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