PD-‐1/PD-‐L1 Blockade in NHL
Immunotherapy in Hematological Malignancies 2018, Cuneo, May 17-‐19, 2018
Carmelo Carlo-‐Stella, MD
Department of Biomedical Sciences, Humanitas University, Rozzano, Italy Department of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Italy
MHC
PD-‐L1
PD-‐1 PD-‐1
PD-‐1 PD-‐1
Nivolumab blocks the PD-‐1 receptor
Recogni>on of tumor by T cell through MHC/an>gen interac>on mediates IFNγ release and PD-‐L1/2
upregula>on on tumor
Priming and ac>va>on of T cells through MHC/an>gen & CD28/B7 interac>ons with an>gen-‐presen>ng cells
T-‐cell receptor T-‐cell
receptor
PD-‐L1 PD-‐L2
PD-‐L2
MHC
CD28 B7
T cell
NFκB Other
PI3K Dendri>c
cell Tumor cell
IFNγ
IFNγR
Shp-‐2
Shp-‐2
An#-‐PD-‐1: Mechanism of Ac#on
Checkpoint Blockade Therapy in NHL
Vari F, Blood 131:1809-‐1819, 2018
• Expansion of PD-‐1+CD3-‐CD56hiCD16-‐ve NK cells and PD-‐L1+ monocytes/macrophages is more prominent in cHL than DLBCL
• PD-‐1 blockade reverses the immune evasion mediated by the interac>on of PD-‐1+ NK cells and PD-‐L1+ monocytes/ macrophages
PD-‐L1 Expression: RaWonale for PD-‐1/PD-‐L1 Blockade
NLPHL/PD-‐L1 staining cHL/PD-‐L1 staining
PMBCL/PD-‐L1 staining
NLPHL/PD-‐L1 staining
TCHRBCL/PD-‐L1 staining
Chen B, Clin Cancer Res; 19:3462, 2013
PD-‐L1 Expression: RaWonale for PD-‐1/PD-‐L1 Blockade
NLPHL/PD-‐L1 staining
Chen B, Clin Cancer Res; 19:3462, 2013
EBV-‐pos BLBCL EBV-‐neg PTLD DLBCL-‐NOS PD-‐L1 staining
NLPHL/PD-‐L1 staining Georgiou K, Blood, 2016
• TranslocaWons between PD-‐L1 and the IGH locus represent a geneWc mechanism of PD-‐L1 overexpression in DLBCL • Overall, gains (12%), amplificaWons (3%), and translocaWons (4%) of the PD-‐L1/PD-‐L2 locus were idenWfied in nearly 20% of DLBCL • Strong associaWon between PD-‐L1 protein expression and alteraWons in the PD-‐L1/PD-‐L2 locus • GeneWc alteraWons in the PDL1/PDL-‐2 locus are mainly associated with the non-‐GCB subtype of DLBCL
Nivolumab in NHL
NLPHL/PD-‐L1 staining
Lesokhin AM, JCO, 2016
PD-‐L1-‐Expressing Lymphomas • PMLBCL, GZL, PCNSL, PTL (9p24.1 amplificaWon) • Richter transformaWon of CLL • EBV & other virus-‐related lymphomas • BL HIV-‐related, EBV+ PTLD • PlasmablasWc lymphomas • NK/T-‐cell lymphoma • AngioimmunoblasWc T-‐cell lymphoma • HHV-‐8 PEL • MulWcentric Castleman disease
Pembrolizumab in PMBCL
Zinzani et al, Blood 2017
ORR 7/17 (41%)
CR 2/17 (12%)
Ongoing Responses 6/7 (86%)
Blood, 2017
Conclusions
• TherapeuWc benefit of PD-‐1 blockade as a single agent is undoubtedly much less in NHL then in cHL • However, disWnct NHL subtypes may be afracWve for CBT (i.e., PD-‐L1+ lymphomas) • Building on evolving understanding of the molecular pathobiology of various NHL subtypes • CombinaWon partners for PD-‐1 blockade will extend the benefit of checkpoint blockade across a broad spectrum of NHLs
PD-‐L1 Expression
NLPHL/PD-‐L1 staining
Chen B, Clin Cancer Res 19:3462, 2013
