immuno-pet - aiom · at recist1.1 showed pd as response cut off for sul peack >15.5 se: 80%...
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IMMUNO-PET
DEANDREIS Désirée
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IMMUNOTHERAPY: target
Ipilimumab Nivolumab, Pembrolizumab
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Hodi et al 2010
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The objective response rate in the nivolumabgroup was 40.0% (95% CI, 33.3 to 47.0), whichwas significantly higher than the rate in thedacarbazine group, which was 13.9% (95% CI,9.5 to 19.4) (odds ratio, 4.06; P<0.001).
Robert et al 2015
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Response rate 19% withnivolumab versus 12% withdocetaxel (P = 0.02).
OS 12,2 mo vs 9,4 mo (p=0,002)1y-OS 51% vs 39%18mo-OS 39% vs 23%
Borghaei et al 2015
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New and atypical response
Tumor shrinkage(chemo-like response)
Prolonged stability(TKI-like response)
Pseudoprogression
Pseudoprogression
Wolchok JD et al 2009
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Pseudoprogression
Apparent initial increase in tumor burden related totransient immune-cell infiltrate, edema or continued growth
of the tumor before sufficient immune response occurs.
JAMA oncol. 2015; 1(1):115.
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iRECIST: Response criteria
(Seymour Lancet Oncol 2017)
(iUPD)
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Concept of :
- Total tumor burden (index lesion + new lesion)
- New non-measurable lesions do NOT define progression
- Concept of unconfirmed progression (iUPD)
- Confirmation of progression with further scans necessary
- Concept of resetting the bar if a PD is followed by tumor shrinkage
- Takes clinical stability in consideration
New Response criteria
(Seymour Lancet Oncol 2017)
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IMMUNOPET
18FDG PET/CT
-18F-FLT-11C-MET-18F-FAC-18F-AraG- 64Cu/antiCTL4
- Cell proliferation in vivo-Nucleoside analogs- Aminoacids metabolism- Uptake in activated T-cells- CAR-T cell-tracking reagent- CD8 receptor imaging
Glucose metabolism(Metabolic Response)
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FDG PET/CT: a challenge
Uptake by the T cell might affect the evaluation of response to immunotherapy
McCracken et al 2016
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What do we know?• Few data in the literature • Exploratory studies, small simple size or case
report• Mostly Retrospective and heterogeneous studies • More data on Melanoma compared to other
tumors( high FDG uptake)• Data mostly for ipilimumab treatment • Short Follow up
Goal: searching for early predictive factors ofresponse and criteria to evaluate response.
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PET response CRITERIA
Same problem of RECIST 1.1 criteria
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N 22 patients
Baseline 2 cycles 4 cycles
EJNM 2015
Prediction
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baseline PD PD
baseline SD SD
CASE 1 CASE 2
baselinePD
PR
CASE 3 Increased of 31%of SUVmean
Pseudoprogression at FDG PET: type 1 Increase in uptake intensity and extension (“immune flare”)
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Cho et al J Nucl Med 2017; 58:1421-1428
WHICH CRITERIA?20 pts with melanoma treatedwith ipilimumab (n=16), BMS-936559 (n=3), or nivolumab (n=1).
Baseline 1 cycles
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SD
PD
SDPD
2 CR 2 PR1 SD ipilimumab
All early PDat RECIST1.1Showed PD as Response
Cut off for SUL peack>15.5 Se: 80%Sp:73.3%Accuracy:75%
SD at RECIST 1.1
Criteria to predict eventual response to ICI, by combining anatomic and functional imagingdata collected sensitivity, specificity and accuracy of 100%, 93% and 95% respectively.
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PECRIT : CUT off changePET/CT Criteria for early prediction of Response to Immune checkpoint inhibitor Therapy
From EORTC to PERCIST to PECRIT
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Appearance of new lesions associated with shrinkage of known sites of disease
Pseudoprogression at FDG PET: type 2
Guldbrandsen et al 2017
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Signs of immune related response
• Symmetric hilar and mediastinal nodal uptake in a pattern similar to sarcoidosis, in particular in patients with lung metastasis
• Reactive nodal uptake in the drainage basin of metastases
• Diffuse splenic uptake
• Kind of treatment ( anti CTLA4 more frequent)
• New lesions with decrease of uptake at disease site
Wong et al 2017
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04/12/2014
Metastatic Melanoma
Courtesy of Gustave Roussy, Villejuif
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19/11/2015
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15/02/201619/11/2015
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What about new lesions appearance?
Prospective studyN= 41 patients21.4 months follow up
Baseline 4 cycles
Best clinical response( Follow up, clinical evaluation,Imaging with PET and brain MRI, markers)
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N=31(2 CR8PR)N=10
Absolute number of newly emerged 18 F-FDG-avid lesions is a better marker of treatmentresponse than the SUV changes of singlelesions in particular to differentiate betweenSD and PD.
4 new lesionsSe: 84%Sp: 100%>1 cm size
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PERCIMT The PET Response Evaluation Criteria fir Immunotherapy
Anwar et al 2018
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Baseline 2 cycles
N=41 patientsFollow up 21.4months
EJNM 2018
Best clinical response( Follow up, clinical evaluation,Imaging with PET and brain MRI, markers)
Better correlationbetween PERCIMT andbest clinical responsecompared to EORTCcriteria ( accuracy 87.8vs 70.7%)
More PD
More SD
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Lymphoma
Cheson et al 2014
Based on FDG PET uptake compared to blood pool and normal liver uptake
Complete response Partial response Progressive Disease
Necessity of redefining Progressive Disease
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LYRIC CRITERIA
CR & PR
PD
SAME AS LUGANO CRITERIA
as with Lugano exceptIR : immune-related responseIR(1): ≥50% increase in SPD in first 12 weeksbut without clinical deteriorationIR(2): <50% increase in SPD witha. New lesion(s), orb. ≥ 50% increase in PPD of a lesion or set oflesions at any time during treatmentIR(3): Increase in FDG uptake without aconcomitant increase in lesion size meetingcriteria for PD.
