology 7(648); 1-7 (Year: 2016). [cited by examiner]
Frayer, C.D., et al (2018) Mean Body Weight, Height, Waist circumference, and Body Mass Index Among Adults: United States 1999-2000 through 2015-2016 National Health Statistics Reports 122; 1-16 (Year: 2018). [cited by examiner]
Applikon Biotechnology/BioPharma-Reporter (2016) How automation has changed the way we count cells BioPharma-Reporter.com; 1-4 (Year: 2016). [cited by examiner]
Okern, G., et al (2015) CTS™ immune cell SR for serum free culture and expansion of human T cells Journal for Immuno Therapy of Cancer 3(suppl 2): P1 (Year: 2015). [cited by examiner]
Life Technologies Corporation (2013) OpTmizer™CTS™MT-cell Expansion SFM Technical information; pp. 1-2 (Year: 2013). [cited by examiner]
Berthois, Y., et al (1986) Phenol red in tissue culture media is a weak estrogen: Implications concerning the study of estrogen-responsive cells in culture Proc. Natl. Acad. Sci 83; 2496-2500 (Year: 1986). [cited by examiner]
Navarro, F.C., and S.K. Watkins (2017) Estrogen Stimulation Differentially Impacts Human Male and Female Antigen-specific T cell Anti-Tumor Function and Polyfunctionality Gender and the Genome 1(4); 167-179 (Year: 2017). [cited by examiner]
Hirakawa, M., et al (2015) IL-2, IL-7, IL-15, and IL-6 induce differential activation of naïve and memory T cell subsets Blood 126(23); 3425; pp. 1-4 (Year: 2015). [cited by examiner]
U.S. Appl. No. 16/770,052, filed Jun. 4, 2020, by Pascal et al. (Copy not provided). (Copy not submitted herewith pursuant to the waiver of 37 C.F. R. § 1.98(a)(2)(iii) issued by the Office on Sep. 21, 2004). [cited by applicant]
Abramson et al., “Transcend NHL 001: Ininunotherapy with the CD19-Directed CAR T-Cell Product JCARO17 Results in High Complete Response Rates in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma,” Blood (2016) 128(22):… [cited by applicant]
Argarana et al., “Molecular cloning and nucleotide sequence of the streptavidin gene,” Nucl Acids Res (1986) 14(4):1871-1882. [cited by applicant]
Aksoy et al., “Human primary T cells: a practical guide,” dated Jun. 19, 2018. Retrieved from https://peerj.com/preprints/26993.html. [cited by applicant]
Al-Hujaily et al., “Development of novel immunotherapies for multiple myeloma,” Int J Mol Sci. (2016) 17:1506. [cited by applicant]
Ali et al., “T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma,” Blood (2016) 128 (13): 1688-1700. [cited by applicant]
Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins,” J Mol Biol (1997) 273(4):927-948. [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]
Anonymous, “Scientists helping scietists ™ | WWW Optimization of Human T Cell Expansion Protocol: Effects of Early Cell Dilution,” (2018). [cited by applicant]
Barrett et al., “Chimeric Antigen Receptor Therapy for Cancer,” Annu Rev Med (2014) 65:333-347. [cited by applicant]
Baum et al., “Retrovirus Vectors: Toward the plentivirus,” Mol Ther (2006) 13:1050-1063. [cited by applicant]
Benson et al., “CS1-Directed monoclonal antibody therapy for multiple myeloma,” J Clin Oncol (2012) 30(16):2012-2015. [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. Journal of Clinical Oncology. 2017;35(15_suppl):3010-3010. [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]
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 alighment problem in biology,” SIAM Journal of Applied Mathemathics (1988) 48(5):1073-1082. [cited by applicant]
Carpenter et al., “B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma,” Clin Cancer Res. (2013) 19:2048-2060. [cited by applicant]
Cavaletti et al., “Chemotherapy-induced peripheral neurotoxicity,” Nat Rev Neurol (2010) 6(12):657-666. [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]
Chang et al., “Identification and selective expansion of functionally superior T cells expressing chimeric antigen receptors,” J Transl Med (2015) 13(1):161. [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 sorfer (μFACS),” Lab on a 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]
Chu et al., “CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma,” Leukemia (2014) 28(4):917-927. [cited by applicant]
Church et al., “Tumor-specific CD4+ T cells maintain effector and memory tumor-specific CD8+ T cells,” Eur J Immunol (2014) 44: 69-79. [cited by applicant]
Clackson et al., “Making antibody fragments using phage display libraries,” Nature (1991) 352(6336):624-628. [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,”0 J Mol RecogN (2003) 16:324-332. [cited by applicant]
Cohen et al., “Recognition of Fresh Human Tumor by Human Peripheral Blood Lymphocytes Transduced with a Bicistronic Retroviral Vector Encoding a Murine Anti-p53 TCR,” J Immunol (2005) 175(9):5799-5808. [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]
