Chimeric Antigen Receptor (CAR) T Cell Therapy: A Cure for ...
Exploiting the Immune System: Chimeric Antigen Receptor-T Cell...
Transcript of Exploiting the Immune System: Chimeric Antigen Receptor-T Cell...
Maurice Alexander, PharmD, BCOP, CPP Clinical Specialist, Blood and Marrow Transplant UNC Bone Marrow Transplant and Cellular Therapy Program
Exploiting the Immune System: Chimeric Antigen Receptor-T Cell Therapy for Hematologic Malignancies
Disclosures
• I have the following disclosures
• Off-label use disclosure
– This session will include a discussion of off-label treatment and investigational agents not approved by the FDA for use in the US
Company Role
Juno Therapeutics Advisory Board
Jazz Pharmaceuticals Advisory Board
Objectives
• Understand the engineering process and administration of chimeric antigen receptor-T (CAR-T) cells
• Interpret clinical data for the use of CAR-T cells in the management of hematologic malignancies
• Describe the management of toxicities associated with CAR-T therapy
CAR-T ENGINEERING AND ADMINISTRATION STRATEGIES
CAR-T cell Therapy for Hematologic Malignancies
Chimeric Antigen Receptor-T (CAR-T) Cells
• Chimeric Antigen Receptors (CARs) – Recombinant molecules that target a
specific antigen
– Mediate cell activation
• T-cells – Activated after CAR exposure to the
cancer antigen
– Destruction of tumor cells and
proliferation of CAR-Ts
Kulemzin SV, et al. Acta Naturae 2017;9(1):6-14.
Ramos CA, et al. Annu Rev Med 2016;67:165-183.
CAR-T Engineering Process
Mato A, et al. Blood 2015;126:478-485.
CAR-T Engineering
Batlevi CL, et al. Nat Rev Clin Oncol 2016;13(1):25-40.
Lymphodepletion
• Depletes endogenous lymphocytes
• Elimination of regulatory T cells
• Removal of competing targets
• Prevents T-cell mediated responses against CARs
• Improves CAR-T persistence
• May include disease-targeted agents
. Gattinoni L, et al. J Exp Med 2015;202(7):907-912.
CAR-T Infusion • Dosing
– 1 x 105 – 1 x 108 cells/kg
– Dose level associated with both response and toxicity
– No uniform/standard dose
• Infusion strategies
– Single infusions
– Fractionated/multiple infusions
Davila ML, et al. Sci Transl Med 2014;6(224):224ra25.
Maude L, et al. N Engl J Med 2014;371:1507-1517.
Lee DW, et al. Lancet 2015;385:517-28.
Turtle CJ, et al. J Clin Invest 2016;126(6):2123-2138.
Audience Response Question 1
Which of the following components of CAR-T cells have been modified for enhancement of activity in newer generation CAR-Ts?
a. Antigen recognition domain
b. Hinge/Spacer
c. Transmembrane domain
d. Signaling/Costimulatory domain
CLINICAL DATA CAR-T cell Therapy for Hematologic Malignancies
CD19 Expression
Blanc V, et al. Clin Cancer Res 2011;17(20);6448-6458.
Acute Lymphoblastic Leukemia (ALL) • Relapsed/refractory disease remains a challenge
– Initial CR: > 80%
– Refractory: ~20%
– Relapse: > 50%
• Responses to salvage therapies are poor
Fielding AK, et al. Blood 2007;109:944-950.
Gokbuget N, et al. Blood 2012;120(10):2032-2041.
Relapse number Previous therapy Salvage treatment
number CR Rate
1st Chemotherapy 1st ~40%
2nd Chemotherapy 2nd ~30%
1st Stem Cell Transplant 1st ~20%
CR: Complete Remission
CAR-T Cell Therapy for ALL Study Population
Lympho- depletion
Costimulation/ Cell dose (cells/kg)
Response Rate N (%)
Davila ML, et al. Sci Transl Med 2014
N = 16 Adults
Cy CD28
3 x 106 CR: 14 (88)
CRm: 12 (75)
Maude S, et al. NEJM 2014
N = 30 Peds (25) Adults (5)
Various 4-1BB
8 x 105 – 2 x 107 CR: 27 (90)
CRm: 23 (77)
Lee DW, et al. Lancet 2015
N = 21 Peds (16) Adults (5)
Cy/Flu CD28
1 x 106 – 3 x 106 CR: 14 (70)
CRm: 12 (60)
Turtle CJ, et al. J Clin Invest 2016
N = 32 Adults
Cy Cy/Etop Cy/Flu
4-1BB 2 x 105 – 2 x 107
CR: 27 (93) CRm: 25 (86)
Davila ML, et al. Sci Transl Med 2014;6(224):224ra25.
