Immunotherapy for Lymphoma:
Finally?
F B Hagemeister, MDProfessor of Medicine
Department of Lymphoma and MyelomaM D Anderson Cancer Center
Bangkok 29 August 2015
Chimeric Antigen Receptor-T Cell Therapy for Lymphomas
• Development of CAR-Ts• Studies in Adults with B-Cell
Lymphomas• Identification and Management of
Toxicities
ASCT for Relapsed DLBCL: Pre-Rituximab Era (PARMA study)
7 year EFS was 41% vs 13% in for ASCT vs the chemo alone arm
EFS (months)
Surv
ival
(%)
DHAP x 6(n = 54)
DHAP x2 + ASCT (BEAC)(n = 55)
p = 0.002
41%
13%
100908070605040302010
00 30 60 90 120 150
Results are only for those in PR/CR after 2 DHAP Only CRs to initial chemotherapy were enrolled
EFS (induction ITT) OS (induction ITT)
R-ICE/ASCT vs R-DHAP/ASCT for Rel/Ref DLBCL: EFS and OS by Induction
Surv
ival
pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60 72OS (months)
Surv
ival
pro
babi
lity
EFS (months)
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60 72
p = 0.2672 p = 0.3380
R-ICER-DHAP
R-ICER-DHAP
Gisselbrecht et al. JCO 28:4184–4190, 2010.Includes all patients! Note: Not much improvement in 20 years of research!
The Limited Benefit of ASCT for Relapsed DLBCL
300 patientsDLBCL
200 Cured with RCHOP
100 RelapseOr refractory
50 Transplantcandidate
50 Transplantineligible
25 Chemo-refractory
25 Respond and ASCT
Friedberg 2011 ASH Educational Session
210 Cured
90 receive Palliation. Most likely die from DLBCL
15 patients relapse
10 Cured after ASCT
Mechanisms of T-Cell Anergy in Therapy of Cancer
• T-cell response to antigens requires:– Recognition of antigen– Activation of the T cell– Persistence of T-cell function
• T-cell anergy is caused by:– Inhibition or lack of activating signals– Loss of antigen presentation– Activation of suppressive cells– Presence of suppressive ligands
Gotsman et al Circulation Res 109: 1220-1231, 2008. Scott et al. Nature Rev Cancer 14: 517-534, 2014.
Design of CAR-T Cells for Cancer Immunotherapy
• Basic Design: Two Fundamental Domains– Antigen binding portion• A single chain variable fragment (scFv)
derived from a monoclonal antibody– One or more intracellular T-cell signaling
domains• CAR-Ts must expand, persist, exhibit enduring
antitumor cytotoxicity, withstand an immunosuppressive microenvironment, and overcome tumor antigen escape
CAR-T Cells Recognize Antigen But Must Be Activated and Persist
• The tumor specific portion recognizing the tumor antigen can come from two sources – A T cell that is naturally occurring or from a
transgenic mouse– A tumor specific antibody found on normal B cells
• Activation requires modification of the T cell by adding a naturally occurring protein (CD3zeta, 1st generation)
• Persistence induced by stimulation via other proteins (CD28, 2nd generation) or costimulants (4-1BB or OX40 or other, 3rd generation)
Kershaw et al. Nature Rev Cancer 13: 525-541, 2013. Cassuri et al. J Cancer 2: 378-382, 2011>
Development of CARs for Therapy of Cancer
Components of an Artificial TCR
1st, 2nd, and 3rd Generation CARs
Resultant CAR can be inserted into T Cells by transfection with viruses of other means
CD19 as an Antigenic Target in Lymphoma and Myeloma
An Ideal Antigen? Lymphoma MyelomaExpressed on Most Tumor Cells
Yes No
Expressed on Cell Surface
Yes Yes
Essential for Tumor Growth
Unknown Unknown
Expressed on Clonogenic Cells
Probably Unknown
Not Expressed on Normal Cells or Target Toxicity Acceptable
B-Cell Depletion Acceptable
B-Cell depletion Acceptable
Kochenderfer er al. Blood 119: 2709-2720, 2014.
