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