IMMUNO-PET

DEANDREIS Désirée

IMMUNOTHERAPY: target

Ipilimumab Nivolumab, Pembrolizumab

Hodi et al 2010

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

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

New and atypical response

Tumor shrinkage(chemo-like response)

Prolonged stability(TKI-like response)

Pseudoprogression

Pseudoprogression

Wolchok JD et al 2009

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.

iRECIST: Response criteria

(Seymour Lancet Oncol 2017)

(iUPD)

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)

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)

FDG PET/CT: a challenge

Uptake by the T cell might affect the evaluation of response to immunotherapy

McCracken et al 2016

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.

PET response CRITERIA

Same problem of RECIST 1.1 criteria

N 22 patients

Baseline 2 cycles 4 cycles

EJNM 2015

Prediction

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”)

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

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.

PECRIT : CUT off changePET/CT Criteria for early prediction of Response to Immune checkpoint inhibitor Therapy

From EORTC to PERCIST to PECRIT

Appearance of new lesions associated with shrinkage of known sites of disease

Pseudoprogression at FDG PET: type 2

Guldbrandsen et al 2017

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

04/12/2014

Metastatic Melanoma

Courtesy of Gustave Roussy, Villejuif

19/11/2015

15/02/201619/11/2015

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)

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

PERCIMT The PET Response Evaluation Criteria fir Immunotherapy

Anwar et al 2018

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

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

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

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

Response after 6 cycles of nivolumab as second line therapy (HI negative for PD-L1)

2016

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

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

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

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

Ehlerding et al 2016, Tavare et al 2015

Heterogeneous uptake in tumorUptake in normal tissueMurine Ab

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

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

Grazie per l’attenzione

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.

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.

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.

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