IMMUNOLOGY IN CMLDra. Blanca Xicoy

Servei d’Hematologia Clínica

Barcelona, 11/10/2019

AT DIAGNOSIS

UNDER TKI

DISCONTINUATION OF TKI

ROLE OF IFNIMMUNE

CHECKPOINT

PATHWAY

IMMUNOLOGY IN CML

VACCINES

IMMUNOGENICITY &

STEM-CELL

PERSISTENCE

IMMUNOGENICITY &

STEM-CELL

PERSISTENCE

AT DIAGNOSIS

UNDER TKI

DISCONTINUATION OF TKI

ROLE OF IFNIMMUNE

CHECKPOINT

PATHWAY

IMMUNOLOGY IN CML

VACCINES

Hughes A, Front Immunol 2017

• Immunological GVL effect by donor T and NK cells,

targeting alloantigens

• GVL effect by DLIs

BCR-ABL weakly immunogenic in itself,

but upregulates multiple genes with

expression of LAAS

Eibl B, Genes Chromosomes Cancer 1997; Scheich F, Blood 2007

Rakhra K, Cancer Cell 2010

Rakhra K, Cancer Cell. 2010

Rousselot P, J Clin Oncol 2014

Saussele S, Lancet Oncol 2018

IMMUNOGENICITY &

STEM-CELL

PERSISTENCE

AT DIAGNOSIS

UNDER TKI

DISCONTINUATION OF TKI

ROLE OF IFNIMMUNE

CHECKPOINT

PATHWAY

IMMUNOLOGY IN CML

VACCINES

Hughes A, Front Immunol 2017

Molldrem J, Nat Med 2000; Mumprecht S, Blood 2009; Mellqvist UH, Blood 2000; Dong R, Blood 2003; Eisendele K, Br J Haematol

2003; Wesolovski R, J Immunother Cancer 2013; Chen Cl, Leukemia 2012; Humlova Z, Clin Dev Immunol.2010; Kreutzmann A, PLoS

One 2010; Christiansson, PLoS One 2013; Ilander M, Leukemia 2016; Hughes A, Blood 2017; Schüz C, Leukemia 2017; Sopper S, J

Clin Oncol 2017

SUPPRESOR CELLS

EFFECTOR CELLS

Hughes, Front Immunol 2017, Sopper S, Leukemia 2017; Yeung DT, Blood 2015

• More mature, cytolytic NK cells

• LAA-specific CTL responses

Hughes A, Blood 2017

• Increased NK cell LAA-specific CTL responses

• Reduced T-cell PD-1 expression

• Reduced numbers of MDSCs

• Persistence of Treg and PD-1 T cells

Mustjoki S, Leukemia 2009; Nagata Y, Int J Hematol 2010; Kim DH, Haematologica 2009, Najima Y, Leuk Res 2018

• Lymphocytosis, expansion of LGLs

• 50% in 2nd line, at 4-5 months

• Associated with DMR

• Pleural effusions, colitis

• Reduction of Tregs, increase NK and CTL counts, differentiation of NK cells

Ilander M, Oncotarget 2017; Ilander M, Leukemia 2017

Rea D, Haematologica 2017; Ilander M, Leukemia 2017, Schütz C,

Leukemia 2017; Imagawa J, Lancet haematol 2015; Kumagai T,

Cancer Sci 2018Rea D, Haematologica 2017

Caocci G, Exp Hematol. 2015

• Lack of expression of KIR2DL5B associated with DMR

• KIR genotypes associated increased likelihood of TFR success (?)

Yeung DT, Blood. 2015; Caocci G, Exp Hematol 2015; Ilander M, Leukemia 2017; Dumas P, Cancer Medicine 219

Expression of the CTLA-4 ligand CD86 on pDC predicts risk of

disease recurrence after treatment discontinuation

Inselmann S, Cancer Res 2018; Schütz C, Leukemia 2017

Clark, Lancet Haematol 2017; Austin GM, Br J Haematol 2019

• Decrease in Tregs, CD56dim and CD56bright NK cell subsets during TKI de-escalation

• No further changes are seen on stopping for any subset

• A rise in the effector memory CD8+ subset during de-escalation predicts molecular recurrence

Hughes TP, 21st Annual John Goldman Conference on Chronic Myeloid Leukemia: Biology and Therapy

