immunomodulation in lymphomas sattva s. neelapu, m.d. department of lymphoma and myeloma ut md...
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Immunomodulation in lymphomas
Sattva S. Neelapu, M.D.
Department of Lymphoma and Myeloma
UT MD Anderson Cancer Center
Houston, TX
Texas Fresh AIR
October 23-24, 2014
Target tumor
Activate immune cells
Lymphoma immunotherapy
Naked monoclonal Abs
Radio-immunotherapy
Ab-drug conjugates
Immunotoxins
CAR T-cell therapy
Vaccines
Stimulatory agonists
Checkpoint antagonists
Why active immunotherapy for lymphoma?Results after non-myeloablative SCT
OSPFS
Median F/U – 5 yrs
Khouri et al, Blood 2008
Median F/U – 8 yrs
OSPFS
Khouri et al, Blood 2012
PFS
Chemosensitive
Chemorefractory
Khouri et al, Blood 2012
Tumor-infiltrating T-cells recognize autologous tumor cells in follicular lymphoma (FL)
CD20
Bulk tumor cells
12%
CD
3
After in vitro stimulation and expansion with tumor
0.2%
CD4 alone
CD69
TN
F-
42%
CD4 + Tumor
CD69
TN
F-
67%
33%
CD
4
CD4 vs CD8 T cells
CD310x
CD3/CD20
Series1
0
500
1000
1500
2000
2500
3000
GM-CSF IFN-
pg
/ m
l
T Tum T+Tum T Tum T+Tum
FL1 - Peripheral blood and intratumoral T cells recognized mutated neo-antigens in FL
FL – TIL at DxMutated vs. Wild type
FL – TIL at DxHLA Restriction
FL – PB T cells at Dx 16 peptide screen
Pep Gene HLA binding Wt affinity Mt affinity
P1 DDX58 I343S HLA-DRB40101 15.3 21.5
P4 HIST1H4C N65K HLA-DRB40101
28.9 21.8
P12 PSPH D32G HLA-DRB40101 63.2 130.7
P14 TDO2 S353L HLA-DRB40101 146.4 18.3
FL2 - Peripheral blood and intratumoral T cells recognized mutated neo-antigens in FL
P17 – MUC6 Q1821H
HLA-DRB10701
Wt affinity (TATSFQTTTTYPT ) – 9.3 nM
Mt affinity (TATSFHTTTTYPT) – 14.6 nM
FL4 – TIL at Dx
FL4 – PB T cells at Dx20 peptide screen
FL4 – PB T cells in remission
FL3 - Peripheral blood and intratumoral T cells recognized mutated neo-antigens in FL
FL5 – TIL at Dx
FL5 – PB T cells at Dx29 peptide screen
FL5 – PB T cells in remission
Pep Gene HLA binding Wt affinity Mt affinity
P4 ZIM2 P318L HLA-DRB10404 390 230
P5 NLGN1 T782I HLA-DRB10404 7 7
P12 MTSS1 R381Q HLA-DRB10404 56 41
P17 KCNJ12 S343L HLA-DRB10404 254 90
P27 CEACAMs V83A HLA-DRB10404 76 130
Coinhibitory molecules on intratumoral T cells in FL
PD-1+ CD4 & CD8 T cells are increased in the peripheral blood and tumor of FL
42.0917.644.353.50 17.30 65.82
CD4
PD
-1
PD
-1
CD8
PD-1 expression in other lymphomas
**
PBMC Tumor
** ** ** **
CD4
CD8
Days 1 29 57 85 113
CT/PET/BM 0 57 113 q3mo
Core Bx 0 14 113
Blood/PBMC 1,2 14
Pidilizumab 1 2 3 4
n = 30
RituximabDays 17 24 31 38
If SD/PR/CR continue 8 more infusions every 4 wks
Pidilizumab + rituximab in relapsed FL patients
• Pidilizumab – iv infusion at 3.0 mg/kg/cycle q 4 weeks for up to 12 cycles
• Rituximab - iv infusion at a dose of 375 mg/m2 weekly for 4 weeks
Pidilizumab + Rituximab in relapsed FL 66% ORR 52% CR rate
Westin, et al [Neelapu], Lancet Oncol, 2014
86%
• ORR did not correlate with FLIPI1 or FLIPI2 score, amount of prior rituximab, prior chemotherapy, or duration of prior response (p>0.05)
Time to response and duration of response
Westin, et al [Neelapu], Lancet Oncol, 2014
Median time to response was 88 days
Biomarker of response after pidilizumab and rituximab therapy in FL
PD-L1 status vs response to nivolumab in melanoma
Topalian et al, N Engl J Med, 2012
