US2022387492A1PendingUtilityA1
Chimeric antigen receptor t cell therapy
Est. expiryNov 6, 2039(~13.3 yrs left)· nominal 20-yr term from priority
G01N 33/57505A61P 35/02C07K 2317/76A61K 35/545C07K 14/70521C07K 14/7051A61K 39/3955G01N 33/505A61K 2039/804C07K 2317/622G01N 2800/52C07K 2319/03A61K 31/675C07K 2319/00C07K 16/2803A61K 38/1774C07K 2319/30A61K 31/7076A61K 2039/545C12N 2510/00C07K 2319/33A61K 9/0019C12N 2501/505A61P 35/00C12N 2506/11A61K 35/17G01N 33/57426A61K 39/001112A61K 2039/5156A61K 40/11A61K 40/31A61K 40/4211A61K 2239/48A61K 2239/38C12N 5/0636
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Claims
Abstract
Provided herein are methods for preparing, producing, processing, culturing, isolating, or making cells suitable for immune or cell therapy, and for their use in cell therapy.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method for treating mantle cell lymphoma (MCL) or B cell ALL in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a T cell product comprising autologous T cells expressing an anti-CD19 chimeric antigen receptor (CAR).
2 . The method of claim 1 , wherein the MCL and B cell ALL are relapsed or refractory MCL and B cell ALL, optionally wherein the MCL is classical, blastoid, and pleomorphic MCL.
3 . The method of any one of claims 1 and 2 , wherein the MCL and B cell ALL is refractory to, or has relapsed following, one or more of chemotherapy, radiotherapy, immunotherapy (including a T cell therapy and/or treatment with an antibody or antibody-drug conjugate), an autologous stem cell transplant, or any combination thereof.
4 . The method of any one of claims 1 through 3 , wherein the subject has received 1-5 prior treatments, optionally wherein at least one of the prior treatments is selected from autologous SCT, anti-CD20 antibody, anthracycline- or bendamustine-containing chemotherapy, and/or a Bruton Tyrosine Kinase inhibitor (BTKi).
5 . The method of claim 4 , wherein the BTKi is ibrutinib or acalabrutinib.
6 . The method of any one of claims 1 through 5 , wherein R/R B cell ALL is defined as refractory to first-line therapy (i.e., primary refractory), relapsed ≤12 months after first remission, relapsed or refractory after ≥2 prior lines of systemic therapy, or relapsed after allogeneic stem cell transplant (SCT), optionally, wherein the subject is required to have ≥5% bone marrow blasts, an Eastern Cooperative Oncology Group performance status of 0 or 1, and/or adequate renal, hepatic, and cardiac function.
7 . The method of any one of claims 1 through 6 , wherein if the B cell ALL subject has received prior blinatumomab, the subject is required to have leukemic blasts with CD19 expression ≥90%.
8 . The method of any one of claims 1 through 7 , wherein the subject receives bridging therapy after leukapheresis and before conditioning/lymphodepleting chemotherapy.
9 . The method of any one of claims 1 through 8 , wherein the MCL subject receives a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m 2 intravenously and fludarabine 30 mg/m 2 intravenously, both given on each of the fifth, fourth, and third days before T cell infusion.
10 . The method of any one of claims 1 through 9 , wherein the B cell ALL subject receives a lymphodepleting regimen of fludarabine intravenous (IV) 25 mg/m 2 /day on each of the fourth, third, second days before T cell infusion, and cyclophosphamide IV 900 mg/m 2 /day on the second day before infusion.
11 . The method of any one of claims 8 through 10 , wherein the MCL bridging therapy is selected from dexamethasone (e.g., 20-40 mg or equivalent PO or IV daily for 1-4 days); methylprednisolone, ibrutinib (e.g., 560 mg PO daily), and/or acalabrutinib (e.g, 100 mg PO twice daily); an immunomodulator; R-CHOP, bendamustine; alkylating agents; and/or platinum-based agents, wherein the bridging therapy is administered after leukapheresis and completed in, for example, 5 days or less before conditioning chemotherapy.
