Distinct PD-L1/PD1 Profiles and Clinical Implications in ...
01 PD1 NHL - ER Congressi · PD#1/PD#L1’Blockade’in’NHL’...
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PD1/PDL1 Blockade in NHL Immunotherapy in Hematological Malignancies 2018, Cuneo, May 1719, 2018 Carmelo CarloStella, MD Department of Biomedical Sciences, Humanitas University, Rozzano, Italy Department of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Italy
Transcript of 01 PD1 NHL - ER Congressi · PD#1/PD#L1’Blockade’in’NHL’...
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