PD-L1 expression on lymphoma tumors
Brown et al, J Immunol 2003; Marzec et al, PNAS, 2008; Xerri et al, Hum Pathol, 2008;Andorsky et al, Clin Cancer Res, 2011; Chen et al, Clin Cancer Res, 2013
Lymphoma subtype PD-L1 positive (% cases)
Hodgkin (NS and MC) 89%
ABC DLBCL 57%
T-cell/histiocyte-rich B-cell 91%
PMBCL 100%
EBV+ DLBCL 100%
EBV+/- PTLD 60%
Plasmablastic 44%
HHV8-associated PEL 50%
ALK+ ALCL 100%
PTCL 64%
Extranodal NK/TCL 67%
NLP Hodgkin 13%
DLBCL NOS 11%
FL, SLL, MZL, MCL, EBV+ BL 0%
CD4+PD-1+ T cell subsets in FL
Rel
ativ
e m
RN
A l
evel
Bcl6 - Tfh
T-bet – Th1
GATA3 – Th2
RORc – Th17
IFN- g - Th1
IL-4 - Tfh
IL-21 - Tfh
Tfh – protumorTh1 - antitumor
αPD-1 Ab
Tumorregression
Th1(PD-1int/lo)
Tfh(PD-1hi)
Impact of PD-1+ T-cell subsets in FL
Th1(PD-1int/lo)
Tfh(PD-1hi)
No response or Tumor progression
αPD-1 Ab
Neelapu, Oncoimmunol, 2014
CD4+ T-cell subsets in FL tumors
(Tfh)
(Th1)
Westin et al, [Neelapu], Lancet Oncol, 2014
Teff-gene signature correlated with PFS after pidilizumab + rituximab therapy
41-gene signature in pretreatment tumors
Signature average
Dichotomization
N = 18 patients
PFS according to 41-gene signature
P=0.004
Westin et al, [Neelapu], Lancet Oncol, 2014
Does the Teff-gene signature predict outcome after chemotherapy?
Teff-gene signature did not correlate with survival in FL patients treated with chemotherapy
N = 191Dave et al, N Engl J Med 2004; 351:2109
41-gene signature in Dave et al studySignature average
Dichotomization
OS according to 41-gene signature
P=0.139
Westin et al, [Neelapu], Lancet Oncol, 2014
Summary – Pidilizumab + rituximab in FL
• Highly effective in relapsed follicular lymphoma with an ORR of 66% and CR of 52%
• Compares favorably to previous rituximab retreatment data - ORR of 40% & CR of 11% - Davis et al, J Clin Oncol 2000
• High Teff-gene signature may suggest more Th1 vs. Tfh in the tumor and therefore, a pre-existing antitumor immune response and may be predictive of outcome after anti-PD-1 Ab therapy
• Needs to be confirmed in larger trials
• Teff-gene signature may also serve as a predictive biomarker for other immunotherapy agents
Westin et al, [Neelapu], Lancet Oncol, 2014
T-cell dysregulation in FL
Th1/Tc1(Exhaustion /
Synapse)
Tfh(Increased IL-4)
Tregs(Induction/
Recruitment)
Altered numbers
Altered function /
differentiation
T-cell dysregulatio
n
Teffs
Tregs
Teff:Treg
Tum
TumTum
Tum
TumTum
Tum
Follicle
FDC
LT-a
Increased Treg recruitment in FLCross talk between Tumor, FDC, Tfh, Tregs
IL-4CD40 – CD40L
BAFF
Tfh
TfhTfh
Tfh
Tfh
CXCL13
HEV
Treg
Treg
Treg
Treg
TregCCL17
CCL22
Rawal et al [Neelapu], J Immunol 2013
Blood vessel
Differentiation and effects of macrophages in FL
Lymph node
Tumor
Tfh
Th1/Tc1
Tregs
IFN-g
IL-4/IL-21
IL-10/TGF-b
TregsInduction
Th1/Tc1
Suppression
Monocytes
Tumor
ApoptosisSurvivalGrowthChemoprotectionGenomic instability
Angiogenesis
Macrophages
CSF-1
Eradicate
Combination immunotherapy for lymphomas
Activa
te
Tregs
MMMΦ /
MDSC
CD4+T CD8+T
Tumor Tumor
• Vaccines• Novel immune stimulants eg: 4-1BB Ab, OX-40 Ab
• Co-inhibitory receptors / ligands
• PD-1 Antibody• CTLA-4 Ab• LAG3 Ab
• OX-40 Antibody• TLR ligands
Combination immunotherapy • CSF-1R Ab
• S100A9 Ab
• Rituximab• Ab-drug conjugates• Targeted therapies
CAR T cells
Reprogram the tumor microenvironment in follicular lymphoma?
