immunotherapy for cancer patients: an introduction · nanda r et al. sabcs 2014; 7. moskowitz c et...
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Immunotherapy for cancer patients: An introduction
Sandrine Aspeslagh, MD, PhD
7 sept 2019
AMUB
Conflits d’intérêt en rapport avec la présentation
• SA recieved personal fees for oral presentations by MSD, BMS, Astra Zeneca, Roche, Amgen and Novartis during the past 3 years
Nivolumab(BMS)
Pembrolizumab(Merck)
Spartalizumab (Novartis)
Cemiplimab (Sanofi)
SHR (Chinese Ab)
Atezolizumab(Roche/Genentech)
Durvalumab(AZ/Medimmune)
Avelumab(Pfizer)
LY3300054 (Lily)
Anti-PD-1 Anti-PD-L1
Ipilimumab(BMS)
Tremelimumab(AZ)
Anti-CTLA-4
Immune checkpoint blockers
Efficacy of anti-CTLA4: revolution in Oncology
Schadendorf D et al, 2015, JCO
Variable Sensitivity to Immunotherapy
1. Daud A et al. 2014 SMR; 2. Garon EB et al. ESMO 2014; 3. Chow LQ et al. ESMO 2014; 4. O’Donnell P et al. 2015 Genitourinary Cancers Symposium; 5. Muro K et al. 2015 Gastrointestinal Cancers Symposium; 6. Nanda R et al. SABCS 2014; 7. Moskowitz C et al. 2014 ASH Annual Meeting; 8. Alley EA et al. 2015 AACR.
Immune Checkpoints
Sharma et al, NRC, 2011
Signal 1
SIGNAL 2
Immune Checkpoint Blockade Therapy
Sharma et al, NRC, 2011
SIGNAL 2
SIGNAL 1
atezolizumab RCC
Blocking PD-1/PD-L1 induces an anti-tumoral CD8 T cell response
Variable Sensitivity to Immunotherapy
Hirsh L et al 2019 BMJ
Reimbursment Immunecheckpoint blockade Belgium sept 2019
Several medical need programms are ongoing...
Only immunity against cancer cells?Lymphocyte
Tumor cell'self’ cell
Champiat et al, 2015 Annals Onco
RESPIRATORYPneumonitis
PleuritisSarcoidosis
EYEUveitis
Conjonctivitis(epi)ScleritisBlepharitis
Rétinitis
CARDIOVASCULARMyocarditisPericarditisVascularitis
RENALNephritis
NEUROLOGICALNeuropathy
MyelitisMeningitis
Encephalitis Myasthenia
RHEUMATOLOGICALArthritisMyositis
HEMATOLOGICALHemolytic anemiaThrombocytopenia
NeutropeniaHemophilia
CUTANEOUSEruption
PruritPsoriasisVitiligo
Stevens Johnson
HEPATICALHepatitis
Cholangitis
GASTROINTESTINALColitisIleitis
PancreatitisGastritis
ENDOCRINALHypothyroïdyHyperthyroïdyHypophysitis
Adrenal insufficiencyDiabetes
New
Diverse
Rare
Manageable
Lethal?
Adapted from Wang DY et al. JAMA Oncol 2018;doi:10.1001/jamaoncol.2018.3923.
Be aware of neurotox!
Dec 2015 Febr 2016
Merkel cell CAInvasion of the lower leg
(82y old male)
Nice regression of the lesions of the
lower leg
March 2016
Minimal confusion(cannot close shoes anymore) Suspicion urinary infection Paralysis both lower legs after 1 wk Hospitalisation at neurology ward
CHIMIO + anti-PDL1
Anti-PD1 IVq 2 weeks Diagnosis of Guillain Barré
syndrome PlasmapheresesisSlight improvement
BUT disease progression
https://www.bsmo.be/immunomanager/irae/
Wilgenhof S and Neyns B 2011 Ann of Onc
Collaboration with BNS
Pneumonitis
Saturation 88% (arterial, no oxygen?)Required 10L O2, no BAL, improvement on corticoids
B9991016 avelumab vs placebo + Cisplatinum cCRTOrofarynxcarcinoom T1N2bM0 RT untill 19/12
30/01/2018 01/02/2019 27/02/2019 07/03/2019
Restartavelumab/placebo C8
Saturation 90%Good resolution uponcorticoidtreatmentand AB
Saturation 86%Just before C8 avelumab: avelox + Medrol 2x 32mg
GRADE 1Symptom Grade
Managementescalation pathway
Radiographic changes only
Ground glass charge, non-specific interstitial pneumonia
GRADE 2
Mild /moderate new symptoms
Dyspnoea, cough, chest pain
GRADE 3
Severe new symptoms
New or worsening hypoxia
Life threatening
Difficulty in breathing, ARDS
Consider delay of treatment
Monitor symptoms every 2-3 weeks
When worsening treat as grade 2 or 3-4
Withhold ICPI
Start Ab if suspicion of infection(fever, CRP, neutrophil counts)
If no evidence of infection or noimprovement with Ab after 48hadd in prednisolone 1 mg/kg/day orally
High resolution CT +/bronchoscopyand BAL
Consider Pneumocystis prophylaxis
Discontinue ICPI
Admit patient, baseline tests as above (methyl) prednisolone i.v.2 mg/kg/day
High resolution CT ad respiratory review +/- bronchoscopy and BAL pending appearances
Cover with empiric AB
Non specific interstitial pneumonitis COP-like
Hypersensitivity AIP/ARDS
Adapted from Castanon, E. 2016.Clin. Cancer Res. 22, 5956–5958
Pulmonary toxicity
Suresh et al, JTO 2018
Bad prognosis if corticoid R!
