ESTRO 36 Abstract Book

S306

ESTRO 36 2017

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dose-dependent. BT allows better function performing

smaller glossectomies in tongue carcinomas and with less

xerostomy than SBRT, and with preservation of sphincter

in anal canal cancer. Organs at risk are clearly preserved

in prostate carcinoma delivering lower doses to rectum

and bladder, as well as allowing focal therapy. Last but

not least, the biological effect of BT due to the high dose

inside the treated volume, can have an influence in

decreasing the risk of relapse in breast carcinoma at long-

term FU. Therefore, non-invasive techniques can b e more

comfortable and desirable, but the main goal in oncology

is long-term tumor control with minimal late effects in

organs at risk, and BT in selected situations is still the best

option nowadays.

Symposium with Proffered Papers: Novel approaches in

tumour control

SP-0589 Molecular mechanisms of radiation-induced in

situ tumor vaccination

S. Demaria

Weill Cornell Medical College, Radiation Oncology and

Pathology, New York, USA

Growing pre-clinical and clinical evidence supports the

hypothesis that ionizing radiation applied locally to a

tumor has the ability to induce the activation of tumor-

specific T cells. This property of radiation, which is likely

responsible for the occasional occurrence of abscopal

effects (regression of tumors outside of the radiation

field), has attained increasing importance in the new era

of immuno-oncology with radiotherapy being tested in a

large number of clinical studies as a treatment that can

increase patients responses to immunotherapy (1). In fact,

radiation-induced in situ vaccination could provide a

relatively simple and widely available modality to achieve

the personalized immunization of a patient towards

mutated proteins expressed by his/her tumor (2). Proof-

of-principle evidence that radiotherapy in combination

with immune checkpoint inhibitors elicits powerful and

durable anti-tumor responses has been obtained in several

pre-clinical models (3). However, the mechanisms

underlying radiation’s ability to induce effective anti-

tumor immune responses remain incompletely understood

(4).

My lab studies the radiation-induced molecular pathways

responsible for effective activation of robust anti-tumor T

cells that medicate abscopal effects. Recruitment to the

tumor of a Batf3-dependent subset of dendritic cells

specialized in cross-presentation of tumor-derived

antigens to CD8

cytotoxic T cells (CTLs) is driven by type

I interferon (IFN-I) and has been shown to be essential for

activation of anti-tumor CD8

T cells. We have recently

found that in tumors refractory to treatment with immune

checkpoint inhibitors radiotherapy induces cancer cell-

intrinsic activation of IFN-I pathway and release of

interferon-beta, mimicking a viral infection, and resulting

in recruitment of Batf3-dependent DCs. Importantly, the

dose and fractionation of radiation are critical for

induction of IFN-I production by irradiated cancer cells,

with a lower (doses >2-4 Gy) and an upper (doses>12 Gy)

threshold for the induction of IFN-I, creating a therapeutic

window that defines the immunogenicity of radiotherapy.

The molecular mechanisms that regulate this therapeutic

window will be presented. Fractionation, i.e., repeated

(three times) daily delivery of radiation therapy at doses

within this window, amplifies the IFN-I pathway activation

in the carcinoma cells, an effect that requires

upregulation of IFNRA. Furthermore, the synergy of

radiation with immune checkpoint inhibitors and the

induction of abscopal effects are completely dependent

on the ability of radiotherapy to induce cancer cell-

intrinsic IFN-I. These findings have critical implications for

the use of radiotherapy to increase responses to

immunotherapy in the clinic.

Supported by NIH 1R01CA201246 and 1R01CA198533,

Breast Cancer Research Foundation, and The

Chemotherapy Foundation.

References

1. Kang J, Demaria S, Formenti S. Current clinical trials

testing the combination of immunotherapy with

radiotherapy. J Immunother Cancer. 2016;4:51.

2. Schumacher TN, Schreiber RD. Neoantigens in cancer

immunotherapy. Science. 2015;348:69-74.

3. Pilones KA, Vanpouille-Box C, Demaria S. Combination

of radiotherapy and immune checkpoint inhibitors. Semin

Radiat Oncol. 2015;25:28-33.

4. Demaria S, Coleman CN, Formenti S. Radiotherapy:

Changing the Game in Immunotherapy. Trends in Cancer.

2016;2:286-94.

SP- 0590 Novel developments in paediatric cancer

M.G. McCabe

University of Manchester,

Division of Molecular and Clinical Cancer Sciences,

Manchester, United Kingdom

The last decade has seen only incremental improvements

in survival when compared to the dramatic changes that

followed the centralisation of specialist care and the

introduction of multi-agent chemotherapy regimens and

combination treatments during the last half century.

Although in some cases subtle, those incremental changes

have been apparent across almost all types of childhood

cancer, even the most refractory to change. Five-year

overall survival for childhood cancer in the last EUROCARE

cohort was just under 80%, and in many European

countries now exceeds 80%.

The explosion in high throughput '-omics' technologies and

expertise currently underway is rapidly expanding our

knowledge of the mechanistic drivers of tumour growth

and treatment resistance. Progress is not evenly

distributed across childhood cancer; the brain tumour

community has benefited particularly from molecular

technologies, with the recognition of some novel tumour

entities, subclassification of others and the de-

classification of one major tumour group altogether. More

accurate recapitulation of tumour biology by

in vivo

models is also contributing to understanding

tumorigenesis and treatment effects, and holds promise

for individually tailored therapies.

Whilst molecular profiling has undoubtedly increased our

ability to accurately diagnose and risk stratify tumours,

and in many cases identified the mutations responsible for

tumorigenesis, that knowledge has yet to lead to a

paradigm shift in treatment for most paediatric

cancers. Childhood cancers in general have fewer

mutations than their adult counterparts and could be

expected to have more sensitivity to appropriately

targeted therapies. The challenges, however, are

multifactorial: redundancy in signal transduction

pathways, a predominance of driver mutations in genes

encoding proteins that are difficult to target,

tumorigenesis driven by missing tumour suppressor genes

rather than over-expressed oncogenes, and a commercial

and legislative environment that does not foster the

development of novel therapies for rare cancers.

Notwithstanding the challenges, progress is being on

multiple fronts. There are examples of successful

incorporation of molecular therapies into standard

treatment

haematological

and

solid

malignancies. Individual tumour profiling is becoming

increasingly routine in clinical practice. Several European

countries now have paedidatric stratified medicine

programmes underway or in development, and the first

multi-arm, multi-Pharma company European paediatric

basket trial – e-SMART – is due to open for relapsed and

refractory tumours. At a strategic level, consultation is