Maude L, et al. N Engl J Med 2014;371:1507-1517.
Cy: Cyclophosphamide; Flu: Fludarabine; Etop: Etoposide; CR: Complete remission; CRm: Complete molecular remission
Lee DW, et al. Lancet 2015;385:517-28.
Turtle CJ, et al. J Clin Invest 2016;126(6):2123-2138.
CAR-T Cell Therapy for ALL
Study Proceeded to
transplant Comments
Davila ML, et al. Sci Transl Med 2014
44% overall 70% of eligible
No relapse in transplanted patients; Follow up: 2 -24 months
Maude S, et al. NEJM 2014
10% overall Sustained responses for up to 2 years
Lee DW, et al. Lancet 2015
48% overall 83% of eligible
No relapse in transplanted patients; Median follow up: 10 months
Davila ML, et al. Sci Transl Med 2014;6(224):224ra25.
Maude L, et al. N Engl J Med 2014;371:1507-1517.
Lee DW, et al. Lancet 2015;385:517-28.
Chronic Lymphocytic Leukemia (CLL)
Agent Response
Rate Survival Comments
Ibrutinib ORR: 63%
CR: 0% 6-month PFS: 88%
1-yr OS: 90% Similar responses in high-risk patients
Ibrutinib + Rituximab
ORR: 95% CR: 8%
18-month PFS: 78% 18-month OS: 84%
High-risk population Median DOR: 15.4 months
Idelalisib + Rituximab
ORR: 81% CR: 0%
6-month PFS: 45% 1-year OS: 92%
Frail population Similar responses in high-risk patients
Venetoclax ORR: 79% CR: 20%
15-month PFS: 69% Similar responses in high-risk patients
Median DOR: 24 months
Venetoclax + Rituximab
ORR: 86% CR: 51%
2-year PFS: 82% 2-year ongoing response: 89%
Byrd JC, et al. N Engl J Med 2014;321:213-223.
Burger JA, et al. Lancet Oncol 2014;15:1090-1099.
Furman RR, et al. N Engl J Med 2014;370:997-1007.
ORR: Objective response rate; CR: Complete response; PFS: Progression-free survival; OS: Overall survival; DOR: Duration of response
Roberts AW, et al. N Engl J Med 2016;374(4):311-322.
Seymour JF, et al. Lancet Oncol 2017;18:230-40.
CAR-T cell Therapy for CLL
Porter DL, et al. Sci Transl Med 2015;7(303):303ra139.
Porter DL, et al. Blood 2014;124(21):1982.
Kalos M, et al. Sci Transl Med 2011;3(95):95ra73.
Study N ORR
N (%) CR
N (%) DOR
(months)
Porter DL, et al. Sci Transl Med 2015 14 8 (57) 4 (29) 5-53
Porter DL, et al. Blood 2014 23 9 (39) 5 (22) NR
Kalos, et al. Sci Transl Med 2011 3 3 (100) 2 (67) 7-11
Kochenderfer, et al. JCO 2015 4 4 (100) 3 (75) 4-23
Kochenderfer, et al. Blood 2012 4 3 (75) 1 (25) 7-15
Brentjens R, et al. Blood 2011 8 1 (13) 0 (0) 6
Kochenderfer, et al. J Clin Oncol 2015;33(6):540-549.
Kochenderfer, et al. Blood 2012;119(12):2709-2720.
Brentjens R, et al. Blood 2011;118(18):4817-4828.
ORR: Objective response rate; CR: Complete response; DOR: Duration of response
CAR-T Therapy for Lymphoma
Study Population CAR Response Rate
N (%)
Turtle, et al. Sci Transl Med 2016
N = 32 R/R NHL
CD19 ORR: 19 (63) CR: 10 (33)
Locke, et al. Mol Ther 2017
N = 7 R/R DLBCL
CD19 ORR: 5 (71) CR: 4 (57)
Wang C, et al. Clin Cancer Res 2017
N = 18 R/R HL
CD30 ORR: 7 (39)
CR: 0 (0)
Turtle CJ, et al. Sci Transl Med 2016;8(355):355ra116.
