ESTRO 36 Abstract Book

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S541 ESTRO 36 2017
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Neoadjuvant radiotherapy (NeoRT) improves tumor local
control and facilitates tumor resection in many cancers.
The timing between the end of the NeoRT and surgery is
driven by the occurrence of side effects or the tumor
downsizing. Some clinical studies demonstrated that the
timing of surgery and the RT schedule influence tumor
dissemination and subsequently patient overall survival.
Previously, we developed a pre-clinical model
demonstrating an impact of NeoRT schedule and the
timing of surgery on metastatic spreading (Leroi et al.
Oncotarget 2015). Here, we evaluate the impact of NeoRT
on the tumor microenvironment by functional MRI (fMRI).
We aim to identify non-invasive markers allowing to
determine the best timing to perform surgery and avoiding
tumor spreading.
Material and Methods
Based on our NeoRT model, MDA-MB 231 and 4T1 cells
were implanted in the flank of SCID and BalbC mice,
respectively. We locally irradiated tumors with 2x5Gy and
then surgically removed at different time points after RT.
Diffusion Weighted (DW) -MRI was performed every 2 days
between RT and surgery. For each tumors we acquired 8
slices of 1 mm thickness and 0.5 mm gap with an 'in plane
voxel resolution” of 0.5 mm. For DW-MRI, we performed
FSEMS (Fast Spin Echo MultiSlice) sequences, with 9
different B-value (from 40 to 1000) and B0, in the 3 main
directions. We performed IVIM (IntraVoxel Incoherent
Motion) analysis to obtain information on intravascular
diffusion, related to perfusion (F: perfusion factor) and
subsequently tumor vessels perfusion.
Results
With the MDA-MB 231, we observed a significant peak of F
at day 6 after irradiation, this increasing is about 60% of
the basal value (n=6, p<0,05). Moreover, D* parameters
(also related to perfusion) increase at the same time. The
other parameters of the DW-MRI, ADC and D presented no
modification. We observed similar results with 4T1 cells,
where F increased at day 3 (about 55%, n=10, p<0,05) then
returned to initial level. The difference in timing for the
peak of F (day 6 vs day 3) could be related to the
difference in tumor growth according to the cell line (four
weeks for MDA-MB 231 cells vs one week for 4T1cells). We
performed surgery at the time of the F parameter peak in
the MDA-MB 231 and we observed a decrease of the
metastasic burden compared to surgery performed at day
4 or day 11(absolute number of metastasis 23 VS 1 VS 8
with n=4).
Conclusion
For the first time, we demonstrate the feasibility of
repetitive fMRI imaging in preclinical models after NeoRT.
With these models, we show a significant difference in
perfusion-related parameters (D* and F) at a specific time
point depending of the tumor cells. These modifications
are correlated to a decrease of metastasis spreading
related to the surgery procedure. These results open new
perspectives in the personalized medicine and MRI guided
surgery timing after NeoRT.
PO-0989 Sub-lethal radiation allows an efficient
antitumor therapy with engineered T-cells in RIP-Tag2
mice
F. Maione1, E. Garibaldi2, X. Zhuang3, J. Robinson3, R.
Bicknell 3, E. Delmastro2, A. Miranti 4, S.P. Lee3, P.
Gabriele2, E. Giraudo1
1 Candiolo Cancer Institute- Torino- Italy, Department of
Science and Drug Technology, Candiolo TO, Italy
2 Candiolo Cancer Institute- Torino- Italy, Radiotherapy
Unit, Candiolo TO, Italy
3 University of Birmingham, Institute of Immunology and
Immunotherapy, Birmingham, United Kingdom
4 Candiolo Cancer Institute- Torino- Italy, Medical Physics
Unit, Candiolo TO, Italy
Purpose or Objective
The important goal of tumor immunotherapy is to identify
strategies to modulate in vivo the anti-tumor immunity in
order to achieve clinical efficacy. In the last decade great
progresses have been made in the field of tumor
immunology and an increasing number of tumor antigens
have been identified. In particular, several different
engineering T-cells were designed to express receptors
specific for antigens expressed in the tumor compartment.
Herein, in order to block tumor progression, we employed
Chimeric Antigen Receptors (CARs) technology to target
the tumor vasculature. To this aim we used a spontaneous
mouse tumor model of pancreatic neuroendocrine
insulinoma, RIP-Tag2. Despite its low frequency in cancer
patients, we chose this model, since develops invasive
tumors through well-characterized and synchronous pre-
malignant stages, sustained by active angiogenesis. Little
is known about the effects of ionizing radiation on tumor
burden of RIP-Tag2 mice and the impact of whole-body
irradiation on the overall survival.
Material and Methods
In the current study tumor-bearing RIP-Tag2 mice were
irradiated with two different sub-lethal dosages (5 and 6
Gy respectively), by means of 6MV x rays of Tomotherapy;
a treatment plan was performed and evaluated for each
cage pie . We hypothesized that sub-lethal radiation might
be more effective than a lethal dose radiation and
clinically acceptable in promoting anti-tumor immunity.
The day after the irradiation mice were injected with
enginered T-cells (20 million cells).
Results
Firstly,we observed that irradiation per se did not affect
tumor growth and all the mice survived until the end of
treatment. Furthermore, by means of this approach, we
found statistically significant inhibition of tumor growth in
mice treated with anti-vasular CAR-T-cells compared with
controls. Interestingly, we noticed a strong reduction in
tumor vessel area and a decrease of blood vessel
permeability.
Conclusion
These data suggest that the tumor vasculature can be
efficiently targeted by specific CAR-T-cells, causing a
significant reduction in the tumor burden of RIP-Tag2 mice
and potentially in other tumor types.
PO-0990 Combining radiotherapy and notch inhibition
in melanoma
K. Thippu Jayaprakash1,2 , M. Hussein3, A. Nisbet3,4, R.
Shaffer2, M. Ajaz1,2
1University of Surrey, Department of Clinical and
Experimental Medicine, Guildford, United Kingdom
2St Luke's Cancer Centre- Royal Surrey County Hospital,
Department of Oncology, Guildford, United Kingdom
3St Luke's Cancer Centre- Royal Surrey County Hospital,
Department of Medical Physics, Guildford, United
Kingdom
4University of Surrey, Department of Physics, Guildford,
United Kingdom
Purpose or Objective
Melanoma is classically viewed as a radioresistant tumour.
Phenotypic plasticity, specifically the emergence of a
cancer stem cell (CSC) population, may be one reason for
this. The notch signalling pathway plays a crucial role in
maintenance of the CSC phenotype, and also in cell
migration. This pathway is frequently aberrant in
melanoma and is therefore a potential mechanism for the
observed radioresistance. The aims of this project were
(1) to investigate whether notch inhibition with the γ -
secretase inhibitor, RO4929097 that targets γ - secretase
cleavage and thereby inhibiting the notch signalling
pathway, improves the radiation sensitivity of melanoma
cell lines; (2) to investigate the effects of notch inhibition
and radiotherapy on melanoma cell migration.
Material and Methods