Importance of the Microenvironment in Limitation of CAR-T Effectiveness
• Endogenous immunosuppressive cells– CD4 regulatory T cells– Myeloid-derived suppressor cells– Plasmacytoid dendritic cells– Tumor-associated macrophages
• Immune checkpoint inhibitors• Immunosuppressive soluble ligands and
cytokines– Interleukin (IL)-10– Transforming growth factor (TGF)-beta
Variables Potentially Affecting Results in CAR-T Trials
Variables ImplicationsAntigen Efficacy
Safety (Off Tumor/On Target Toxicity)
CAR Construct Type CD28 (MSKCC) 4-BB (U Penn)
Comparisons of Efficacy and Persistence Unknown
Delivery Vector Lentivirus, Other Retrovirus CD3 Beads, Cytokines
EfficiencyUnknown Effect on Efficacy
T Cells (Bulk vs Subsets)Lymphodepleting Therapy Impact Always Significant
Control of Immune FunctionTumor Volume May Be Important
Chimeric Antigen Receptor-T Cell Therapy for Lymphomas
• Development of CAR-Ts• Studies in Adults with B-Cell
Lymphomas• Identification and Management of
Adverse Events
Phase I 19-28z CAR-T After ASCT for Rel/Ref Aggressive B-NHL
• 11 patients with disease chemosensitive to relapse therapy
• Eligibility– PET positive disease after > 2 cycles of relapse
therapy, but PR by other criteria– Marrow involvement at time of relapse or
refractory disease and not an allo candidate• Phase I Study: Generate CAR using CD28 for
persistence, attached to activated scFv-C3zeta chain (19-28z CAR)
• Retrovirus used to insert CAR into T cell
Sauter et al. ASCO 2015, Abst 8515.
Potential Advantages of 19-28z CAR-T Cells Post-Ablative Chemotherapy and ASCT• After expansion of resultant CAR-Ts (weeks), cells
are infused following AutoSCT into eligible patients
• Potential advantages of this sequence– Modulation of a hostile immunosuppressive
tumor microenvironment• Elimination of regulatory T cells• Elimination of myeloid suppressor cells
– Elimination of cytokine “sinks” for optimized proliferative expansion of 19-28z CAR-T cells
Sauter et al. ASCO 2015, Abst 8515.
Phase I 19-28z CAR-T After ASCT for Rel/Ref Aggressive B-NHL
Sauter et al. ASCO 2015, Abst 8515.
Salvage Chemo Leukapheresis Generation of CAR-Ts
-7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +10
Hospital
BEAM
Pegfilgrastim
ASCT
Infusion 19-28z CAR-Ts
Anticipated Engraftment
Dose Levels-1 2 x 106
+ 1 5 x 106
+2 1 x 107
+ 3 2 x 107
Phase I CAR-Ts After ASCT for Rel/Ref Agg B-NHL: Patients and Results
• 11 patients enrolled, med age: 61 (34-75 years)• Pathology: DLBCL-5; tFL/MZL/CLL-4; BL-1; Blastoid
MCL-1.• Status prior to ASCT: 10 PR (2 with BM involved), 1
PET CR but with leukemic phase• Median prior therapies: 2 (range 2-4)• CAR-T doses: 10 receive 5 x 106 /kg, 1 receives 10/kg• Toxicity: 7/11 have CRS/CNS toxicity, 1 dies at 1 mo• Response (10 eval): CR – 6 patients; 2 CRs have PD• PFS: 10 eval, 4 CRs still in CR at 13, 15, 20, 21 mo
Sauter et al. ASCO 2015, Abst 8515.
CAR-T Cells for Relapsed/Refractory CD19 Positive NHLs
• CTL019 engineered T cells contain:• Chimeric antigen receptor (CAR) specific
for CD19. • Activation and signaling via a CD3-zeta
domain.• Costimulatory signaling via a CD137 (4-
1BB) domain. • Other chimeric antigen receptor-modified T
cell therapy against CD19 has been effective in treating relapsed and refractory ALL and CLL.
Maude et al. N Engl J Med 2014; 371:1507-17.Grupp et al. N Engl J Med 2013; 368:1509-18.Porter et al. N Engl J Med 2011; 365:725-33.
Chimeric Antigen Receptor
(CAR)
CD19
CD3-ζ
Schuster et al. ASCO 2015, Abst 8516.
CAR-T Cells for Relapsed/Refractory CD19 Positive NHLs: Criteria for Entry
DLBCL• Progression after ASCT or ineligible for ASCT • Transformation from CLL/SLL or FL allowed
FL• > 2 prior regimens • Progression < 2 years after last therapy
MCL• Progression after ASCT • Any relapse or progression and ineligible for
ASCT or AlloSCT
Schuster et al. ASCO 2015, Abst 8516.
Month +3 response assessment
CAR-T Cells for Rel/Ref CD19 Positive NHLs: Treatment Schema
CD19+ Lymphoma•Eligibility determination•Enrollment
Apheresis•Baseline immune assays
Restaging and Lymphodepleting ChemotherapyCT Scans and Bone Marrow. Therapy Physician Choice.
Ends 1-4 Days before CTL019 infusion
CTL019 Infusion, Monitoring and Response Assessments
Day 0
Month +1
Month +2 and +3evaluations
Quarterly f/u x 2 yr F/U 15 years
Adverse event monitoring
CTL019 infusion
= Clinical evaluation; immune/CTL019 assays
Day -1
Schuster et al. ASCO 2015, Abst 8516.