Locke FL, et al. Mol Ther 2017;25(1):285-295.
Wang C, et al. Clin Cancer Res 2017;23(5):1156-1166.
R/R: Relapsed/refractory; NHL: Non-Hodgkin lymphoma; DLBCL: Diffuse large B-cell lymphoma; HL: Hodgkin lymphoma; ORR: Objective response rate; CR: Complete response
Multiple Myeloma (MM)
• CD19 expression in MM
– Minor component of the MM clone
– CD19 CAR-T activity despite low level expression
Garfall AL, et al. N Engl J Med 2015;373(11):1040-1047.
Blanc V, et al. Clin Cancer Res 2011;17(20);6448-6458.
CAR-T Therapy for MM • Alternative targets: CD38, CD56, CD138, BCMA
Study N CAR Responses
N (%)
Guo, B, et al. J Cell Immunother 2016
5 CD138 SD: 4 (80)
Ali SA, et al. Blood 2015
11 BCMA sCR: 1 (9)
VGPR: 2 (18) PR: 1 (9)
Cohen AD, et al. Blood 2016
6 BCMA sCR: 1 (17)
VGPR: 1 (17)
Fan F, et al. J Clin Oncol 2017
19 BCMA sCR: 14 (74) VGPR: 4 (21)
PR: 1 (11)
Guo B, et al. J Cell Immonther 2016;2:28-35.
Ali SA, et al. Blood 2015;126:LBA-1.
Cohen AD, et al. Blood 2016;128:1147.
Fan F, et al. J Clin Oncol 2017;35 (suppl; abstr LBA3001).
BCMA: B-cell maturation antigen; SD: Stable
disease; sCR: Stringent complete response;
VGPR: Very good partial response; PR: Partial
response
Audience Response Question 2
Clinical data for CAR-T therapy in hematologic malignancies suggest which of the following? a. CAR-T responses in ALL are typically transient,
requiring additional therapy b. Complete remissions have been reported in up to 90%
of patients with ALL c. Patients with ALL are unlikely to be able to proceed to
stem cell transplant after receiving CD19 CAR-T therapy
d. CD19 is the ideal CAR-T target antigen for multiple myeloma and has resulted in high CR rates
MANAGING TOXICITIES CAR-T cell Therapy for Hematologic Malignancies
Cytokine Release Syndrome (CRS) • Non-antigen specific toxicity
• Results from widespread immune activation
– Elevation of systemic cytokines
• Reversible, but potentially fatal
Organ System Signs/Symptoms
Constitutional Fevers, rigors, malaise, myalgias/arthralgias
Gastrointestinal Nausea, vomiting, diarrhea
Cardiovascular Tachycardia, hypotension
Renal Azotemia, renal failure
Hepatic Transaminitis, hyperbilirubinemia
Neurologic Altered mental status, confusion, delirium, seizures, etc.
Respiratory Tachypnea, hypoxia
Lee DW, et al. Blood 2014;124(2):188-195.
Brundo JN, et al. Blood 2016;127(26):3321-3330.
CRS: Grading Grade Signs/Symptoms
1 Constitutional symptoms; requires only symptomatic management
2
Hypotension (responsive to fluids or low dose vasopressor) Oxygen requirement < 40% Grade 2 organ toxicity
3
Hypotension (requiring high dose or > 1 vasopressor) Oxygen requirement ≥ 40% Grade 3 organ toxicity Grade 4 transaminitis
4 Ventilator support required Grade 4 organ toxicity
5 Death
Lee DW, et al. Blood 2014;124(2):188-195.
CRS: Risk Factors • CAR-T cell dose
• Burden of disease
Lee DW, et al. Lancet 2015;385:517-28.
Cytokine Elevations
Lee DW, et al. Lancet 2015;385:517-28.
C-Reactive Protein (CRP) Interleukin-6 (IL-6)
Association between CRP and IL-6
Neurotoxicity • Spectrum of neurologic symptoms
– Confusion/delirium to obtundation
– Seizure activity
• Pathogenesis
– Direct CAR-T toxicity on CNS tissues vs. generalized T-cell mediated inflammatory state
Lee DW, et al. Lancet 2015;385:517-28.