2017
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Abscopal effect at FDG PET: type 3
The abscopal is a rare clinical effect defined by a regression of metastatic cancer at adistance from the irradiated site. Such effect may be driven and potentiates whenimmune a checkpoint blockade treatment is used concomitantly
Michaud et al 2016
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Response after 6 cycles of nivolumab as second line therapy (HI negative for PD-L1)
2016
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56 patientsNivolumab (44) Pembrolizumab (6)
baseline <16 weeks
6 patients presented new lesions with PR in 4 and SD in 2 in tumor target lesions
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High NPV of PET/CT when immunotherapy is used: 12 of 27 patients classified as negative,remained free of progression still after 15 months (usefull for ceasing treatment?)
Pet performed a median of 15.2 months after treatment
N 20 pembrolizumabN 7 nivolumab1 early pseudoprogression
Late assessment
7 9 5 6
Possibility of inflammatory infiltrationPersistence
53
1 FP
1 FP
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ToxicitiesColitis
Hypophisitis(anti CTLA-4)
Pancreatitis
Mekki et al 2018Tirumani et al 2015Goethals et al 2011Koo et al 2014
Thyroditis
Early after treatment on most patients
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IMMUNOPET: Other targetsPre-clinical setting
[89Zr]-oxine CD8 T cells which could find utility inapplications such as monitoring CAR T-cells post-infusion.
[18F]-FLT: thymidine that is a substrate for thymidine kinase 1 (TK1).
64Cu]-DOTA-anti CTLA4-PD1- PDL1-C3-mAb
([18F]- F-AraG)Mythocondrial dGKexpressed in activated T cells
([18F]-FAC) substrate of dCK
McCracken et al 2016
IN VIVOEX VIVO
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Ehlerding et al 2016, Tavare et al 2015
Heterogeneous uptake in tumorUptake in normal tissueMurine Ab
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Zr89-atezolizumab:
• Fist in human Pet imaging of PD-L1 expression
• NSCLC, bladder cancer, triple negative breast cancer
• Accumulation in lymphoid tissue (liver and spleen)
• Uptake in tumor lesions was heterogeneous within and between patients and even PD-L1 IHC 0 tumors showed clear tracer uptake
Bensch and Veen, Cancer Research 77; 2017 AACR abstract
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Open questions and conclusions
FOLLOW-UP
FDG PET and immunotherapy
BASELINE PET YES if used forfollow up in avidFDG tumor
EARLY EVALUATION Timing to be defined. Maybe not too earlybecause of pseudoprogression.
RE-EVALUATION 4 WEEKS to confirmor not PD
Confirmation toolHigh NPV
Proposal of new PET criteria to be validated: needs for clinical trial(FIR trial, NCT03584334,NCT02476734, NCT00316901, NCT02608528).
Search for new target or tracers are under consideration
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Grazie per l’attenzione
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FDG PET prior to surgery in 36 adenocarcinomas, 18 squamous cell carcinomas(SCC) and 1 sarcomatoid carcinoma
Comparison between PET parameters and CD68-TAMs, CD8-TILs, PD-1-TILs and PDL-1 tumor expression evaluated by HI
Significant correlation between SUVmax and SUVmean with the expression of CD8 TILs (p = 0.027) and PD-1 (p = 0.017 and p =0.009, respectively) were found.
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Significant correlation between SUVmax and SUVmean with the expression of CD8 TILs (p = 0.027) and PD-1 (p = 0.017 and p =0.009, respectively) were found.
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New tracers: T cells imaging
[18F]-FLT: thymidine that is a substrate for thymidine kinase 1 (TK1). The accumulation of [18F]-FLT isused as a marker for cell proliferation in vivo. [18F]-FLT demonstrated an increased signal in lymphnodes and spleen of metastatic melanoma patients being treated with anti-CTLA4. ( Ribas et al 2010)
1-(2’-deoxy-2’-[18F]fluoroarabinofuranosyl) cytosine ([18F]-FAC): nucleoside analogs to assessactivity of nucleoside salvage pathways, which are upregulated in immune responses, selectivelyaccumulated in activated CD8 T cell in the thymus, lymph nodes, and spleen ( Kim et al 2016, Radu etal 2008)
2ʹ-deoxy-2ʹ-[18F]fl uoro-9-β-D-arabinofuranosylguanine ([18F]- F-AraG) guanosine analog, has beenshown to preferentially accumulate in activated T-cells and in a leukemic cell line. (Namavari et al2011)
[64Cu]-DOTA-anti CTLA4-PDL1-C3 mAb version as a PET tracer for imaging target expression in tumor-bearing mice.
89Zr-pembrolizumab/atezolizumab: distribution in vivo of T cells
[89Zr]-oxine which could find utility in applications such as monitoring CAR T-cells post-infusion.Direct imaging of endogenous markers and cells using radiolabeled antibodies and engineeredfragments remains an area of interest.
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IMMUNOPET: conclusions
• Few data in the literature and small sample size
• 18F-FDG PET/TC can be considered as an evaluation tool to assess responsein association to morphological imaging but further evaluation are needed.
• Clear protocol of scan acquisition are not available and furtherprospective trials are required (FIR trial, NCT03584334,NCT02476734,NCT00316901, NCT02608528).
• Some new PET criteria have been proposed but not validated
• Consider type of treatment and disease
• Indirect signs can be useful in the response evaluation
• Search for new target or tracers are under consideration