th 2015 Radioimmunotherapy of cancer Therapeutic efficacy underlying mechanisms and potential applications Paula Kroon Nicole Haynes Victoria Iglesias Guimarais Ricky Johnstone ID: 1044062
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1. World Congress on Breast Cancer, Birmingham, August 4th 2015Radio-immunotherapy of cancerTherapeutic efficacy, underlying mechanisms and potential applicationsPaula Kroon, Nicole Haynes, Victoria Iglesias-Guimarais, Ricky Johnstone, Jules Gadiot, Marcel Verheij, Christian Blank, Jacques Neefjes, Jannie Borst, Inge Verbrugge
2. Curing metastatic cancer with systemic therapyImmunotherapyEliciting anti-tumor cytotoxic T cell responses(CTL)MHC I
3. Established tumors are poorly immunogenicBottlenecksLack of ‘foreign’ antigensT cells do not recognize tumor cellsInhibition CTL activity by tumor / tumor micro-environmentPD-1 signalingMHC I downregulation tumor cellsInspired by: Grosso JF et al. Can Immunity 2013;13:5-18
4. T cell-mediated immunotherapy; Signal (1) TCR triggering
5. TILT cellCo-stimulatory receptore.g. CD137 (4-1BB)Co-inhibitory receptor e.g. PD-1, CTLA-4T cell-mediated immunotherapy; Signal (2) co-stimulation
6. Antibody-based immune-modulationPembrolizumabNivolumabIpilimumab
7. Antibody-based immune-modulation
8. Antibody-based immune-modulationKILL
9. Problem:Immunotherapy as single-agent promising, but sub-optimal‘Radio-immunotherapy’Solution:Combine immunotherapy with radiotherapy
10. DNA damage1. Reducing tumor cell clonogenicity(Irreversible) cell cycle arrestMitotic catastropheApoptosisRadiotherapy
11. DNA damage1. Reducing tumor cell clonogenicity(Irreversible) cell cycle arrestMitotic catastropheApoptosisRadiotherapy2. Immunomodulatory effectsInduce anti-tumor immune responses through release of tumor Ags- Upregulate MHCI
12. 1) Efficacy?2) Mechanism?3) Potential applications?
13. Triple-negative breast cancer cell line Transplantable AT-3 breast cancer model(
14. Small animal Image-Guided RadiotherapyMovie: Jan-Jakob Sonke
15. Radiotherapy improves the response to immunotherapyVerbrugge I et al. Cancer Res 2012;72:3163-3174Control Immunotherapy Radiotherapy Radio-immunotherapy
16. 1) Efficacy?2) Mechanism?3) Potential applications?
17.
18. Does it work?How does it work?
19. Verbrugge I et al. (2012) Cancer Research;72:3163-3174IR+IT: radio-immunotherapyStart Tx: Day 14n = 6 mice /groupCD8+ T cells crucial for radio-immunotherapy
20. Does it work?How does it work?
21. Radiotherapy upregulates surface MHC I on AT-3 tumor cellsTumor Antigens (peptides)Radiotherapy
22. mTOR inhibition abrogates Radiotherapy-induced MHC I upregulationmTOR inhibitorRadiotherapyVerbrugge I et al. (2014) Radiation Research;182:219-229Reits EA et al. (2006) J Exp Med; 203;1259-1271
23. Importance of mTOR signaling to the therapeutic effect of radio-immunotherapy
24. Inhibition of mTOR signaling abrogates the therapeutic response to radio-immunotherapyParentheses: fraction tumor-free mice at day 100Verbrugge I et al. (2014) Radiation Research;182: 219-229
25. ??Radio-immunotherapy: summary and potential applications
26. AcknowledgementsNetherlands Cancer Insitute (Amsterdam)Paula KroonJannie BorstJacques NeefjesVictoria IglesiasJulia WalkerAlessia GaspariniJavier SalgueroJan-Jakob SonkeMarcel VerheijBlank groupSchumacher groupDe Visser groupCliniciansPeterMac (Melbourne, Australia)Nicole HaynesJim HagekyriakouMark SmythRicky JohnstoneJuntendo University (Tokyo, Japan)Hideo Yagita (antibodies)
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