Radiotherapie en immunotherapy

Transcription

1 Radiotherapie en immunotherapy 1+1=3? 5 D dagen, Ermelo Evert Jan Van Limbergen, MD, PhD Radiation oncologist MAASTRO clinic

2 Disclosure No conflict of interest

3 Overzicht Introductie Historisch perspectief Immunogene cel dood Preklinische data & Klinische data over effectiviteit Toekomstperspectief Take home messages

4 Het vergeten verleden Stone et al. JNCI 1979

5 Case reports: out of field responses following RT

6 Abscopal response is immune regulated Postow et al.nejm 2012

7 Abscopal response is immunoe related Postow et al.nejm 2012

8 Abscopaal effect Respons op RT Abscopaal Effect buiten bestralingsveld

9 Het concept immunogene celdood dood cellen Injecteer lysaat fase I Tumor: Geen immunogene celdood fase II No-Tumor: Immunogene celdood als vaccinatieeffect

10 Mediatoren van immunogene celdood Galluzi et al. Nat Rev Immunol 2017

11 Radiation alters the MHC class I associated peptide profile Reits et al. J Exp Med 2006

12 Immunotherapie onder de motorkap Mellman et al (2011) Nature 2011 Dec 21;480(7378):480-9

13 Radiotherapie als immuunactivator: hoe het werkt EJ Van Limbergen et al. BJR 2017

14 CRT rectal cancer induction of CD8+ infiltration and PD1 expression Lim YJ et al. IJROBP 2017

15 Radiotherapy + immunotherapy (Pre)clinical data on efficacy

16 Proof-of-Concept trial Golden et al. Lancet Oncol 2015

17 Proof-of-Concept trial Abscopal responses in 11/41 patients! Golden et al. Lancet Oncol 2015

18 SBRT + IL2 bij RCC of melanoma ptn IL2 + radiotherapy RR 3+2/5+2 in RCC, en 5/7 % in melanoma 75% of patients keep response at last Fup (480 days median) Sci transl med 2012 Jun 6;4(137):137 (phase I)

19 MAASTRICHT phase I L19-IL2+ radiotherapy C51 colon tumor model Zegers 2015 CCR Rekers 2017 Oncoimunol.

20 Ipilumumab and Radiotherapy P= patients, single institution, retrospective Metastatic melanoma 70 pts recieved ipi + RT concurrent 31 pts recieved ipi monotherapy CR 25 % in RT arm vs. 6,5% (p=0,04) Median OS 19 months in RT arm vs 10 months (p=0,01) Koller KM 2017 Cancer Biol Ther

21 Secondary analysis of KEYNOTE-001 Shivardian Lancet Oncol 2017

22 PACIFIC trial, stage III NSCLC: CRT followed by anti PDL-1 PFS Time to death or M+ Antonia et al 2017 NEJM

23 Clinical aspects Future prospects: Integration of radiotherapy in immunotherapy trials

24 Future prospects DOSE/ FRACTIONATION

25 Optimal fractionng? Local: higher (fraction) dose seems better C.T. Garnett, et al. Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes, Cancer Res. 64 (2004) Single fraction: Higher dose is better 1 x 20 Gy > 1x 10 Gy. M. Chakraborty et al., Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy, J. Immunol. 170 (2003) Single fraction: Higher dose is better 1 x 50 Gy > 1 x 20 Gy > 1 x 10 Gy M. Chakraborty, et al External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing, Cancer Res. 64 (2004) Single fraction: Higher dose is better A.A. Lugade, et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor, J. Immunol. 174 (2005) Same dose (15 Gy) in single fraction is better than fractionated Y. Lee et al., Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment, Blood 114 (2009) Same dose (20 Gy) in single fraction is better than fractionated Verbrugge et al., Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies, Cancer Res. 72 (2012) x 12Gy > 4 x 5Gy > 5 x 4 Gy lokal

26 Optimal fractioning? Abscopal Higher fraction dose may not always be better! Dose 2 x 2,75 Gy somewhat better that 5 Gy SF, 15 Gy SF is too high. 2 x 7,5 Gy is best. D. Schaue, Maximizing tumor immunity with fractionated radiation, Int. J. Radiat. Oncol. Biol. Phys. 83 (2012)

27 Optimal fractioning? Abscopal Higher fraction dose may not always be better! Dewan MZ et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti- CTLA-4 antibody. Clin Cancer Res. 2009;15(17): Fractionation is better than single dose for abscopal effects (dose 3x 8 Gy / fr better than 1x12Gy or 5 x 6 Gy) Irradiated tumor Not irradiated tumor 20 Gy 5 x 6 Gy 3 x 8 Gy MC38 CRC model

28 Timing seems to depend on the drug. CTLA-4 + RT: Better first immunotherapy, then radiotherapy Young et al Plos ONE

29 Timing seems to depend on the drug. apd-1(l) + RT: Better first immunotherapy, then radiotherapy Dovedi et al Cancer Res

30 Clinical aspects A note on treatment techniques low dose bath of arc therapy Pugh J, et al J immunol 2014