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