This is not disease progression!!!
Pradère, P. et al. 2018 Eur. J. Cancer 93, 144–146
BOOP
Pneumonitis
ICB induced Colitis
Mekki et al, 2018, EJC
Foppen M et al 2017, ESMO open
Rapid switch to TNFablockers if corticoid R!
What is the effect of corticoids/anti-TNF?
Horvat et al. J Clin Oncol 2009 Johnson et al 2018, JITC
The effect of other immunosuppressiva on cancer evolution such as Leflunomide, Vedolizumab, Tocilizumab, MMF,... is rather unclear...
Corticoids are not always required
De Martin et al J hepatology 2018 + comment Gauci M et al 2018
Gastritis: cave anorexia!
Nishimara et al , case reports in oncology 2017
Arthralgia• No clinical swelling
• Joint pain
• Stiffness
Inflammatory arthralgia• Pain at rest
• Awaking at night
• Early morning stiffness >30 minutes
• No clinical swelling
Arthralgia
Arthritis• Signs of inflammation
• Joint swelling
• Awaking of pain at night
• Early morning stiffness (>30min)
• Pain at rest
• Multiple joints may be affected
Arthralgia
In case of preexisting autoimmunity
contact the organ specialist who treats
the autoimmune disorder
• 71 yo woman treated for a metastatic cervical CA
• After 6 pembrolizumab infusions > acute polyarthritis- CRP 147mgr/L- RF/ACPA negative- hands and feet X-ray normal
• Acute seronegative polyarthritis> Synovial biopsy of the 1st metatarsophalangeal joint
• Histology: synovitis with mild synoviocytehyperplasia and diffuse lymphocyticinfiltration with CD3+ and also CD68+ macrophages
Clinical case
Courtesy of Dr. Laurent Melnic de Bellefon, UCL
Importance of collaboration
Cappelli et al 2018, seminars in rhumatology
Special populations excluded from IT trials
Guidelines BSMO
Patients with preexisting autoimmune disease
Danlos et al. Eur. J. Cancer 2018;91:21–29
Case report: arthritis
Mai 2018 Febr 2019
Medical History:• RA for which patient was treated with intermittent
corticoids, last episode of arthritis in sept 2018, declined MTX treatment
Abdominal wall relapse of
melanoma: resection: BRAF V600E mutation
PET scan: lung mets and one
bone metastasis (sacrum)
anti-PD-1(1 march)
[images of hands required]
Anti-BRAF + anti-MEK
17 march 2019Complaints: I cannot make
wrists any more + fever first 48h after anti-PD1
injection
Age and toxicity
irAEs 95% CI p
<70 (YP) 0.25 0.21- 0.29 0.035
≥ 70 (OP) 0.33 0.26 - 0.40
102
63
412
191
0
100
200
300
400
500
< 70 ≥ 70 Age, years
irAEs ≥ grade 2according to age
Nu
mb
er
of
pat
ien
ts
25% 33%
irAEs ≥ grade 2No irAEs or grade 1
Dr. Baldini, IGR
The more combinations, the more toxicity?
7,7%
18,6%
39,6%
0,0%
10,0%
20,0%
30,0%
40,0%
50,0%
nivolumab ipilimumab nivo+ipi
Grade 3-4 Tox
Larkin J et al. N Engl J Med 2015;373:23–34.
Anti-PD-1
Anti-CTLA4
Anti-PD-1 + Anti-CTLA4
We need to be prepared and create a network with up to date physicians
Future: Personalize immunotherapy
Inflamed Cold Immune excluded
TLR agonist
Immunogenic
chemotherapy
Macrophage
modulation
VEGF
modulation
Epigenetic
alteration of MHC CDK4/6 inhibition
CAR T cell therapy
Thank you
Adapted from Hoos A et al. Nat Rev Drug Discov 2016;15:235–47.