CAR-T Cells for Rel/Ref CD19 Positive NHLs: Patient Features
Feature DLBCL (N=19) FL (N=8) MCL (N=3)
Med age, Yr (range) 56 (25 - 77) 61 (43-71) 55
Med # prior Txs (range) 4 (1 - 8) 6 (4-8) 4 (3-6)
Prior SCT, N (%) 7 (37) 2 (25) 1 (33)
Stage III-IV, N (%) 12 (63) 7 (88) 3 (100)
High LDH, N (%) 14 (74) 5 (63) 2 (66)
> 1 ENS, N (%) 6 (32) 1 (13) 3 (100)
Med PS (range) 1 (0 - 1) 0 (0-1) 1 (0-1)
Schuster et al. ASCO 2015, Abst 8516.
DLBCL: ORR at 3 Mo 50% (N = 13) Best Response 50% (N = 13) - CR: 2- PR: 4- PD: 6- Response not yet assessed: 1
- CR: 5- PR: 1- PD: 6- Response not yet assessed: 1
• 3 PR at 3 mo converted to CR at 6; 1 PR at 3 mo had PD at 6
CAR-T Cells for CD19 Positive NHLs: Response Rates for DLBCL and FL
FL: ORR at 3 Mo 100% (N = 7) Best Response 100% (N = 7)
- CR: 3- PR: 4
- CR: 6- PR: 1
• 3 PR at 3 mo converted to CR by 6 mo; 1 PR at 9 mo had PD at 12
Schuster et al. ASCO 2015, Abst 8516.
CAR-T Cells for Rel/Rel CD19 Positive NHLs: PFS Results for DLBCLs
N = 13Median PFS 90 days
1.00
0.75
0.50
0.25
0.000 100 200 300 400
Days
Schuster et al. ASCO 2015, Abst 8516.
CAR-T Cells for Rel/Ref CD19 Positive NHLs: PFS Results for FLs
N = 7Median not reachedMedian follow-up 290 days
1.00
0.75
0.50
0.25
0.000 100 200 300 400
Days
Schuster et al. ASCO 2015, Abst 8516.
AE G3 G4 AE G3 G4
Renal 2 Infections 2
Anemia 1 Hypophosphatemia 3 1
CRS 1 1 Hypotension 1 1
Delirium 1 Leukopenia 3 2
Fever 1 Lymphopenia 10 8
Hypertension 2 Neutropenia 3 6
Hypocalcemia 1 Thrombocytopenia 1
Hypokalemia 1 Transaminitis 1
Hyponatremia 1
CAR-Ts for Rel/Ref NHLs: Grade 3-4 AEs in > 2 Patients Regardless of Cause
Schuster et al. ASCO 2015, Abst 8516.
Current CAR Studies for Lymphomas or Myelomas (2015)
• Seven centers have trials targeting CD19– NCI (Bethesda)– MSKCC (New York)– Fred Hutchinson (Seattle)– U Penn (Philadelphia)– City of Hope (Los Angeles)– Baylor (Houston)– MDACC (Houston)
• Multicenter Trials– Kite– Novartis
• One study targeting CD22 at NCI
Chimeric Antigen Receptor-T Cell Therapy for Lymphomas
• Development of CAR-Ts• Studies in Adults with B-Cell
Lymphomas• Identification and Management of
Adverse Events
Classic Toxicity Associated with CAR-T Cell Therapy
• Cytokine Release Syndrome (CRS)– High fevers, hypotension, hypoxia– Mild Coagulopathy (Elevated D-Dimer, Low
Fibrinogen, C-Reactive Protein)– Hepatosplenomegaly, mild transaminitis– Elevated cytokines: IL-6, TNF
• Macrophase Activation Syndrome– High Ferritin levels– Moderate marrow hemophagocytosis (HLH)
Neurologic Symptoms Observed in CD19 CAR-T Trials
• Mental status changes associated with hypotension and fevers– Classically confusion; obtundation when severe – Occasionally mild, with focal neurologic changes,
including aphasia and myoclonus– Easiest identification: handwriting– Most resolve in days to weeks
• Exact cause unknown– Associated with larger tumor burden, marrow
involvement– Also thought to be off target toxicity, CARs found in
CSF
Unmet Needs in CAR-T Research• Improve Efficacy– Improve antigens or combinations– Improve CAR-T effector function and persistence.– Decrease immunosuppression in microenvironment
(better conditioning, humanization of scFv)• Improve Safety– Better understand causes/prevention of CRS and
neurotoxicity– Include safeguards (suicide genes) in next CAR-Ts
• Integrate into Standard Care and Improve Feasibility– Develop combination therapies– Study applicability beyond specialized centers
Chimeric Antigen Receptor-T Cell Therapy for Lymphomas
• Development of CAR-Ts• Studies in Adults with B-Cell
Lymphomas• Identification and Management of
Adverse Events
Immunotherapy for Lymphoma: Finally?
F B Hagemeister, MDProfessor of Medicine
Department of Lymphoma and MyelomaM D Anderson Cancer Center
Bangkok 29 August 2015
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