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Radio-immunotherapy in cancer
Inge Verbrugge
The Netherlands Cancer Institute
Radiotherapy
• One of three /four main treatment modalities
• Used in ~50% of cancer patients
• Administered locally: minimizes normal tissue damage
1. (Irreversible) cell cycle arrest senescence 2. Death due to mitotic catastrophe 3. Apoptotic cell death
Effects of radiotherapy on tumor cell clonogenicity
DNA damage
Radiotherapy alone may not be curative
RADIOTHERAPY
Curing metastasized cancer with systemic therapy
• Immunotherapy - Eliciting systemic anti-tumor cytotoxic T cell (CTL) responses
MHC I
(CTL)
Radiotherapy: Clinical systemic (=‘abscopal’) responses
Pre-radiotherapy Post-radiotherapy
‘Abscopal Effect’
Ohba K et al., Gut 1998;43:575-577
Radiotherapy may support local and systemic tumor immunity
Radiotherapy may support local and systemic tumor immunity
‘abscopal effect’
Co-stimulation
Established tumors evade immune responses
Bottlenecks 1. Lack of recognizable ‘tumor’
antigens
2. Lack of ‘danger signals’
3. Lack of T cell infiltration into tumor
4. Inhibition CTL activity by tumor / tumor micro-environment
Pembrolizumab Nivolumab
Ipilimumab
Antibodies modulating T cell responses
Mellman I et al., Nature 2011;480:480-489
Pembrolizumab Nivolumab
Ipilimumab
Antibodies modulating T cell responses
Mellman I et al., Nature 2011;480:480-489
Antibody-based immunotherapy: local and systemic effects
Co-stimulatory receptor
Co-inhibitory receptor
Radio-immunotherapy: Combining radiotherapy with immunotherapy
α-PD-1, α-CD137
Costimulation
Blocking coinhibition
Radio-immunotherapy promise:
Achieving SYSTEMIC synergism by combining
LOCAL radiotherapy with immune-modulation
Radio-immunotherapy: opportunities
α-PD-1, α-CD137
Costimulation
Blocking coinhibition
1. Inducing curative local combined responses
2. Achieving systemic combined effect by promoting relevant immune responses
Radio-immunotherapy induces local tumor control
α-PD-1, α-CD137
α-CD137
α-PD-1
α-PD-1, α-CD137
Costimulation
Blocking coinhibition
2. Achieving systemic combined effect by promoting relevant immune responses
Achieving systemic combined effects by radio-immunotherapy
Irradiated tumor: CD8+ T cell mediated tumor rejection
Non-irradiated tumor: No tumor rejection
Radio-immunotherapy does not result in improved regression of abscopal tumors
Systemic effects of radio-immunotherapy: Status field 2015
Twyman-Saint Victor C et al., Nature 2015;520:373-377
Radiotherapy + α-CTLA-4 (melanoma patients)
Radiotherapy + α-CTLA-4 (melanoma-bearing mice)
AT-3 tumors; Lines represent averages of 5-6 mice / group
α-PD-1, α-CD137
DC activation/ T cell priming?
T cell infiltration?
Tumor immune suppression?
No abscopal responses… Why not?
Radio-immunotherapy: (clinical) opportunities
α-PD-1, α-CD137 α-CD137
α-PD-1
1. Requirements to induce local combined responses
2. Achieving a systemic combined effect by promoting relevant immune responses
Ohba K et al., Gut 1998;43:575-577
Ambition: cure cancer patients by radio-immunotherapy
Pre-radiotherapy Post-radiotherapy
‘Abscopal Effect’
Juntendo University (Tokyo, Japan)
Hideo Yagita (antibodies)
Acknowledgements
Division of Immunology
Paula Kroon Victoria Iglesias Elselien Frijlink Yanling Xiao Tomasz Ahrends Nikolina Bąbała
Blank group Jules Gadiot Marcel Deken
Schumacher group Mireille Toebes Marit van Buren Carsten Linnemann Pia Kvistborg Lorenzo Fanchi
De Visser group Jannie Borst
Division of Cell Biology II
Dris el Atmioui Henk Hilkman Jacques Neefjes
Department of Radiotherapy
Alessia Gasparini Javier Salguero Artem Khmelinskii Gerben Borst Nicola Russell Jan-Jakob Sonke Marcel Verheij
PeterMac (Melbourne, Australia)
Nicole Haynes Ricky Johnstone
Clinicians
Stefan Willems Marleen Kok Willemijn Engelsman Michel vd Heuvel Lotje Zuur
Intervention unit
Animal Facility (G1, G2-south, G3, T1)
Flow cytometry facility