radiotherapy, abscopal effect immunotherapy · radiotherapy, abscopal effect & immunotherapy...
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Radiotherapy, abscopal effect &
immunotherapy
Prof. Eric F. Lartigau General Director, Centre Oscar Lambret
Lille, France
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C. O. I.
Eric F. LARTIGAU has been
consultant in the last 5 years for
Accuray, Amgen, Astellas & Merck-
Serono
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DEFINITION of OLIGOMETASTASES :
1995 : Hellman & Weichselbaum, JCO 1995 ; 13 : 8-10
« tumors early in the chain of progression may have metastases limited in
number and location because the facility for metastatic growth has not
been fully developed… »
« some patients so affected should be amenable to a curative therapeutic
strategy ! »
2011 : the patient shows distant relapse in only a
« limited » number of regions (5 ?).
Oligo recurrence = same with primary cancer site controlled
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Local treatment : an issue ?
Concept of ablative treatment :
• Surgery : (brain, liver) brings long survival….
• Radiotherapy : high dose, few fractions ???
• Radiosurgery (brain)
• SBRT: liver, lung, nodes…….
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SBRT=
we have
the tools !!!!
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SBRT is a standard
in many clinical situations
Today : brain, lung, spine, retreatment
Tomorrow : liver, prostate, partial breast
After tomorrow : most of ???
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2 months
Colorectal liver metastases
Results in Lille
Probability of local control :
45 Gy (3 X 15 Gy)
versus
40 Gy (4 X 10 Gy)
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Overall
survival
Disease free
survival
Local relapse free survival
hepatic lung
12 months 0.8649 0.7577
24 months 0.6758 0.6062
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Renal metastase 3 x 15 Gy
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At 3 years
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Radioresistant tumours ?
Biology of High dose / fraction : BED > 100 Gy
Melanoma
Renal tumours
Sarcomas
…
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» Wachsberger ; Clin Cancer Res 2003
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Apoptosis
Sphingomyelin
A-SMase
Ceramide
DNA damage
Apoptosis Survival Mitotic death
A-SMase
The sphingolipid ceramide : a new molecular actor induced after high dose of radiation
Cell signaling
Repair Misrepair
Cell cycle arrest
DNA sensor
By courtesy of F. PARIS, INSERM, ICO, Nantes Courtesy F. Paris
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Limits in targeted therapies
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Mutational heterogeneity in cancer
Lawrence MS. 2013 Jul 11;499(7457):214-
218.
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Molecular Basis of Cancer Immunotherapy
Vasaturo A, Front Immunol. 2013 Dec 3;4:417.
Stimulatory and inhibitory molecules expressed in the tumor
microenvironment targeted for therapeutic intervention.
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Checkpoint inhibitors (solid tumors)
Agent (trade mark)
[testing PDL1] Target Firm
Nivolumab (Opdivo*)
[Dako 28-8] Anti-PD1 BMS
Pembrolizumab (Keytruda*)
[Dako 22C3] Anti-PD1 Merck/MSD
Atezolizumab (Tecentriq*)
[Ventana SP 142] Anti-PDL1 Roche
Durvalumab (Imfinzi*) Anti-PDL1 AZ
Avelumab (Bavencio*) Anti-PDL1 Pfizer
Ipilmumab (Yervoy*) Ant-CTLA4 BMS
Tremelimumab Ant-CTLA4 AZ
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NSCLC with PDL1 ≥ 50%. Pembrolizumab vs chemo on 1st line.
Keynote 024 trial. PO: PFS. All comers with TPS ≥ 50%
Reck M et al. N Engl J Med. 2016 Nov 10;375(19):1823-1833
PFS: 10.3 vs. 6 mois
HR 0.50, p<0.001
PD-L1 expression : IHC 22C3 Dako.
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How to predict and assess the toxicity of immunotherapy?
➢ Immunotherapy may revolutionize the treatment of cancers
➢ Will toxicity be a limitation for immunotherapy ???
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Immunotherapy induced toxicity (irAEs)
Pneumonitis (anti-PD-1)
Reticular erythematous
rash Perivascular lymphocyte infiltrate
extending into epidermis
Bowel oedema and ulceration in the
descending colon
Gastrointestinal adverse events (anti-CTLA-4)2
Rash (anti-CTLA-4)1
Colonoscopy Histopathology
Focal active colitis (left) with crypt destruction, loss of goblet cells, and
neutrophilic infiltrates in the crypt epithelium (right)
1. Hodi F, et al. Proc Natl Acad Sci USA. 2003;100:4712–4717
2. 2. Maker A, et al. Ann Surg Oncol. 2005;12:1005–1016.
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Immunotherapy induced toxicity: Pneumonitis
(**)
(*)
(*)
Anti-PD1 induced pneumonitis
ground glass opacities (*) and condensation (**)
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immunotherapy toxicity (irAEs). Kinetics of appearance
Weber JS. J Clin Oncol 2012;30:2691-2697
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HOW TO ASSESS TOXICITY OF IMMUNOTHERAPY AND WHAT IS ITS
IMPACT ?
HOW TO IDENTIFY NEW PREDICTIVE BIOLOGICAL MARKERS OF TOXICITIES
OF IMMUNOTHERAPY?
HOW TO IDENTIFY NEW PREDICTIVE NEUROPHYSIOLOGICAL AND PSYCHOLOGICAL MARKERS?
Integrated research
❖ Basic research
❖ Translational research
❖ Clinical research
Integrated markers
❖ Clinical markers
❖ Biological markers
❖ Neurophysiological and
psychological markers
A Signature of high risk of toxicity based on
clinical, biological, psychological and neurophysiological markers
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Immunotherapy . Financial toxicity
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Immunotherapy (IT). Main factors infuencing treatment decisions
Adapted from Ascierto et al. J Transl Med (2017) 15:205
PDL1
status
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New technology = New delivery/dose
New biology = New indications
High precision RT to eradicate
gross tumour burden
in combined modalities