12 . The method of any one of claims 8 through 10 , wherein the B cell ALL subject may receive any one or more of the following bridging chemotherapy regimens:
Predefined Bridging Chemotherapy Regimens
Attenuated VAD
Vincristine non-liposomal (1-2 mg IV weekly) or liposomal (2.25
mg/m 2 IV weekly), and dexamethasone 20-40 mg IV or PO daily ×
3-4 days per week. Optional doxorubicin 50 mg/m 2 IV × 1 (first
week only)
Mercaptopurine
50-75 mg/m 2 /day by mouth (administer at bedtime on an empty
(6-MP)
stomach to improve absorption)
Hydroxyurea
Doses titrated between 15-50 mg/kg/day (rounded to the nearest
500 mg capsule and given as a single daily oral dose on a
continuous basis)
DOMP
Dexamethasone 6 mg/m 2 /day PO (or IV) divided BID
days 1-5, vincristine 1.5 mg/m 2 (maximum dose 2 mg) IV on
day 1, methotrexate 20 mg/m 2 PO weekly, 6-MP
50-75 mg/m 2 /day PO daily
Attenuated
Fludarabine 30 mg/m 2 IV days 1-2, cytarabine 2 g/m 2 IV days 1-2,
FLAG/FLAG-IDA
G-CSF 5 μg/kg SC or IV starts on day 3 and can continue until
day before the start of conditioning chemotherapy. With or
without idarubicin 6 mg/m 2 IV days 1-2
Mini-hyper CVAD
Course A: Cyclophosphamide 150 mg/m 2 every 12 h × 3 days,
(courses A and/or
dexamethasone 20 mg/d IV or PO daily days 1-4 and 11-14,
B)
vincristine 2 mg IV × 1
Course B: methotrexate 250 mg/m 2 IV over 24 hours on day 1,
cytarabine 0.5 g/m 2 IV every 12 hours x 4 doses on days 2 and 3
13 . The method of any one of claims 1 through 12 , wherein the T cell product comprises CD4+ and CD8+ CAR T cells that are prepared from peripheral blood mononuclear cells (PBMCs) by positive enrichment and consequent partial or complete depletion of circulating cancer cells.
14 . The method of claim 13 , wherein the PBMC are enriched for T cells by positive selection for CD4+ and CD8+ cells, activated with anti-CD3 and anti-CD28 antibodies in the presence of IL-2, and then transduced with a replication-incompetent viral vector containing FMC63-28Z CAR, a chimeric antigen receptor (CAR) comprising an anti-CD19 single-chain variable fragment (scFv), CD28 and CD3-zeta domains.
15 . The method of any one of claims 13 and 14 , wherein the T cell product comprises fewer cancer cells than a T cell product comprising T cells from a leukapheresis product that have not been positively selected for CD4+ and CD8+ T cells.
16 . The method of any one of claims 13 through 15 , wherein the T cell product has other superior product attributes relative to a T cell product comprising T cells from a leukapheresis product that have not been positively selected/enriched for CD4+ and CD8+ T cells.
17 . The method of claim 16 , wherein the superior product attributes are selected from increased percentage of CDRA45+ CCR7+(naïve-like) T cells, decreased percentage of differentiated T cells, increased percentage of CD3+ cells, decreased IFN-gamma production, decreased percentage of CD3− cells.
18 . The method of any one of claims 1 through 17 , wherein the MCL subject is administered one or more doses of 1.8×10 6 , 1.9×10 6 , or 2×10 6 CAR positive viable T cells per kg body weight, with a maximum of 2×10 8 CAR positive viable T cells (for patients 100 kg and above) and the B cell ALL subject is administered 0.5×10 6 , 1×10 6 , or 2×10 6 CAR positive viable T cells per kg body weight, with a maximum of 2×10 8 CAR positive viable T cells (for patients 100 kg and above).
