Zachary Morris MDPhD Assistant Prof Dept of Human Oncology September 11 2019 gt70 of breast cancers are ER Growth of 2540 is resistant to antiestrogens Metastatic ER cancers account for most breast ID: 932644
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Slide1
Combining estrogen receptor blockade and radiation therapy to improve the response of breast cancer to immunotherapies
Zachary Morris, MD/PhDAssistant Prof. Dept of Human Oncology
September 11, 2019
Slide2>70% of breast cancers are
ER
+Growth of 25-40% is resistant to anti-estrogens
Metastatic ER+ cancers account for most breast
cancer
mortality
Breast Cancers
ER+
Anti-E
Resistant
The Challenge of Metastatic ER+ Breast Cancer
Slide3ER+ breast cancer is typically immunologically “cold”
Few mutations =
few antigensFew tumor infiltrating lymphocytesLower response to immune checkpoint inhibitors
Slide4Radiation may overcome mechanisms of tumor immune escape
Radiation
Immunogenic cell
death
Changes
in cells surviving radiation
Inflammation
Seconds
Hours
Days
Weeks
Temporary local depletion of
suppressor immune cells
Increased immune infiltrate
Immune recognition of tumor antigens not recognized prior to radiation
Slide5Slide6Radiation may increase tumor infiltration by and activation of immune suppressive myeloid cells
Anti-tumor Response
No anti-tumor ResponseJeong et al., Blood Res, 2016
Slide7Estrogen
and anti-estrogens modulate recruitment and activation of suppressive immune cells in tumors
Need immunocompetent model of ER+ breast cancer
Slide8NRL-PRL transgenic
model produces
spontaneous, metastatic ER+ cancers in mice
H&E
ER
α
PgR
Allows testing of estrogen and immune interactions
Bone
Lung
ER
α
•
Anti-estrogens fail
to inhibit
growth
•
Estrogen activity modulates gene expression
•
Few mutations
•
Few CD8
+ lymphocytic
infiltrate but
higher numbers of F4/80+ immune
cells
Slide9Combined radiation and estrogen inhibition modify tumor cell immune susceptibility
Slide10Dose-dependent activation of viral response pathways in tumor cells surviving radiation
Suppressive cells (MDSC)
Antigen presenting helper cells (DCs)Ratio of effector : suppressor T cells
Slide11Radiation + estrogen inhibition increases response to anti-PD-1 immune checkpoint blockade
Slide12Approaches to better propagate the
anti-tumor immune response to radiation + ER inhibition + anti-PD-1 in breast cancer - Deliver radiation to all tumor sites
- Overcome additional mechanisms of tumor immune suppression
Slide13NM600,
a MTRT agent, is capable of safely delivering
radiation to all sites of disease in various murine and human cancers Yttrium-90; molecular radiotherapeuticYttrium-86; PET imaging
NM600 – Alkylphosphocholine
with specific uptake in B78
melanoma and most tumors
86Y-NM600
Free 86
YMelanoma (B78)86Y-NM600 PET/CT
TC11 Breast Cancer
Slide14NM600 can deliver low dose radiation to all tumor sites in breast cancer models and improve response to immune checkpoint blockade
Slide15Approaches to better propagate the
anti-tumor immune response to radiation + ER inhibition + anti-PD-1 in breast cancer - Deliver radiation to all tumor sites
- Overcome additional mechanisms of tumor immune suppression
Slide16CD73 expression may reduce the immunogenic effects of radiotherapy
S. de
Leve et al., Front Immunol, 2019
Slide17CD73 is highly expressed on murine breast cancer cells and is associated with poor prognosis in ER+ breast cancer patients
Slide18Experimental
Design
ER+
TC11 cells
Initiate
treatment when tumors
150 mm
3
:
8 Gy x1 (d1)Fulvestrant, 5 mg weekly (d-6, 1, 8)MEDI9447 anti-CD73, 12.5 mg/kg IP (d3)ER-
4T1
cells
Slide19Acknowledgements
Morris LabRaghava SriramaneniRavi PatelWonjong JinAmber Bates
Paul ClarkBen LanJustin JagodinskyElizabeth SumiecSarah EmmaErin NystuenClaire BanielPeter CarlsonFundingUWCCC CITI Pilot AwardSupportAstraZeneca - MedImmuneSchuler LabKathy O’Leary