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