• Regulatory T-cells: CD3+CD4+CD25hiCD127lowFoxP3+

• Monocytic myeloid-derived suppressor cells (MDSCs): CD11b+CD33+CD66blowCD14

Effector Suppressor score = 0.738 + 0.166*NKcells – 0.36*Tregs – 0.168*Mo-MDSC

IMMUNOGENICITY

OF CML

AT DIAGNOSIS

UNDER TKI

DISCONTINUATION OF TKI

ROLE OF IFNIMMUNE

CHECKPOINT

PATHWAY

IMMUNOLOGY IN CML

VACCINES

Talpaz M, Ann Hematol 2015; Ross DM, Blood 2013;

Takahashi N, Haematologica 2012; Kreutzmann A, PLoS One 2011; Burchert A, J Clin Oncol 2010

• Induces apoptosis

• Supresses angiogenesis

• Supresses hematopoiesis

• Activates immune effector cell (specific T-cell

responses)

• Increased NK cell counts associated with TFR

Cytogenetic responses with IFN, molecular with TKI

Faster & better molecular responses in combination with TKI compared to TKI alone

Burchert A, Leukemia 2015

IFN may allow a higher rate of TFR, even in MR3.0 before discontinuation

Burchert A, J Clin Oncol 2010; Burchert A, Leukemia 2015

• Deepening response with IFN maintenance

• Activating immune response to PR-3 by IFN

• Cytogenetic responses, durable even after discontinuation

• Immune control at discontinuation different and/or better than TKI (?)

• Cytogenetic responses, durable even after discontinuation

• Immune control at discontinuation different and/or better than TKI (?)

• Cytogenetic responses, durable even after discontinuation

• Immune control at discontinuation different and/or better than TKI (?)

• Cytogenetic responses, durable even after discontinuation

• Immune control at discontinuation different and/or better than TKI (?)

Ross DM, Br J Haematol 2019

• Closed prematurely

• Increase of thrombotic risk with imatinib & lenalidomide at discontinuation of imatinib

• Mechanisms (?)

Increase of NK-cells and LAA-CTL responses

IMMUNOGENICITY

OF CML

AT DIAGNOSIS

UNDER TKI

DISCONTINUATION OF TKI

ROLE OF IFNIMMUNE

CHECKPOINT

PATHWAY

IMMUNOLOGY IN CML

VACCINES

Munprecht S, Blood 2009; Riether C, Leukemia 2015, Brück O, Leukemia 2018

• PD-L1 expression in CML cells & high expresión of PD-1 in CML-specific CTLs at

diagnosis

• PD-1 expression decreases in CD8+ T cells during TKI treatment

Blocking the PD-1 or CTLA4 may restore the function of CML-specific CTLs

Westerwieel, Front Oncol 2019

IMMUNOGENICITY

OF CML

AT DIAGNOSIS

UNDER TKI

DISCONTINUATION OF TKI

ROLE OF IFNIMMUNE

CHECKPOINT

PATHWAY

IMMUNOLOGY IN CML

VACCINES

Single-arm studies, prospective randomized trials are required

IMMUNOLOGY IN CML

SUMMARY

• CML is immunogenic

• CML is immunogenic

• Suppresion of immune system at diagnosis, but restoration under

TKI & maximal restoration associated with deep molecular response

• CML is immunogenic

• Suppresion of immune system at diagnosis, but restoration under

TKI & maximal restoration associated with deep molecular response

• Differenciated and cytotoxic NK cells associated with TFR

• CML is immunogenic

• Suppresion of immune system at diagnosis, but restoration under

TKI & maximal restoration associated with deep molecular response

• Differenciated and cytotoxic NK cells associated with TFR

• Controversial role of KIRs and other components of the immune

system (?)

• A major goal is the delineation of the precise mechanisms

involved in TFR success and the identification of a robust

immunological biomarker that predicts TFR after discontinuation

• A major goal is the delineation of the precise mechanisms

involved in TFR success and the identification of a robust

immunological biomarker that predicts TFR after discontinuation

• IFN plays an important role inducing specific T-cell responses

• A major goal is the delineation of the precise mechanisms

involved in TFR success and the identification of a robust

immunological biomarker that predicts TFR after discontinuation

• IFN plays an important role inducing specific T-cell responses

• Trials using IFN in combination with a second-generation TKI to

enhance immune-modulation prior to a TFR attempt are ongoing

• A major goal is the delineation of the precise mechanisms

involved in TFR success and the identification of a robust

immunological biomarker that predicts TFR after discontinuation

• IFN plays an important role inducing specific T-cell responses

• Trials using IFN in combination with a second-generation TKI to

enhance immune-modulation prior to a TFR attempt are ongoing

• Future: combinations of TKI with checkpoint inhibidors and other

targets of the immune system, vaccines