Upfront with Archana Hingorani of IL&FS Investment Managers (PEI Asia, June 2009)
Enhancement Of T-Cell Immunity To Osteosarcoma By Modulation Of Programmed Death Receptor Pathway...
Transcript of Enhancement Of T-Cell Immunity To Osteosarcoma By Modulation Of Programmed Death Receptor Pathway...
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Enhancement Of T-Cell Immunity To Osteosarcoma By Modulation Of
Programmed Death Receptor Pathway
Pooja Hingorani, Danielle Lussier, Joseph Blattman
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Overview
• T cell tolerance and immune inhibitory pathways in osteosarcoma
• Review our data
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Immune tolerance in osteosarcoma
• Loss of Class I HLA expression in osteosarcoma tumors related to worse overall survival*
• CTLA4 polymorphisms are associated with higher risk of developing osteosarcoma**
• Metastatic osteosarcoma expresses T cell Ig/mucin molecule 3 (TIM3), which in other tumor settings inhibits the function of infiltrating CTL, leading to tumor progression #
• B7-H3 expression, a co-inhibitory protein involved in tumor immune escape from T cells, inversely correlates with CTL infiltration in human osteosarcoma, and is indicative of poor prognosis in osteosarcoma patients @
*Tshukahara et al., Cancer Sci 2006; **Liu et al, DNA Cell Bio 2011; #Shang et al., Oncol Lett 2013; @ Wang et al., Plos One 2013
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Relative expression of PDL1 in osteosarcoma
Shen J K et al. Cancer Immunol Res 2014;2:690-698
©2014 by American Association for Cancer Research
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Overall survival of 37 patients with osteosarcoma in relation to PDL1 gene expression.
Shen J K et al. Cancer Immunol Res 2014;2:690-698
©2014 by American Association for Cancer Research
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Characterization of the origins of metastases.
Shen J K et al. Cancer Immunol Res 2014;2:690-698
©2014 by American Association for Cancer Research
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Specific Aims• Evaluate expression of PD-L1 on tumor cells and PD-1 on TILs in patient
samples and metastatic osteosarcoma cell line (in vitro and in vivo)• Evaluate the functional ability of TILs infiltrating metastatic tumors• Evaluate the effect of PD-L1 blockade on development and progression of
pulmonary metastases in vivo• Evaluate the effect of combinational therapies (PD-L1 antibody +
chemotherapy; PD-L1 antibody + ipilimumab)
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PD-L1 is expressed in human metastatic osteosarcoma
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Isotype
Metastatic Osteosarcoma
PD-L1
Primary Osteosarcoma50um
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12/ 16 (75% ) of metastatic tumors had some PD-L1 expression
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PD-1 is expressed on human metastatic TILs
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Isotype
PD-1
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Metastatic Osteosarcoma Primary Osteosarcoma
-13/16 (81%) of metastatic tumors had PD-1+ TILs-In 11/16 (70%) metastatic tumors, PD-1 expression on TILs correlated with PD-L1 expression on tumor cells
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PD-L1 expression is increased in K7M2 osteosarcoma cells
PD-L1
% o
f Max
imum
40731848
Pre Implantation Post Tumor
30%
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TILs from lung metastases are PD-1+
%PD
1+
SPLEEN CD8 TIL CD8
*
CD8
PD-1
SPLEEN TIL
94%
6% 87%
13%
Isotype
PD1
Healthy Lung
Late Disease Lung
Early Disease Lung 50 µm50 µm 50 µm
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TILs are functionally impaired in the presence of tumor cells
**
%IF
Nγ+
*
*
*
- + - + AgPD-L1+ K7M2
PD-L1- 4T1
%TN
F+
*
**
- + - + AgPD-L1+ K7M2
PD-L1- 4T1
%IL
-2+
**
- + - + AgPD-L1+ K7M2
PD-L1- 4T1
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%IF
Nγ+
Control PD-L1 Ab
**
%TN
F+
**
*
Control PD-L1 Ab
%IL
-2+
**
*
Control PD-L1 Ab
A.
B.
C.PD-L1 blockade restores function to TILs
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Blockade of PD-1:PD-L1 significantly enhances survival in metastatic osteosarcoma model
Days post implant
Perc
ent S
urvi
val
P=0.0005
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30 day PD-L1 antibody treatment does not significantly improve survival compared to 15 day treatment
Is immune escape occurring?
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PD-L1 antibody treatment changes inhibitory receptor expression
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PD-L1 antibody treated osteosarcoma is resistant to additional treatment when injected into naïve mice.
PD-L1
% o
f Max
imum
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Combinational PD-L1 antibody treatment coupled with conventional chemotherapy
The combination improves survival as compared to chemotherapy alone but is similar to PD-L1 antibody alone.
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Combinational PD-L1 antibody coupled with CTLA-4 antibody treatment improves survival
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In conclusion
• PD-1/PD-L1 interaction induces immune tolerance in metastatic osteosarcoma
• PD-L1 blockade improves survival but not 100%• Resistance to therapy develops by up-regulation of alternative
immune escape pathways • Combinational immune therapies may have the highest
impact on disease control in metastatic osteosarcoma
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• Joseph Blattman• Danielle Lussier• John Johnson• Lauren O’Neill• Lizbeth Nieves• Megan McAfee• Susan Holechek
• Paul Dickman• Patients and families
Acknowledgements