Rituximab + Lenalidomide in frontline indolent NHL
FL(N=46)
MZL(N=27)
SLL(N=30)
All(N=103)
ORR (N/%) 45 (98) 24 (89) 24 (80) 93 (92)
CR rate 40 (87) 18 (67) 7 (23) 65 (64)
PFS (mo) NR 53.8 40.4 53.8
Fowler et al, [Neelapu] Lancet Oncol, 2014
• Rituximab was administered once per cycle
• Lenalidomide was administered for 21 / 28 days per cycle
Increased activated T-cell infiltration into tumorsRituximab + lenalidomide in FL
Pre
On therapy
PD-1CD4 CD8
Fowler et al, [Neelapu] Lancet Oncol, 2014
Activated T cells in peripheral blood in FL on lenalidomide
Fowler et al [Neelapu], Lancet Oncol, 2014
Memory CD4+ and CD8+ T cells PD-1+ CD4+ and CD8+ T cells
? Compartmental shift due to altered chemokine gradients in tumor, improved immunogenicity of tumor, and better immune synapse formation
Pre On therapy
CD80
AcknowledgementsNeelapu Laboratory• Fuliang Chu• Xiaoyun Cheng• Elena Percivalle• Anupama Gopisetty• Seung Tae Lee• Rakesh Sharma
Former members• Myriam Foglietta• David Delgado• Seema Rawal
Department of Lymphoma, MDACC• R. Eric Davis• Jason Westin• Luis Fayad• Larry Kwak• Nathan Fowler• Jorge Romaguera• Frederick Hagemeister• Michelle Fanale• Felipe Samaniego• Rochelle Allen• Min Zhang
Collaborators, MDACCDepartment of Immunology• Chen Dong• Tomohide Yamazaki• Natalia Orozco• Luis Vence
Department of Biostatistics• Lei Feng• Veera Baladandayuthapani
Funding agencies• NIH (R01CA155143; R21CA143785)• Leukemia Lymphoma Society
Immunotherapy + Chemotherapy Combination in Aggressive Lymphomas
Window design
Immunotherapy withchemo-free window
1-2 cycles
Tumor reduction
No tumor reduction
Chemo
Chemo
Immunotherapy
Alternative Rx
Neo-adjuvant Rx Assess response Induction Consolidation - Imaging - IgVH sequencing
• Determine efficacy of immunotherapy alone• Study novel agents in front-line setting• Pre-selection of patients that will benefit from consolidation
Anti-PD-1 Ab monotherapy trials in NHL
Agent Company Type Isotype Binding affinity
Pidilizumab (CT-011) Cure Tech Humanized IgG1k ~ 25 nM
Nivolumab (MDX-1106) BMS Fully human IgG4k ~ 3 nM
Pembrolizumab (MK-3745) Merck Humanized IgG4k ~ 0.03 nM
AMP-514 Medi/AZ Humanized IgG4k ~ 3 nM
Agent Sponsor Phase Lymphoma subtype
Nivolumab BMS I Hem malignancies
Nivolumab BMS II DLBCL
Nivolumab BMS II Follicular lymphoma
Nivolumab BMS II Hodgkin lymphoma
Pembrolizumab Merck Ib Hem malignancies
AMP-514 Medi/AZ I Hem malignancies
Pidilizumab after auto-SCT in DLCL – Phase II
• N = 66
• 3 doses of pidilizumab at 1.5 mg/kg Q 6 wks starting 1-3 months after SCT
• ORR of 51% in patients with measurable disease after SCT
• PFS of 72% and OS of 85% at 16 months
Armand, et al, J Clin Oncol, 2013