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Immunotherapy: general principles
Ruggero De Maria, MD Institute of General Pathology
TheCancerImmunityCycleThebody’sinherentprotectionagainstcancer
Immunosurveillance:experimentalevidence(from1950s…)
TumorAntigenIdentification(1980s)
TheCancerImmunoeditingHypothesisTumorsinimmunocompetentmicearequalitativelydifferentfromtumorsinimmunodeficientmice
RobertD.Schreiberetal.Science2011;331:1565-1570
The3EsofCancerImmunoediting
Cancer Immunotherapy has been under evaluation formore than a century, but onlyrecently has it entered a renaissance phase with approval of multiple agents for thetreatmentofcancer
CancerImmunotherapyTimeline
ENTHUSIASMPHASE
1978-1985
SKEPTICISMPHASE
1985-1997
REINASSANCEPHASE
1997-PRESENT
• IMMUNEINFILTRATESINTUMORSOBSERVED
• BACTERIALPRODUCTSSTUDIED
• DENDRITICCELLSDISCOVERED
• HUMANTUMOR-ASSOCIATEDANTIGENSCHARACTERIZED
• CARTCELLS
• ADOPTIVET-CELLTRANSFER
• IDOINHIBITION• CTLA4PATHWAY• OX40PATHWAY
• PD-L1/PD-1PATHWAY
• CSF-1R
Discoveriesinimmunepathwayresearchhavehelpedrefinecancerimmunotherapystrategiestobecomemoretargeted
Encompassesseveraldifferenttreatmentapproaches,eachofwhichhasadistinct
mechanismofaction,andallofwhicharedesignedtoboostorrestoreimmunefunction
CancerImmunotherapy
ü ActiveImmunotherapy
CheckpointInhibitors
CostimulatorsandCytokines
CancerVaccines
ü PassiveImmunotherapy
AdoptiveCellTherapy
Graft-versus-LeukemiaEffect
AntitumorAntibodies
NonspecificStimulators
ActiveImmunotherapy–CancerVaccines
ActiveImmunotherapy–CheckpointInhibitorsThe camouflageof tumor cells to evadeeffector cells canbe reached throughtheexpressionof‘checkpoint’proteinssuchasCTLA-4andPD-1,whichfunctionasabrakeontheimmunesystembypreventingT-cellactivation
MHC-ITCR
Activatedimmunecell
Inactivatedimmunecell
IMMUNECHECKPOINTS
Cancercell-death GO STOP
Immune Checkpoint Blockade: CTLA-4 and PD-1 targets
Abril-Rodriguez & Ribas, 2017
Robertetal.NEnglJMed364:2517,2011
Wolchok et al. NEJM 2017
Lon-term therapeutic effect of anti-immune checkpoint in previously untreated metastatic melanoma
Brahmer J et al. N Engl J Med 2015;373:123-135.
Efficacy of Nivolumab versus Docetaxel in Patients with Advanced Squamous-Cell Non–Small-Cell Lung Cancer.
MS Lawrence et al. Nature 2013
Somatic mutation frequencies observed in exomes from 3,083 tumour–normal pairs.
Somatic mutation rate in human cancers
Carcinogens
MutationalloadpredictsIpilimumabsensitivityinmetastaticmelanoma
Snydereta.NEJM,2014
Mutationalload
Le, NEJM, 372:26, 2015
Inhibitorytumor-metabolism(LDH)
Keldermannetal.CancerImmunolImmunother63:449,2014 Weideetal.ClinCancerRes.22:5487,2016
Melanoma
1yOS: HighLDH:2,3months LowLDH:16.1months
1yOS:HighLDH:3.7months LowLDH:14.7months
Ipilimumab Pembrolizumab
Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab
Ferrucci et al. Ann Oncol. 27:732, 2016
Intra-tumor CD8butnotCD4infiltrate
Correlateswithresponse
PD1/PD-L1expressionCorrelateswithresponse
TcellclonalityCorrelateswithresponse
Nosingleparameterperfectlydiscriminatesrespondersfromnon-responders
Intra-tumoralimmune-cellinfiltrationInvasive
margin
CD8+ PD-1+ PD-L1+ CD4+
Pembrolizumabinmelanoma,TumehNature;515:568,2014
Herbst et al. Lancet 2016
Therapeutic effect of Pembrolizumab in NSCLC
>1% PDL1
>50% PDL1 17.3
14.9
8.2
12.7
10.4
8.5
Median survival (months)
Median survival (months)
OncomineImmune-ResponseResearchAssay
Expressionof395genes
ACC retrospective study of anti-PD-1 treated NSCLC
Good
Responders
Fast
Progressors
Fast Progressors are defined as patients having a Progression Disease at first evaluation (8 weeks) Good Responders are defined as patients having an Overall Survival equals or more than 10 months.
• Whole-Exome Sequencing • RNA-seq • TCR repertoire • HLA typing • Immune infiltrate analysis by IHC • Metabolome