Cruz-Guilloty et al., “Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs,” J Exp Med (2009) 206: 51-9. [cited by applicant]
Darling et al., “Kinetic exclusion assay technology: characterization of molecular interactions,” Assay Drug Dev Technol. (2004) 2:647-657. [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]
Davila et al., “Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia,” Science Translational Medicine (2014) 6(224):224ra25. [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]
Dimopoulos et al., “Current treatment landscape for relapsed and/or refractory multiple myeloma,” Nat Rev Clin Oncol. (2015) 12:42-54. [cited by applicant]
Fairhead et al., “Plug-and-Play Pairing via Defined Divalent Streptavidins,” J Mol Biol (2014) 426(1):199-214. [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,” Journal of Clinical Oncology (2017) 35(18_suppl): LBA3001-LBA30… [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]
Fraietta et al., “Biomarkers of Response to Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with Chronic Lymphocytic Leukemia,” Blood (2016) 128(22):57. [cited by applicant]
Fraietta et al., “Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia,” Nat Med. (May 2018) 24(5):563-571. Epub Apr. 30, 2018. [cited by applicant]
Frecha et al., “Advances in the field of lentivector-based transduction of T and B lymphocytes for gene therapy,” Mol Ther (2010) 18(10):1748-1757. [cited by applicant]
Garfall et al., “Immunotherapy with chimeric antigen receptors for multiple myeloma,” Discov Med (2014) 17(91):37-46. [cited by applicant]
Gargett et al., “Different cytokine and stimulation conditions influence the expansion and immune phenotype of third-generation chimeric antigen receptor T cells specific for tumor antigen GD2,” Cytotherapy (2015) 17(4)… [cited by applicant]
Gattinoni et al., “T memory stem cells in health and disease,” Nat Med (2017), 23: 18-27. [cited by applicant]
Gearing et al., “The international standard for human interleukin-2. Calibration by international collaborative study,” J Immunological Methods (1988) 114(1-2):3-9. [cited by applicant]
Ghassemi et al., “Reducing Ex Vivo Culture Improves the Antileukemic Activity of Chimeric Antigen Receptor (CAR) T Cells”, Cancer Immunol Res. (Sep. 2018) 6(9):1100-1109. Epub Jul. 20, 2018. [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 Biophotonics (2008) 1(5):355-376. [cited by applicant]
Grupp et al., “Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia,” N Engl J Med (2013) 368:1509-1518. [cited by applicant]
Hackett et al., “A transposon and transposase system for human application,” Molecular Therapy: The Journal of the American Society of Gene Therapy (2010) 18:674-683. [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 Immunol Methods (2004) 285(1):25-40. [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]
Honegger et al., “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol (2001) 309(3):657-670. [cited by applicant]
Howarth et al., “A monovalent streptavidin with a single femtomolar biotin binding site,” Nature Methods (2006) 3:267-273 [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]
Hudecek et al., “The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity,” Cancer Immunol Res (2015) 3(2):125-135. [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). [cited by applicant]
Imamoto et al., “Advantages of AlaGln as an additive to cell culture medium: use with anti-CD20 chimeric antibody-producing POTELLIGENT™ CHO cell lines,” Cytotechnology (2013) 65:135-143. [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. 3, 2017) 8:267. [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]
Kapustin et al., “Cryptic splice sites and split genes,” Nucleic Acids Res. (2011) 39(14):5837-5844. [cited by applicant]
Klebanoff et al., “IL-15 enhances the in vivo antitumor activity oftumor-reactive CD8+ T cells,” Proc Natl Acad Sci USA (2004) 101: 1969-74. [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., “B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells,” Blood (2012) 119(12):2709-2720. [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]
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]
Lada et al., “Quantitation of integrated HIV provirus by pulsed-field gel electrophoresis and droplet digital PCR,” J Clin Microbiol (2018) 56(12):e01158. [cited by applicant]
Lee et al., “Current concepts in the diagnosis and management of cytokine release syndrome,” Blood (2014) 124(2):188-195. [cited by applicant]
Lefranc et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and lg superfamily V-like domains,” Dev Comp Immunol (2003) 27(1):55-77. [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]
Li et al., “Directed evolution of human T-cell receptors with picomolar affinities by phage display,” Nature Biotechnology (2005) 23:349-354. [cited by applicant]