19 . The method of any one of claims 1 through 17 , wherein if the subject has achieved complete response to the first infusion, the subject may receive a second infusion of anti-CD19 CAR T cells, if progressing following >3 months of remission, provided CD19 expression has been retained and neutralizing antibodies against the CAR are not suspected, wherein response is assessed using the Lugano classification.
20 . The method of any one of claims 1 through 19 , wherein the subject is monitored for signs and symptoms of cytokine release syndrome (CRS) and neurologic toxicity after T cell administration.
21 . The method of claim 20 , wherein the subject is monitored daily for at least seven days, preferably for four weeks, following infusion for signs and symptoms of CRS and neurologic toxicity.
22 . The method of any one of claims 20 and 21 , wherein the signs or symptoms associated with CRS include fever, chills, fatigue, tachycardia, nausea, hypoxia, and hypotension and the signs or symptoms associated with neurologic events include encephalopathy, seizures, changes in level of consciousness, speech disorders, tremors, and confusion.
23 . The method of any one of claims 20 through 22 , wherein cytokine release syndrome in MCL subjects is managed in accordance with the following protocol:
CRS Grade
Tocilizumab
Corticosteroids
Grade 1
If not improving after 24
Not applicable.
Symptoms require
hours, administer tocilizumab
symptomatic treatment only
8 mg/kg intravenously over 1
(e.g., fever, nausea, fatigue,
hour (not to exceed 800 mg).
headache, myalgia, malaise).
Grade 2
Administer tocilizumab 8
Manage per Grade 3
Symptoms require and
mg/kg intravenously over 1
if no improvement
respond to moderate
hour (not to exceed 800 mg).
within 24 hours after
intervention.
Repeat tocilizumab every 8
starting tocilizumab.
Oxygen requirement less than
hours as needed if not
If improving, taper
40% FiO2 or hypotension
responsive to intravenous fluids
corticosteroids.
responsive to fluids or low
or increasing supplemental
dose of one vasopressor or
oxygen. Limit to a maximum of
Grade 2 organ toxicity.
3 doses in a 24-hour period;
maximum total of 4 doses if no
clinical improvement in the
signs and symptoms of CRS.
If improving,
discontinue
tocilizumab.
Grade 3
Per Grade 2
Administer
Symptoms require and
methylprednisolone 1
respond to aggressive
mg/kg intravenously
intervention.
twice daily or
Oxygen requirement greater
equivalent
than or equal to 40% FiO2 or
dexamethasone (e.g.,
hypotension requiring high-
10 mg intravenously
dose or multiple vasopressors
every 6 hours) until
or Grade 3 organ toxicity or
Grade 1, then taper
Grade 4 transaminitis.
corticosteroids.
If improving, manage
as Grade 2.
If not improving,
manage as Grade 4.
Grade 4
Per Grade 2
Administer
Life-threatening symptoms.
methylprednisolo
Requirements for ventilator
ne 1000 mg
support or continuous veno-
intravenously per
venous hemodialysis
day for 3 days.
(CVVHD), or Grade 4 organ
If improving, taper
toxicity (excluding
corticosteroids, and
transaminitis).
manage as Grade 3.
If not
improving,
consider
alternate
immunosuppres
sants.
24 . The method of any one of claims 20 through 23 , wherein neurologic toxicity in MCL subjects is managed in accordance with the following protocol:
Grading
Assessment
Concurrent CRS
No Concurrent CRS
Grade 2
Administer tocilizumab per claim
Administer dexamethasone 10
15 for management of Grade 2
mg intravenously every 6
CRS.
hours until the event is Grade
If not improving within 24 hours after
1 or less, then taper
starting tocilizumab, administer
corticosteroids.
dexamethasone 10 mg intravenously
every 6 hours until the event is Grade 1
or less, then taper corticosteroids.
