Radio-immunotherapy in cancer

Transcription

1 Radio-immunotherapy in cancer Inge Verbrugge The Netherlands Cancer Institute

2 Radiotherapy One of three /four main treatment modalities Used in ~50% of cancer patients Administered locally: minimizes normal tissue damage

3 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

4 RADIOTHERAPY Radiotherapy alone may not be curative

5 Curing metastasized cancer with systemic therapy Immunotherapy - Eliciting systemic anti-tumor cytotoxic T cell (CTL) responses (CTL) MHC I

6 Radiotherapy: Clinical systemic (= abscopal ) responses Pre-radiotherapy Post-radiotherapy Abscopal Effect Ohba K et al., Gut 1998;43:

7 Radiotherapy may support local and systemic tumor immunity

8 Radiotherapy may support local and systemic tumor immunity Co-stimulation abscopal effect

9 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

10 Antibodies modulating T cell responses Ipilimumab Pembrolizumab Nivolumab Mellman I et al., Nature 2011;480:

11 Antibodies modulating T cell responses Ipilimumab Pembrolizumab Nivolumab Mellman I et al., Nature 2011;480:

12 Antibody-based immunotherapy: local and systemic effects Co-inhibitory receptor Co-stimulatory receptor

13 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

14 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

15 Radio-immunotherapy induces local tumor control α-pd-1 α-pd-1, α-cd137 α-cd137

16 2. Achieving systemic combined effect by promoting relevant immune responses Achieving systemic combined effects by radio-immunotherapy Blocking coinhibition α-pd-1, α-cd137 Costimulation

17 Radio-immunotherapy does not result in improved regression of abscopal tumors Irradiated tumor: CD8 + T cell mediated tumor rejection Non-irradiated tumor: No tumor rejection

18 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:

19 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

20 2. Achieving a systemic combined effect by promoting relevant immune responses Radio-immunotherapy: (clinical) opportunities α-pd-1 α-pd-1, α-cd137 α-cd Requirements to induce local combined responses

21 Ambition: cure cancer patients by radio-immunotherapy Pre-radiotherapy Post-radiotherapy Abscopal Effect Ohba K et al., Gut 1998;43:

22 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 Department of Radiotherapy Alessia Gasparini Javier Salguero Artem Khmelinskii Gerben Borst Nicola Russell Jan-Jakob Sonke Marcel Verheij Division of Cell Biology II Dris el Atmioui Henk Hilkman Jacques Neefjes Clinicians Stefan Willems Marleen Kok Willemijn Engelsman Michel vd Heuvel Lotje Zuur PeterMac (Melbourne, Australia) Nicole Haynes Ricky Johnstone Juntendo University (Tokyo, Japan) Hideo Yagita (antibodies) Animal Facility (G1, G2-south, G3, T1) Intervention unit Flow cytometry facility

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