Li et al., “Comparison of anti-CD3 and anti-CD28-coated beads with soluble anti-CD3 for expanding human T cells: Differing impact on CD8 T cell phenotype and responsiveness to restimulation,” J Transl Med (2010) 8(1):10… [cited by applicant]
Ll et al., “Comparison of inlet geomery in microfluidic cell affinity chromatography,” Analytical chemistry (2011) 83(3):774-781. [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]
Llm et al., “Engineered streptavidin monomer and dimer with improved stability and function,” Biochemistry (2010) 50:8682-8691. [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 (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 (2016) 27(6):209-218. [cited by applicant]
Lupton et al., “Dominant positive and negative selection using a hygromycin phosphotransferase-Thymidine kinase dusion gene,” Molecular and cellular biology (1991) 11(6):3374-3378. [cited by applicant]
MacCallum et al., “Antibody-antigen interactions: contact analysis and binding site topography,” J Mol Biol (1996) 262(5):732-745. [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]
Martin et al., “Modeling antibody hypervariable loops: a combined algorithm,” PNAS (1989) 86(23):9268-9272. [cited by applicant]
Miller et al., “Improved retroviral vectors for gene transfer and expression,” BioTechniques (1989) 7:980-990. [cited by applicant]
Miller et al., “Retrovirus packaging cells,” Human Gene Therapy (1990) 1:5-14. [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]
Neeson et al., “Ex vivo culture of chimeric antigen receptor T cells generates functional CD8+ T cells with effector and central memory-like phenotype,” Gene Therapy (2010) 17(9):1105-1116. [cited by applicant]
Okamoto et al., “A promising vector for TCR gene therapy: differential effect of siRNA, 2A peptide, and disulfide bond on the introduced TCR expression,” Mol Ther Nucl Acids (2012) 1(12):1-11. [cited by applicant]
Park et al., “Treating cancer with genetically engineered T cells,” Trends Biotechnol. (2011) 29(11): 550-557. [cited by applicant]
Parkhurst et al., “Characterization of genetically modified T-cell receptors that recognize the CEA:691-699 peptide in the context of HLA-A2.1 on human colorectal cancer cells,” Clin Cancer Res (2009) 15:169-180. [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]
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., “The Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Department of Medicine, Division of Oncology Oct. 7, 1991,” Human Gene Therapy (1992) 3:319-338. [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]
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) 859-869. [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]
Smith et al., “Ex vivo expansion of human T cells for adoptive immunotherapy using the novel xeno-free CTS immune cell serum replacement,” Clin Transl Immunol (2015) 4:e31. [cited by applicant]
Soman et al., “MTS dye based colorimetric CTLL-2 cell proliferation assay for product release and stability monitoring of interleukin-15: assay qualification, standardization and statistical analysis,” J Immunol Methods… [cited by applicant]
Sommermeyer et al., “Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo,” Leukemia (2016) 30: 492-500. [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., “Defective CD8 T cell memory following acute infection without CD4 T cell help,” Science (2003) 300: 339-42. [cited by applicant]
Tai et al., “Targeting B-cell maturation antigen in multiple myeloma,” Immunotherapy (2015) 7:1187-1199. [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]
Tran et al., “Minimally cultured tumor-infiltrating lymphocytes display optimal characteristics for adoptive cell therapy,” J Immunother (2008) 31: 742-51. [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., “CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients,” J. Clin. Invest. (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]
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]
Varela-Rohena et al., “Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor,” Nature Medicine (2008) 14(12):1390-1395. [cited by applicant]
Venkateshaiah 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]
Verhoeyen et al., “Lentiviral vector gene transfer into human T cells,” Methods Mol Biol. (2009) 506: 97-114. [cited by applicant]
Vormittag et al., “A guide to manufacturing CAR T cell therapies,” Curr Opin in Biotechnology (2018) 53:164-181. [cited by applicant]
Wadhwa et al., “Receptor mediated glycotargeting,” J. Drug Targeting (1995) 3: 111. [cited by applicant]
Wadhwa et al., “Strategies for detection, measurement and characterization of unwanted antibodies induced by therapeutic biologicals,” J Immunol Methods (2003) 278(1-2):1-17. [cited by applicant]
