Radio-immunotherapy: Immunotherapeuticsand radiotherapy. Inge Verbrugge The Netherlands Cancer Institute

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1 Radio-immunotherapy: Immunotherapeuticsand radiotherapy Inge Verbrugge The Netherlands Cancer Institute

2 Radiotherapy One of three 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 may support local and systemic tumor immunity

7 Radiotherapy may support local and systemic tumor immunity

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

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

10 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

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

12 Antibody-based immunotherapy: releasing co-inhibition

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

14 Antibody-based immunotherapy: engaging co-stimulation Co-stimulatory receptor

15 Combining immunotherapy with radiotherapy Radio-immunotherapy Blocking coinhibition α-pd-1, α-cd137 Costimulation

16 Radio-immunotherapy: concept Blocking coinhibition Radio-immunotherapy promise: Achieving SYSTEMIC α-pd-1, synergism α-cd137 by combining LOCAL radiotherapy with immune-modulation Costimulation

17 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

18 Radio-immunotherapy: pre-clinical Blocking coinhibition α-pd-1, α-cd137 Costimulation 1. Inducing curative local combined responses

19 Small animal image-guided radiotherapy: mimicking clinical protocols Movies: Jan-Jakob Sonke

20 Inducing local combined responses: AT-3 model Triple-negative breast cancer cell line, implantation: subcutaneous and orthotopic Derived from MMTV-Polyoma virus Middle T (PyMT)-transgenic mouse Radiotherapy Immunotherapy (

21 Immunotherapy improves the response to radiotherapy Costimulation α-cd137 Control Immunotherapy α-pd-1 Blocking coinhibition Radiotherapy Radio-immunotherapy Verbrugge I et al., Cancer Res 2012;72:

22 CD8 + Tcells crucial for radio-immunotherapy Verbrugge I et al., Cancer Res 2012;72: IR+IT: radio-immunotherapy Start Tx: Day 14 n = 6 mice /group

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

24 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

25 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:

26 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

27 Radio-immunotherapy trials ongoing at NKI - NSCLC: RT + Selectikine Phase Ib Completed SBRT + Pembrolizumab vs. Pembro Phase I-II Accruing - Breast: Nivolumab after induction SBRT Phase II Accruing - H&N: Immunological effects of chemoradiation Phase II Accruing - GBM: Nivolumab + RT vs TMZ + RT Phase II Accruing - MM: RT + Ipilimumab Under review - SCLC: RT + α-pd-1 mab Under review - Urothelial: α-pd-l1/α-ox40 mabs +/- RT Phase II In preparation

28 Radio-immunotherapy: clinical opportunities Blocking coinhibition α-pd-1, α-cd137 Costimulation 1. Requirements to induce local combined responses Sub-clinical 2. Achieving systemic combined effect by promoting relevant immune responses

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

30 Acknowledgements Division of Immunology Paula Kroon Victoria Iglesias 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 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 Jim Hagekyriakou Mark Smyth 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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