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Víctor Andrés Arrieta González
MD,PhD
Exploring Predictive
Biomarkers and ERK1/2
Phosphorylation: A New
Horizon in Forecasting Survival
and Response to Immune
Checkpoint Blockade in
Glioblastoma Treatment
Clinical GBM responder and non-responder to PD-1 blockade
49.4 0.11
16.7
33.8
0 10
3
10
4
CD4 APC-Cy7
0
10
3
10
4
CD8
PE-Cy7-A
74.2 0.54
18.4
6.91
0 10
3
10
4
Comp-APC-Cy7-A
0
10
3
10
4
Comp-PE-Cy7-A
38.4 0.12
56.8
4.72
0 10
3
10
4
CD4 APC-Cy7
0
10
3
10
4
CD8
PE-Cy7
Start of
anti-PD-1
therapy
Start of
anti-PD-1
therapy
Last seen
alive 21
months after
PD-1 blockade
2 weeks 10 months 11 months 13 months 15 months
Resection
Resection
Resection
2 months Death 6
months
after PD-1
blockade
Recurrence
Recurrence
Responder
Non-responder
CD3 Blood Resected tissue
CSF
200 µm
Arrieta VA, Chen AX, et al, Nat Cancer 2021
Enrichment of BRAF/PTPN11 mutations in responder patients
Zhao J et al, Nat Med 2019
MAPK pathway
Pratilas CA et al, Clin Cancer Res 2010
PTPN11
p-ERK is associated with longer survival in recurrent GBM patients treated with
anti-PD-1 therapy
250 µm 250 µm
High p-ERK Low p-ERK
Arrieta VA, Chen AX, et al, Nat Cancer 2021
Patients with longer overall survival exhibited high levels of p-ERK regardless
of the genetic status of the BRAF/PTPN11
Arrieta VA, Chen AX, et al, Nat Cancer 2021
Cloughesy TF et al, Nat Med 2019
p-ERK is associated with overall survival in an independent cohort of
recurrent GBM patients treated with adjuvant PD-1 blockade
Arrieta VA, Chen AX, et al, Nat Cancer 2021
p-ERK is predominantly expressed by GBM cells
p-ERK
IHC
H&E
p-ERK
IHC
H&E
p-ERK
IHC
H&E
BRAFV600E
mutant GBM
High p-ERK
Wild-type BRAF
GBM
High p-ERK
Wild-type
BRAF GBM
Low p-ERK
200 µm 200 µm
200 µm 200 µm
200 µm 200 µm
p-ERK
SOX2 DAPI CD163 DAPI
SOX2 TMEM119
p-ERK
SOX2 DAPI CD163 DAPI
SOX2 TMEM119
p-ERK
SOX2 DAPI CD163 DAPI
SOX2 TMEM119
Arrieta VA, Chen AX, et al, Nat Cancer 2021
High-p-ERK GBMs contain abundant TMEM119+ microglia
p-ERK Iba1
250 µm 250 µm
Arrieta VA, Chen AX, et al, Nat Cancer 2021
TMEM119+ microglia are closer to SOX2+ p-ERK+ cells
TMEM119+ cells
CD163+ cells
SOX2+ p-ERK+
cells
Mean distance to the
nearest neighbor
From
To
SOX2+ p-ERK-
cells
TMEM119+ SOX2+ p-ERK+ TMEM119+ SOX2+ p-ERK+
High p-ERK Low p-ERK
200 µm 200 µm
Arrieta VA, Chen AX, et al, Nat Cancer 2021
CD163+ cells
GFAP+ p-ERK-
cells
Mean distance to the
nearest neighbor
From
To
GFAP+ p-ERK+
cells
Arrieta VA, Chen AX, et al, Nat Cancer 2021
CD163+ GFAP+ pERK+
CD163+ GFAP+ pERK+
High p-ERK Low p-ERK
200 µm 200 µm
CD163+ myeloid cells are closer to GFAP+ p-ERK+ cells
Analysis of GBM-infiltrating microglia and macrophages by single-cell RNA-seq
Arrieta VA, Chen AX, et al, Nat Cancer 2021
Myeloid cells from high p-ERK GBMs
have increased MHC II expression
Arrieta VA, Chen AX, et al, Nat Cancer 2021
GO
MHC
Class
II
protein
Complex
Binding
1.75
1.50
1.25
1.00
0.00
0.75
0.50
0.25
GO MHC Class II protein Complex Binding
0.8
0.6
0.4
0.2
0.0
1.0
0.5
0.0
-0.5
0 5000 10000 15000 20000 25000
High p-ERK
Low p-ERK
Myeloid cells from high p-ERK GBMs
have increased MHC II expression
Arrieta VA, Chen AX, et al, Nat Cancer 2021
• ERK1/2 phosphorylation shows that is a predictive biomarker of immune checkpoint
blockade including anti-PD-1 therapy in three independent cohorts of recurrent GBM
patients.
