M edicine Marianna Nuti Dipartimento di Medicina Sperimentale UP Terapie Cellulari Policlinico Umberto I mariannanutiuniroma1it August 19 2010 Mlecnik et al Jclin Oncol 201129610 ID: 781354
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Cancer Immunotherapy and Precision
Medicine
Marianna Nuti
Dipartimento di Medicina
Sperimentale
,UP
Terapie Cellulari
Policlinico Umberto I, marianna.nuti@uniroma1.it
Slide2Slide3August 19, 2010
Slide4Slide5Mlecnik et al. Jclin Oncol 2011;29:610
CD8 T cells
Central memory
CD8 T cells
Slide6Dalla copertina di Science…….alla recente copertina del Time sull’impatto economico
INCONTR AIOM 2016
Slide7Challenges for curing cancer todayIt is not sufficient to “
treat” the tumorTreat the patient: individualized treatmentImmune system: unique repertoire of molecules and cells specialized to eliminate and control foreign material/sick cells/pathogens
6° MASTER in NEURO-ONCOLOGIA
Slide86° MASTER in NEURO-ONCOLOGIA
Targets host
Targets
tumour
Immunotherapy
Targeted therapy
Single agent targeted therapies cause deep, rapid onset, but non-durable responses
Combination ?
Single agent immunotherapies cause slow-onset, durable responses
Slide9The immune system
Unique repertoire of molecules and cells specialized to eliminate and control foreign
material/sick cells
/pathogensImmune
cells can “find” the target in all
tissue discrict
Can be educated for recognitionMemory
Slide10IMMUNOTHERAPY: “universal” and “shared” therapies for different tumors
Immune system is active in all humansAll cancers can benefit from immunotherapyThe immune fitness of the patient is probably the best indicator of response to immunotherapySeveral factors contribute
to immune fitness: microbiota, genetic
factors, life style, neurological factors etc…
Slide11Slide12Slide13T cell the novel
“drug”for treating cancer: T
cells can
clinically control cancer
First important evidence
: T Lymphocytes can eliminate
also large masses of
tumor (1 Kg of tumor = 1012 cells) Failure to achieve critical mass of T cells explains
previous trials with disappointing resultsTwo potential solutions:Infuse huge numbers of specific T cellsActivate
small
numbers
of T
cells
in-situ (
chemo
/radio and target
therapies
) and
expand
them
in large
quantities
(ICI)
Slide14T cell the novel “drug”for treating cancer: T cells can clinically control cancer
T cells can be “liberated” by immune-check point inhibitorsT cells can be adoptively transferred (car-T)T cells can be induced in vivo by vaccination and/or chemo/radio therapies
6° MASTER in NEURO-ONCOLOGIA
Palucka AK and Coussens LM, Cell 2016
Slide15New shapes of curves and new endpoints
for clinical trials
IDEAL KAPLAN-MEYER
-Reduction in the risk of event is maintained proportional during the observation -Median Survival and HR are both
good surrogate of treatment benfit
TKIs
KAPLAN-MEYER
-Large benefit in favourof the experimental drug is captured entirely by themedians-No difference at the 12-m landmark analysis is observed
IMMUNO KAPLAN-MEYER-Medians do not capture the effect of the drug -Landmark analysis may be the best tool to magnify benefit that will be detected later in the studyPilotto S et al. Transl Lung Cancer Res 2015
Slide16Future scenarios in immunotherapy treatment of cancer
Absolute need for combination of treatments Novel
“
mentality” in designing treatment
protocols and clinical trials
Patient personalized
approach
Slide17Questions to be answered…Can immune biomarkers help?
Explain degree of heterogeneity in responses with ICIHow to extend ICI coverage to the majority of cancer patients who do
not see
control or regression of cancer (biomarkers of response and
toxicity)Should we start ICI treatment at diagnosis?Need of
biomarkers of immune fitness (activation, suppression)Should ICI treatment be
continued beyond progression? Suspended? Other
therapies to re-induce immunogenic death?
