Radio-immunotherapy in cancer

Inge Verbrugge

The 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 (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 modulating T cell responses

Ipilimumab

Pembrolizumab Nivolumab

Mellman I et al., Nature 2011;480:480-489 -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 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 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