If still not improving, manage as Grade 3.
Consider non-sedating anti-seizure medicines (e.g., levetiracetam) for
seizure prophylaxis.
Grade 3
Administer tocilizumab per claim
Administer
15 for management of Grade 2
dexamethasone 10
CRS.
mg intravenously
In addition, administer dexamethasone 10
every 6 hours.
mg intravenously with the first dose of
Continue dexamethasone use
tocilizumab and repeat dexamethasone
until the event is Grade 1 or
dose every 6 hours. Continue
less, then taper corticosteroids.
dexamethasone use until the event is
If not improving, manage as
Grade 1 or less, then taper
Grade 4.
corticosteroids.
If improving, discontinue
tocilizumab and manage as Grade 2.
If still not improving, manage as
Grade 4 (below).
Consider non-sedating anti-seizure medicines (e.g., levetiracetam) for
seizure prophylaxis.
Grade 4
Administer tocilizumab per claim
Administer
15 for management of Grade 2
methylprednisolone 1000
CRS.
mg intravenously per day
Administer methylprednisolone 1000 mg
for 3 days.
intravenously per day with first dose of
If improving, then manage as
tocilizumab and continue
Grade 3.
methylprednisolone 1000 mg
If not improving,
intravenously per day for 2 more days.
consider alternate
If improving, then manage as Grade 3.
immunosuppressants.
If not improving, consider
alternate immunosuppressants.
Consider non-sedating anti-seizure medicines (e.g., levetiracetam) for
seizure prophylaxis.
25 . The method of any one of claims 1 through 24 , wherein the MCL subject is a high-risk patient as determined by a Ki-67 tumor proliferation index ≥50% and/or presence of a TP53 mutation.
26 . The method of any one of claims 20 through 22 , wherein CRS in a B cell ALL subject is managed according to the following protocol:
CRS Grade
Tocilizumab
Corticosteroids
Grade 1
If not improving after 24
Not applicable.
Symptoms require
hours, administer tocilizumab
symptomatic treatment only
8 mg/kg intravenously over 1
(e.g., fever, nausea, fatigue,
hour (not to exceed 800 mg).
headache, myalgia, malaise).
Grade 2
Administer tocilizumab 8
Manage per Grade 3
Symptoms require and
mg/kg intravenously over 1
if no improvement
respond to moderate
hour (not to exceed 800 mg).
within 24 hours after
intervention.
Repeat tocilizumab every 8
starting tocilizumab.
Oxygen requirement less than
hours as needed if not
If improving, taper
40% FiO2 or hypotension
responsive to intravenous fluids
corticosteroids.
responsive to fluids or low
or increasing supplemental
dose of one vasopressor or
oxygen. Limit to a maximum of
Grade 2 organ toxicity.
3 doses in a 24-hour period;
maximum total of 4 doses if no
clinical improvement in the
signs and symptoms of CRS.
If improving,
discontinue
tocilizumab.
Grade 3
Per Grade 2
Administer
Symptoms require and
methylprednisolone 1
respond to aggressive
mg/kg intravenously
intervention.
twice daily or
Oxygen requirement greater
equivalent
than or equal to 40% FiO2 or
dexamethasone (e.g.,
hypotension requiring high-
10 mg intravenously
dose or multiple vasopressors
every 6 hours) until
or Grade 3 organ toxicity or
Grade 1, then taper
Grade 4 transaminitis.
corticosteroids.
If improving, manage
as Grade 2.
If not improving,
manage as Grade 4.
Grade 4
Per Grade 2
Administer
Life-threatening symptoms.
methylprednisolo
Requirements for ventilator
ne 1000 mg
support or continuous veno-
intravenously per
venous hemodialysis
day for 3 days.
(CVVHD), or Grade 4 organ
If improving, taper
toxicity (excluding
corticosteroids, and
transaminitis).
manage as Grade 3.
If not
improving,
consider
alternate
immunosuppres
sants.