Wang et al., “Clinical manufacturing of CAR T cells: foundation of a promising therapy,” Molecular Therapy—Oncolytics (2016) 3:16015. [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]
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]
Wu et al., “Engineering soluble monomeric streptavidin with reversible biotin binding capability,” J Biol Chem (2005) 280(24):23225-23231. [cited by applicant]
Wulflng et al., “Correctly folded T-cell receptor fragments in the periplasm of [cited by applicant]
Xu et al., “Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells,” Cancer Letters (2014) 343(2):172-178. [cited by applicant]
Xu et al., “Multiparameter comparative analysis reveals differential impacts of various cytokines on CART cell phenotype and function ex vivo and in vivo,” Oncotarget (2016) 7(50):82354-82368. [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]
Yarilin, “Immunology principles,” M. Medicine (1999) 184-195, 339-347 (English Translation included). [cited by applicant]
Zhao et al., “Development of the First World Health Organization Lentiviral Vector Standard: Toward the production control and standardization of lentivirus-based gene therapy products,” Human Gene Therapy Methods (2017… [cited by applicant]
Zhang et al., “A novel approach to make homogeneous protease-stable monovalent streptavidin,” Biochem Biophys Res Commun (2015) 463(4):1059-1063. [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]
Cheson et al., “Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification,” J Clin Oncol (2014) 32(27):3059-3068. [cited by applicant]
Coustan-Smith et al., “Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia,” Lancet (1998) 351(9102):P550-554. [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]
Entschladen et al., “Differential requirement of protein tyrosine kinases and protein kinase C in the regulation of T cell locomotion in three-dimensional collagen matrices,” J Immunol. (1997) 159(7): 3203-3210. [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 (2017) 130:3181. [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 (2017) 129(25):3322-3331. [cited by applicant]
Ghobadi et al., “Chimeric antigen receptor T cell therapy for non-Hodgkin lymphoma,” Curr Res Transl Med (2018) 66(2):43-49. [cited by applicant]
Hallek et al., “Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1… [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,” Blood (2017) 130(Suppl_1):1813. [cited by applicant]
Johnson et al., “Imaging for Staging and Response Assessment in Lymphoma,” Radiology (2015) 276(2):323-338. [cited by applicant]
Kisielow et al., “Ly antigens as markers for functionally distinct subpopulations of thymus-derived lymphocytes of the mouse,” Nature (1975) 253: 219-20. [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]
Lee et al., “T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.” The Lancet (2015) 385(9967) : 517-528. [cited by applicant]
Long et al., “4-1BB Costimulation Ameliorates T Cell Exhaustion Induced by Tonic Signaling of Chimeric Antigen Receptors,” Nat Med (2015) 21(6):581-590. [cited by applicant]
Mailankody et al., “JCARH125, Anti-BCMA CAR T-cell Therapy for Relapsed/Refractory Multiple Myeloma: Initial Proof of Concept Results from a Phase ½ Multicenter Study (EVOLVE),” Oral Presentation 957 at 2018 American So… [cited by applicant]
Mailankody et al., “JCARH125, Anti-BCMA CAR T-cell Therapy for Relapsed/Refractory Multiple Myeloma: Initial Proof of Concept Results from a Phase ½ Multicenter Study (EVOLVE),” Blood (2018) 132(Supplement 1):957. [cited by applicant]
Maude et al., “Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia,” New Engl J Med (2018) 378(5):439-448. [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]
Philpott et al., “Use of Nonintegrating Lentiviral Vectors for Gene Therapy,” Human Gene Therapy (2007) 18:483. [cited by applicant]
Rajkumar et al., “International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma,” Lancet Oncol (2014) 15:e538-48. [cited by applicant]
Seckinger et al., “Target Expression, Generation, Preclinical Activity, and Pharmacokinetics of the BCMA-T Cell Bispecific Antibody EM801 for Multiple Myeloma Treatment,” Cancer Cell (2017) 31:396-410. [cited by applicant]
Singh et al., “Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies,” Sci Transl Med (2016) 8(320):320ra3. [cited by applicant]
Smith et al., “Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted Car T Cell Vector,” Mol Ther (2018) 26(6):1447-1456. [cited by applicant]
Tai et al., “Antibody-Based Therapies in Multiple Myeloma,” Bone Marrow Research (2010) vol. 2011. Article ID 924058. [cited by applicant]
U.S. Appl. No. 17/850,875, filed Jun. 27, 2022, by Ramsborg et al. [cited by applicant]