• GBMs that exhibit high numbers of p-ERK+ cells contain abundant TMEM119+ microglia.
• Myeloid cells derived from high p-ERK GBMs exhibit increased MHC class II expression
compared to myeloid cells derived from low p-ERK GBMs.
Conclusions
• There are several aspects to consider before implementing p-ERK as a biomarker for
response to anti-PD-1 therapy:
• Further validation in additional clinical cohorts
• Cut point value optimization
• Alternative techniques for MAPK pathway activation
• Standardized protocols for p-ERK assessment
Considerations
Acknowledgments
Columbia University
• Junfei Zhao
• David Cieremans
• Pavan
Upadhyayula
• Jinzhou Yuan
• Wenting Zhao
• Brice Laffleur
• Uttiya Basu
• Gerson Rothschild
• Peter Sims
• Peter Canoll
• Jeffrey N. Bruce
Northwestern University
• Seong Jae Kang
• Kirsten B. Burdett
• Crismita Dmello
• Andrew Gould
• Matthew McCord
• Li Chen
• Daniel Zhang
• Dinesh Jaishankar
• Joseph Shilati
• Christina Amidei
• Lee D Cooper
• Rimas V. Lukas
• Hui Zhang
• Jonathan T.
Yamaguchi
• Daniel J. Brat
• Bin Zhang
• Roger Stupp
MD Anderson Cancer Center
• Cynthia Kassab
• Xiaoyang Ling
• Jared K. Burks
UCLA
• Robert Prins
• Tim F.
Cloughesy
Andrew X. Chen J. Robert Kane
Adam Sonabend Fabio M. Iwamoto
Raul Rabadan
Amy Heimberger Craig Horbinski Catalina Lee Chang

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Exploring Predictive Biomarkers and ERK1/2 Phosphorylation: A New Horizon in Forecasting Survival and Response to Immune Checkpoint Blockade in Glioblastoma Treatment

  • 1.
  • 2. Víctor Andrés Arrieta González MD,PhD Exploring Predictive Biomarkers and ERK1/2 Phosphorylation: A New Horizon in Forecasting Survival and Response to Immune Checkpoint Blockade in Glioblastoma Treatment
  • 3.
  • 4. Clinical GBM responder and non-responder to PD-1 blockade 49.4 0.11 16.7 33.8 0 10 3 10 4 CD4 APC-Cy7 0 10 3 10 4 CD8 PE-Cy7-A 74.2 0.54 18.4 6.91 0 10 3 10 4 Comp-APC-Cy7-A 0 10 3 10 4 Comp-PE-Cy7-A 38.4 0.12 56.8 4.72 0 10 3 10 4 CD4 APC-Cy7 0 10 3 10 4 CD8 PE-Cy7 Start of anti-PD-1 therapy Start of anti-PD-1 therapy Last seen alive 21 months after PD-1 blockade 2 weeks 10 months 11 months 13 months 15 months Resection Resection Resection 2 months Death 6 months after PD-1 blockade Recurrence Recurrence Responder Non-responder CD3 Blood Resected tissue CSF 200 µm Arrieta VA, Chen AX, et al, Nat Cancer 2021
  • 5. Enrichment of BRAF/PTPN11 mutations in responder patients Zhao J et al, Nat Med 2019 MAPK pathway Pratilas CA et al, Clin Cancer Res 2010 PTPN11
  • 6. p-ERK is associated with longer survival in recurrent GBM patients treated with anti-PD-1 therapy 250 µm 250 µm High p-ERK Low p-ERK Arrieta VA, Chen AX, et al, Nat Cancer 2021
  • 7. Patients with longer overall survival exhibited high levels of p-ERK regardless of the genetic status of the BRAF/PTPN11 Arrieta VA, Chen AX, et al, Nat Cancer 2021
  • 8. Cloughesy TF et al, Nat Med 2019 p-ERK is associated with overall survival in an independent cohort of recurrent GBM patients treated with adjuvant PD-1 blockade Arrieta VA, Chen AX, et al, Nat Cancer 2021