27 . The method of any one of claims 20 through 22 and 26 , wherein neurologic toxicity in a B cell ALL subject is managed in accordance with one of the following two protocols:
NE
Revised Management
Grade
Original Management Guidelines
Guidelines
Grade 1
Supportive care
Supportive care
Neurological examination and
Closely monitor neurologic
additional work-up as clinically
status
indicated
Consider prophylactic
antiepileptic
Grade 2
Supportive Care and Evaluation
Supportive Care and Evaluation
Neurological examination, brain MRI,
Continuous cardiac telemetry
and evaluation of CSF; consider EEG as
and pulse oximetry as
clinically indicated
indicated
Consider prophylactic antiepileptic
Serial neurological
examinations to include
fundoscopy and Glasgow
Coma Score, brain MRI,
evaluation of CSF, EEG;
consider neurology consult
Administer antiepileptics for
patients with seizures
Tocilizumab
Tocilizumab
Consider tocilizumab 8 mg/kg IV over 1
For patients with
hour (not to exceed 800 mg) for patients
concurrent CRS, administer
with comorbid conditions (eg, grade >2
tocilizumab 8 mg/kg IV over
CRS)
1 hour (not to exceed 800
mg); repeat every 4-6 hours
as needed if not responsive to
IV fluids or increasing
supplemental oxygen, for a
maximum of 3 doses in 24
hours
Discontinue tocilizumab if
patient improves
Corticosteroids
Corticosteroids
N/A
For patients without
concurrent CRS, administer
dexamethasone 10 mg IV
every 6 hours
For patients with concurrent
CRS, if no improvement
within 24 hours after starting
tocilizumab, administer
dexamethasone 10 mg IV
every 6 hours
Taper corticosteroids if
patient improves
Grade 3
Supportive Care and Evaluation
Supportive Care and Evaluation
Per grade 2
Manage in monitored care or
Monitor with continuous cardiac
ICU
telemetry and pulse oximetry
Tocilizumab
Tocilizumab
Consider tocilizumab 8 mg/kg IV over 1
Per grade 2
hour (not to exceed 800 mg); repeat
Discontinue tocilizumab if
every 4-6 hours if symptoms have not
patient improves
stabilized or improved
Corticosteroids
Corticosteroids
Consider corticosteroids (eg,
Administer dexamethasone 10
dexamethasone 10 mg IV every 6 hours
mg IV every 6 hours
or methylprednisolone l mg/kg BID)
Taper corticosteroids if
for worsening symptoms despite
patient improves
tocilizumab
Grade
Supportive Care and Evaluation
Supportive Care and Evaluation
Per grade 2
Per grade 3
Monitor with continuous cardiac
Mechanical ventilation may
telemetry and pulse oximetry
be required
Administer
immunosuppresants if patient
does not improve
Tocilizumab
Tocilizumab
Administer tocilizumab per grade 3 if
Per grade 2
not previously administered
Corticosteroids
Corticosteroids
Administer corticosteroids (eg,
Administer high-dose
methylprednisolone ig/d × 3 days,
corticosteroids (eg,
followed by 250 mg BID × 2 days, then
methylprednisone ig/d × 3
125 mg BID × 2 days, then 60 mg BID ×
days)
2 days)
Taper corticosteroids if
patient improves
28 . The method of any one of claims 1 through 27 , wherein the B cell ALL subject may receive any one or more of the following bridging chemotherapy regimens:
Predefined Bridging Chemotherapy Regimens
Attenuated VAD
Vincristine non-liposomal (1-2 mg IV weekly) or liposomal (2.25
mg/m 2 IV weekly), and dexamethasone 20-40 mg IV or PO daily
x 3-4 days per week. Optional doxorubicin 50 mg/m 2 IV × 1 (first
week only)
Mercaptopurine (6-
50-75 mg/m 2 /day by mouth (administer at bedtime on an empty
MP)
stomach to improve absorption)
Hydroxyurea
Doses titrated between 15-50 mg/kg/day (rounded to the nearest
500 mg capsule and given as a single daily oral dose on a
continuous basis)
DOMP