Davila ML, et al. Sci Transl Med 2014;6(224);224ra25.
CRS and Response
Lee DW, et al. Lancet 2015;385:517-28.
Response Rate
Rate of CRS CRS in
Responders CRS in non-Responders
Comments
14/21 16/21 14/14 2/7 All 6 grade 3-4 CRS cases
in responders
Management of CRS
• Grade 1-2
– Supportive measures
• Grade 3-4
– Tocilizumab
• Inhibits soluble (sIL-6R) and membrane-bound (mIL-6R) IL-6 receptors
• Dosing – 4-8 mg/kg (max 800 mg) IV over 1 hour x 1
– Repeat if lack of response
• No CNS penetration
Brundo JN, et al. Blood 2016;127(26):3321-3330.
Management of CRS • Corticosteroids
– Indicated for:
• Tocilizumab refractory CRS
• Grade 3-4 neurotoxicity
– Methylprednisolone 1-2 mg/kg IV every 12 hours
– Dexamethasone 5-10 mg IV every 6-12 hours
Brundo JN, et al. Blood 2016;127(26):3321-3330.
Davila ML, et al. Sci Transl Med 2014;6(224);224ra25.
B-Cell Aplasia
• On-target off-tumor toxicity
• Potential measure of persistence of CD19-targeted CAR-T cells
• Prolonged B-cell aplasia in patients with sustained remissions
• Immunoglobulin deficiencies
– Intravenous immunoglobulin (IVIG) replacement
Dai H, et al. J Natl Cancer Inst 2016;108(7):djv439.
Audience Response Question 3
JR is a 54 year-old male with ALL s/p CD19 CAR-T infusion. JR becomes hypoxic and hypotensive,
ultimately requiring intubation and pressor support. He also has mild confusion. He is given tocilizumab 8 mg/kg IV x 1. Twelve hours later he continues to be hypotensive requiring an
additional pressor, has progressive renal compromise, moderate reduction in alertness
and inability to express speech.
Audience Response Question 3
What is the best approach for the management of JR’s CRS at this time?
a. Dexamethasone 10 mg IV every 12 hours
b. Repeat tocilizumab 8 mg/kg IV x 1
c. Repeat tocilizumab 8 mg/kg IV x 1 and add dexamethasone 10 mg IV every 12 hours
d. Methylprednisolone 1 mg/kg IV every 12 hours
Where Are We Now? Company/
CAR Trial
Trial Population
Response Rates
Approval Status/ US Adopted Name (USAN)
Novartis CTL019
Eliana N = 88
Age 3-23 B-ALL
CR: 83% CRm: 83%
Breakthrough status 7/2014 Granted FDA priority review 2017
tisagenlecleucel-T
Novartis CTL019
Juliet N = 141 Adults DLBCL
ORR: 59% CR: 43%
Breakthrough status 4/2017 BLA filed 2017
tisagenlecleucel-T
KITE KTE-C19
Zuma-1 N = 111 Adults
NHL
ORR: 82% CR: 54%
Breakthrough status 7/2015 Granted FDA priority review 2017
axicabtagene ciloleucel
KITE KTE-C19
Zuma-3 N = 11 Adults B-ALL
CR: 75% CRm: 75%
Trial ongoing
Juno JCAR017
Transcend N = 39 Adults NHL
ORR: 75% CR: 67%
Trial ongoing
Buechner J, et al. EHA Learning Center 2017; 181763.
Schuster SJ, et al. EHA Learning Center 2017; 183934.
Locke, FL, et al. AACR 2017. Abstract nr [CT019].
Shah BD, et al. J Clin Oncol 2017;35 (suppl; abstr 3024).
Abramson JS, et al. Blood 2016;128:4192.
Summary
• Improvements in CAR-T engineering have enhanced clinical efficacy
• CAR-T therapy offers an effective treatment option in the relapsed/refractory setting for hematologic malignancies, particularly ALL
• Toxicities, such as CRS and neurotoxicity, can be fatal and warrant prompt management
Maurice Alexander, PharmD, BCOP, CPP Clinical Specialist, Blood and Marrow Transplant UNC Bone Marrow Transplant and Cellular Therapy Program
Exploiting the Immune System: Chimeric Antigen Receptor – T Cell Therapy for Hematologic Malignancies