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Prognostic and Predictive
Significance of the Immunological
Tumor Environment
Dirk Jäger
Medical Oncology
National Center for Tumor Diseases
University Medical Center Heidelberg
Germany
Metastatic Colorectal Cancer
• If not resectable, mOS around 2,5 years with currently
available systemic treatments
• PFS 8-10 months
• Response rates 50-60%
Metastatic Colorectal Cancer
Liver biopsy patient 1
Liver biopsy patient 2
Both patients underwent chemotherapy + Cetuximab:
- Patient 1 had a complete response after 4 cycles
- Patient 2 was rapidly progressing under
treatment
- PFS 16 months for patient 1
- OS 48 months versus 4 months
How do we know?
Liver biopsy patient 1
Liver biopsy patient 2
Both patients underwent chemotherapy + Cetuximab:
- Patient 1 had a complete response after 4 cycles
- Patient 2 was rapidly progressing under
treatment
- PFS 16 months for patient 1
- OS 48 months versus 4 months
Liver biopsy patient 1
Liver biopsy patient 2
• Histology:
• Moderately differentiated adenocarcinoma, G2
• Mutations:
• Kras wild type
• Braf Wild type
• Lab:
• CEA 6 versus 7,6, LDH normal, no Lab abnormalities
Individual Tumor
Individual Tumor
Tumor cell biology
(genetics)
Individual Tumor
Tumor cell biology
(genetics)
Tumor Immunity
Individual Tumor
Tumor Immunity
Exome sequencing of both tumors could not
explain the different tumor biology......
Liver biopsy patient 1
Liver biopsy patient 2
• Histology:
• Moderately differentiated adenocarcinoma, G2
• Mutations:
• Kras wild type
• Braf Wild type
• Lab:
• CEA 6 versus 7,6, LDH normal, no Lab abnormalities
Infiltrating T cells in ovarian cancer
Zhang, N Engl J Med 2003;
Prognostic significance of infiltrating T cells in CRC
% Patients
Infiltrating T cells
Galon et al., Science, 2006
% Patients
Prognostic significance of infiltrating T cells in CRC
% Patients
Tumor infiltrating memmory T cells
Galon et al., Science, 2006
CRC Liver Metastases: the Invasive Margin
Invasive Margin
(CD3 staining)
Advantages: well-defined border, no morphological ambiguity,
„obvious“ differences were apparent
Variability of infiltrate density at the invasive margin
of CRC liver metastases
CD3 staining („red“) of
two different metastases
from two patients…
…showing an apparent
difference in infiltrate
density at the
Invasive Margin.
Decision on the spot…
Do we
know ?
Evaluated area ~120 mm²
Immunological Tumor Maps
Grid construction for tumor tissue (each square being 1 mm²)
Immunological tumor maps
Primary CRC, no MSI
Halama N, Zoernig I, Michel S, Kloor M, Grauling-Halama S, Schirmacher P, Jäger D, Grabe N.
Tumor Maps: Quantification of Prognostic Immune Cell Markers in Colorectal Cancer Using Whole Slide Imaging, Analytical and
Quantitative Cytology and Histology, 2010
Central Role of the Pathologist
…to be fair: any other observer could substitute here as well…
Experiments with pathologists… part I
Experiments with pathologists… part II
Experiments with pathologists… part III
What if there are two pathologists?
Grid construction for tumor tissue
(each square being 1 mm²)
Whole-slide scanning technology and automated high-throughput
immunohistochemical evaluation of complete tissue sections
(Hamamatsu TIGA Center)
Halama et al. Cancer Immunity 2009
Halama et al. Anal Quant Cytol Histol. 2010
Halama et al. Cancer Res 2011
Halama et al. Clin Cancer Res 2011
Automated Cell Counting
General considerations for cell counting based on „cell area“ and border
recognition
A: cell shapes are uniform, each target cell has almost identical area size
B: cell shapes are uniform, each target cell has almost identical area size
C: cell shapes are not uniform, clusterings are present
Other obstacles: staining artifacts, not uniform staining intensity, etc.
Note: other „countable“ stainings (like NY-BR-1) can also be evaluated…
T cell infiltrates at the invasive margin: density score
0
1
2
3
4
4
Halama et al., Cancer Res. 2011
Evaluation of Immune Cell Density & Clinical Data
Score based on infitrate density (CD3, CD8, GranB), training set from University of Heidelberg
validation set from SLK Heilbronn
Halama et al., Cancer Res. 2011
Exploratory Kaplan-Meier Plots
p<0.001
p<0.001
Logrank test
Logrank test
PFS
OS
Halama et al., Cancer Res. 2011
Validation cohort
Early results:
Patient
Prediction
Response
Halama et al., Cancer Res. 2011 Sep 1;71(17):5670-5677
Correct prediction of response
to treatmnet in 57 out of
66 patients (86%)
Most biopsies were fine
needle biopsies with little
`invasive margin´
Halama et al., Cancer Res. 2011 Sep 1;71(17):5670-5677
Combined analysis:
„Cytokine profiling & Cell composition“
Halama et al. Clin Cancer Res 2011
IL-4
IL-4
IL-4
IL-2
IL-2
IL-6
IL-2
IL-6
PD-1L
PD-1L
IL-2
IL-10
PD-1L
IL-10
PD-1
PD-1
IL-10
PD-1
IL-10
Implications
• Cellular immune responses (infiltrates) at the tumor site have
prognostic and predictive significance in patients undergoing
chemotherapy in CRC
• We established a plattform that allows us to assess and monitor
the complex interplay of different immune cell subsets with tumor
cells and stroma cells
• We now look at metastatic lesions as complex `organs´ with
distinct immunological compartments
• The better understanding of the immunological tumor milieu
opens up various new approaches (targets) for specific
intervention (modulation)
Implications
• Modulating the local immunological environment can be
therapeutically effective
• Intelligent combination treatments
• Interestingly, conventional treatments like chemotherapy,
radiotherapy or targeted drugs have distinct effects on the local
immunological environment
• The assessment of the local environment including immune cell
typing/quantification, cytokine/chemokine profiling in different
tumor areas should be implemented in our routine diagnostic
workup
Jäger Lab
Medical Oncology
CCU Applied Tumor Immunity DKFZ
University Medical Center Heidelberg
Dr. Niels Halama
Prof. Niels Grabe
Dr. Inka Zörnig
Dr. Patrick Schmidt
Max Kordes
Rodrigo Moraleda
Julia Bitzer
Sophia Keim
Sampada Hundekari
Jin Ho Lee
Jutta Funk
Isabella Gosch
Claudia Ziegelmeier
Claudia Luckner-Minden
Iris Kaiser
Petra Narrog
Max Langknecht
DKFZ Heidelberg
Dr. Nektarios Valous
Zeynep Kosaloglu
Anna Spille
Tina Lerchl
Rosa Eurich
Thank you!