Dexamethasone 6 mg/m 2 /day PO (or IV) divided BID
days 1-5, vincristine 1.5 mg/m 2 (maximum dose 2 mg) IV on
day 1, methotrexate 20 mg/m 2 PO weekly, 6-MP
50-75 mg/m 2 /day PO daily
Attenuated
Fludarabine 30 mg/m 2 IV days 1-2, cytarabine 2 g/m 2 IV days 1-2,
FLAG/FLAG-IDA
G-CSF 5 μg/kg SC or IV starts on day 3 and can continue until
day before the start of conditioning chemotherapy. With or
without idarubicin 6 mg/m 2 IV days 1-2
Mini-hyper CVAD
Course A: Cyclophosphamide 150 mg/m 2 every 12 h × 3 days,
(courses A and/or
dexamethasone 20 mg/d IV or PO daily days 1-4 and 11-14,
B)
vincristine 2 mg IV × 1
Course B: methotrexate 250 mg/m 2 IV over 24 hours on day 1,
cytarabine 0.5 g/m 2 IV every 12 hours × 4 doses on days 2 and 3
29 . Autologous T cells expressing an anti-CD19 CAR for use in a method for treating mantle cell lymphoma (MCL) or B cell ALL according to any one of claims 1 through 28 .
30 . Use of autologous T cells expressing an anti-CD19 CAR in the manufacturing of a medicament for treating mantle cell lymphoma (MCL) or B cell ALL according to any one of claims 1 through 28 .
31 . A method of predicting:
(i) objective response of a subject to a CAR T cell treatment (optionally, according to the method of any one of claims 1 through 28 ) comprising measuring peak CAR T cell levels and comparing them to a reference standard, wherein objective response is positively associated with peak CAR T cell levels, wherein objective response includes both complete response and partial response, and wherein all responses are assessed using the Lugano classification. (xii) minimal residual disease (e.g., at week 4) in response to a CAR T cell treatment (optionally, according to the method of any one of claims 1 through 28 ) comprising measuring peak CAR T cell levels and comparing them to a reference standard, wherein negative minimal residual disease is associated with higher peak CAR T cell levels. (xiii) grade ≥3 CRS and/or grade ≥3 neurologic events (NE) in a subject receiving CAR T cell treatment (optionally, according to a method of any one of claims 1 through 28 ) comprising measuring peak CAR T cell expansion after treatment and comparing the levels to a reference value, wherein the higher the CAR T cell expansion, the higher the chance for grade ≥3 CRS and/or grade ≥3 NE events. (xiv) grade ≥3 CRS and/or grade ≥3 NE comprising measuring the peak levels of GM-CSF and IL-6 post-CAR T cell treatment (optionally, according to the method of any one of claims 1 through 28 ) and comparing them to a reference level, wherein the higher the peak level of these cytokines, the higher the chance for grade ≥3 CRS and/or grade ≥3 NE. (xv) grade ≥3 CRS in a subject receiving CAR T cell treatment (optionally, according to a method of any one of claims 1 through 28 ) comprising measuring the peak level of serum ferritin post-CAR T cell treatment and comparing it to a reference level, wherein the higher the peak level of ferritin, the higher the chance for grade ≥3 CRS. (xvi) grade ≥3 CRS comprising measuring the peak levels of serum IL-2 and IFN-gamma post-CAR T cell treatment (optionally, of any one of claims 1 through 28 ) and comparing them to a reference level, wherein the higher the peak level of IL-2 and IFN-gamma, the higher the chance for grade ≥3 NE. (xvii) grade ≥3 CRS comprising measuring the cerebrospinal fluid levels of C-reactive protein, ferritin, IL-6, IL-8, and/or vascular cell adhesion molecule (VCAM) post-CAR T cell treatment (optionally, of any one of claims 1 through 28 ) and comparing them to a reference level, wherein the higher the cerebrospinal fluid levels