  • 9. p-ERK is predominantly expressed by GBM cells p-ERK IHC H&E p-ERK IHC H&E p-ERK IHC H&E BRAFV600E mutant GBM High p-ERK Wild-type BRAF GBM High p-ERK Wild-type BRAF GBM Low p-ERK 200 µm 200 µm 200 µm 200 µm 200 µm 200 µm p-ERK SOX2 DAPI CD163 DAPI SOX2 TMEM119 p-ERK SOX2 DAPI CD163 DAPI SOX2 TMEM119 p-ERK SOX2 DAPI CD163 DAPI SOX2 TMEM119 Arrieta VA, Chen AX, et al, Nat Cancer 2021
  • 10. High-p-ERK GBMs contain abundant TMEM119+ microglia p-ERK Iba1 250 µm 250 µm Arrieta VA, Chen AX, et al, Nat Cancer 2021
  • 11. TMEM119+ microglia are closer to SOX2+ p-ERK+ cells TMEM119+ cells CD163+ cells SOX2+ p-ERK+ cells Mean distance to the nearest neighbor From To SOX2+ p-ERK- cells TMEM119+ SOX2+ p-ERK+ TMEM119+ SOX2+ p-ERK+ High p-ERK Low p-ERK 200 µm 200 µm Arrieta VA, Chen AX, et al, Nat Cancer 2021
  • 12. CD163+ cells GFAP+ p-ERK- cells Mean distance to the nearest neighbor From To GFAP+ p-ERK+ cells Arrieta VA, Chen AX, et al, Nat Cancer 2021 CD163+ GFAP+ pERK+ CD163+ GFAP+ pERK+ High p-ERK Low p-ERK 200 µm 200 µm CD163+ myeloid cells are closer to GFAP+ p-ERK+ cells
  • 13. Analysis of GBM-infiltrating microglia and macrophages by single-cell RNA-seq Arrieta VA, Chen AX, et al, Nat Cancer 2021
  • 14. Myeloid cells from high p-ERK GBMs have increased MHC II expression Arrieta VA, Chen AX, et al, Nat Cancer 2021 GO MHC Class II protein Complex Binding 1.75 1.50 1.25 1.00 0.00 0.75 0.50 0.25 GO MHC Class II protein Complex Binding 0.8 0.6 0.4 0.2 0.0 1.0 0.5 0.0 -0.5 0 5000 10000 15000 20000 25000 High p-ERK Low p-ERK
  • 15. Myeloid cells from high p-ERK GBMs have increased MHC II expression Arrieta VA, Chen AX, et al, Nat Cancer 2021
  • 16. • ERK1/2 phosphorylation shows that is a predictive biomarker of immune checkpoint blockade including anti-PD-1 therapy in three independent cohorts of recurrent GBM patients. • GBMs that exhibit high numbers of p-ERK+ cells contain abundant TMEM119+ microglia. • Myeloid cells derived from high p-ERK GBMs exhibit increased MHC class II expression compared to myeloid cells derived from low p-ERK GBMs. Conclusions
  • 17. • There are several aspects to consider before implementing p-ERK as a biomarker for response to anti-PD-1 therapy: • Further validation in additional clinical cohorts • Cut point value optimization • Alternative techniques for MAPK pathway activation • Standardized protocols for p-ERK assessment Considerations
  • 18. Acknowledgments Columbia University • Junfei Zhao • David Cieremans • Pavan Upadhyayula • Jinzhou Yuan • Wenting Zhao • Brice Laffleur • Uttiya Basu • Gerson Rothschild • Peter Sims • Peter Canoll • Jeffrey N. Bruce Northwestern University • Seong Jae Kang • Kirsten B. Burdett • Crismita Dmello • Andrew Gould • Matthew McCord • Li Chen • Daniel Zhang • Dinesh Jaishankar • Joseph Shilati • Christina Amidei • Lee D Cooper • Rimas V. Lukas • Hui Zhang • Jonathan T. Yamaguchi • Daniel J. Brat • Bin Zhang • Roger Stupp MD Anderson Cancer Center • Cynthia Kassab • Xiaoyang Ling • Jared K. Burks UCLA • Robert Prins • Tim F. Cloughesy Andrew X. Chen J. Robert Kane Adam Sonabend Fabio M. Iwamoto Raul Rabadan Amy Heimberger Craig Horbinski Catalina Lee Chang