of C-reactive protein, ferritin, IL-6, IL-8, and/or vascular cell adhesion molecule (VCAM), the higher the chance for grade ≥3 NE (xviii) grade ≥3 CRS post-CAR T cell treatment (optionally, according to a method of any one of claims 1 through 28 ) comprising measuring peak serum levels of IL-15, IL-2 Rα, IL-6, TNFα, GM-CSF, ferritin, IL-10, IL-8, MIP-1a, MIP-1b, granzyme A, granzyme B, and/or perforin after anti-CD19 CAR T treatment and comparing the levels to reference levels, wherein the peak serum levels of IL-15, IL-2 Rα, IL-6, TNFα, GM-CSF, ferritin, IL-10, IL-8, MIP-1a, MIP-1b, granzyme A, granzyme B, and/or perforin associate positively with grade ≥3 CRS. (xix) grade ≥3 CRS post-CAR T cell treatment of B cell ALL (optionally, according to a method of any one of claims 1 through 28 ) comprising measuring peak serum level of IL-15 after anti-CD19 CAR T treatment and comparing the levels to reference levels, wherein the peak serum level of IL-15 associates negatively with grade ≥3 CRS. (xx) grade ≥3 CRS and/or grade ≥3 NE post-CAR T cell treatment (optionally, according to a method of any one of claims 1 through 28 ) comprising measuring peak serum levels of IL-6, TNFα, GM-CSF, IL-10, MIP-1b, and granzyme B after anti-CD19 CAR T treatment and comparing the levels to reference levels, wherein peak serum levels of IL-6, TNFα, GM-CSF, IL-10, MIP-1b, and granzyme B associate positively with grade ≥3 CRS and grade ≥3 NE. (xxi) whether a patient is going to be MRD (10 −5 sensitivity) negative at 4 weeks/one month post-CAR T cell treatment (optionally, of any one of claims 1 through 28 ), comprising measuring peak serum levels of IFN-γ, IL-6, and/or IL-2 after treatment and comparing the level to a reference standard, wherein peak serum levels of IFN-γ, IL-6, and/or IL-2 associate positively with being MRD negative at one month.
32 . The method of any one of claims 20 through 24 , 26 , 27 , and 30 through 31 , wherein CRS and NE are graded by the method described in Lee et al., Blood 2014; 124: 188-195.
33 . The method of claim 31 , wherein the reference standard is established by any method generally used in the biomarker arts, such as quartile analysis of patient populations with known responses, grades of toxicity, and MRD levels.
34 . The method of claim 31 , wherein CAR T cell levels are measured by CAR gene copies per microgram of DNA in blood.
35 . The method of any one of claims 1 through 34 , further comprising reducing the levels/activity of the cytokines that associate positively with grade ≥3 CRS and/or grade ≥3 NE post CAR T cell infusion to reduce grade ≥3 CRS and/or grade ≥3 NE.
36 . A method of improving the effectiveness of CAR T cell treatment (e.g., of classical, blastoid, and pleomorphic MCL, and B cell ALL), in a subject in need thereof, comprising manipulating the T cell phenotype of the T cell product administered to the subject, optionally wherein the manipulation comprises increasing the number of CD3+ T cells, decreasing the number of CD3− cells, increasing the number/percentage of CDRA45+ CCR7+(naïve-like) T cells and/or decreasing the number/percentage of differentiated cells in the T cell product during production, decreasing the levels of IFN-gamma production by the T cells, wherein the improvement is observed relative to the effectiveness of a T cell product that is prepared without any intentional manipulation of the number/percentage of CDRA45+ CCR7+ (naïve-like) T cells and/or the number/percentage of differentiated cells in the T cell product.Join the waitlist — get patent alerts
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