Slide18Biomarkers in immunotherapy
: precision medicine in immunoncologyTo identify early
responders pts
To anticipate toxicity events
To monitor immunity
during treatment
To stop immune therapy if ininfluent to response (not for resistance)To
tailor on the single pt the right schedule (precision immuno-oncology treatment)
Slide19Biomarcatori validati (più o meno…)
IMMUNOSCORE tissutale
Misura infiltrato immunitario, location infiltrato, può essere tipizzato grossolanamente: correla con prognosi
Possibile solitamente in partenza (tumore primario), non valuta dinamicità, manca di caratterizzazione specificaMUTATIONAL LOAD
Per difetti riparo (MMRD) : ottima risposta con ICILa valutazione non è in realtà utile ai fini clinici IMMUNOMONITORING
Popolazioni cellulari periferiche indicative di attivazione e/o immunosuppressionCitochine-chemochine pro-anti-infiammatorie siericheFondamentale personalizzazione e valutazione durante trattamento (per ora…)
BIOMARKERS NON IMMUNITYLDH indice di high cell turnover e stress/hypoxia (LDH elevato correla con prognosi negativa)
Cell-free DNA, miRNA,exosomes
Slide20Immune related biomarkers: summary of findings related to responseMaster di Immuno Oncologia 27-29 Aprile 2017
T cells:Increase in Absolute Lymphocyte count (ALC) , CD4+ and CD8+(Ki67),low monocyte,low MDSC,high Treg (for IPI)Pre existing primed CD8+ T cells are maintained in long-term survivors (not naive converting to effectors…)….reflects immunogenicity of tumor, capacity of that aplotype to present, rearrangements TcR
Association with low serum IL15 (increased expression of TIM3 and PD-1 on NK and T cells
High IL4 and IFNgamma before IPI
High avidity T cell clones (example virus reactive ,CMV), Less clonotype lossICOS upregulation after IPI, transcription factors EOMES and granzyme B + T cells
Slide21Infiltrato infiammatorio NSCLC
Slide22Confirmed by Djenidi et al., J Immunol 2015
and Donnem et al., Clin Cancer Res 2015
B cells
CD4 T cells
CD8 T cells
Slide23T cell the novel
“drug”for treating cancer: evidences that
T
cells are involved also
in determining the success of cancer
therapies
Therapeutic
benefit from PD-1/PD-L1 blockade requires “hindered” pre-existing immunity reinvigorated by the treatment
Slide24Presseur M. et al., Nat Rev Neurology, 2015
Il percorso per l’attivazione dei linfociti T anti tumore
Slide25Slide 13
Presented By Padmanee Sharma at 2016 ASCO Annual Meeting
Slide26Slide 22
Presented By Laura Chow at 2015 ASCO Annual Meeting
Slide27Not all patients
with an immunological response to pembro (anti-PD1) have clinical benefit
Huang,AC
et al, Nature 2017
NEED TO EXPAND A SIGNIFICANT NUMBER OF SPECIFIC
T
CELLS
Slide28NEED TO EXPAND A SIGNIFICANT NUMBER OF SPECIFIC T CELLS
29 pts stage IV melanoma with prior anti-CTLA4 treatment treated
with
PEMBROMost
pts demonstrated immunological
response ( CD8 Tex
cells Ki67 pos)
Clinical failure due to:Inability to induce immune reinvigorationImbalance between T cell reinvigoration
and tumor burdenMagnitude of reinvigoration of circulationg Tex cells in relation to tumor burden correlates with clinical
response
Huang,AC
et al, Nature 2017
Slide29ICI non responders/refractory pts are:
Pts with defects in IFN signaling Pts with tolerogenic
DC
Pts with defects in
antigen presentation (beta-2 microglobulin
)Pts with unbalanced
T-cell invigorating
/tumour burden ratio
ICI responders pts are:Pts with high mutational loadPts with defects in repair
machinery
Pts
with
tumor
-T
cell
inflammation
Slide30The cancer immunogram.
Christian U. Blank et al. Science 2016;352:658-660
Slide31T cell the novel
“drug”for treating cancer: evidences that
T
cells are involved also
in determining the success of cancer
therapies
CHEMOTHERAPY and TARGET THERAPY need an
intact immune system to be efficacious
Slide32Nota bibliografica
Designing
Vaccines or re-invent chemo/target/
radiotherapy protocols to increase specific anti
tumor T cells trafficking to the tumor
Slide33Nivolumab
OS: Prior sunitinib
Nivolumab
OS: Prior pazopanib
Motzer
RJ, ASCO 2016
Slide34Targeting dei recettori coinvolti nell’attivazione linfocitaria
Slide35CD137 anti-TNF receptor 4-1BB:
biomarker to identify naturally-occurring tumor reactive T cells in tumor
CD 137
is up regulated by TILs
upon encounter with a tumor antigen
CD137 in CD8+ and CD4+ T cells is
MHC dependentCD137 expression
identifies recently activated tumor specific T cellsTargeting del recettore con anticorpi agonisti in clinica: numerosi studi in fase 1, tossicità epaticaTargeting del recettore in studi di adoptive cell
therapy per espansione T cells tumor specific
Slide36Added value
of peripheral blood biomarkers: Take home message from
initial immunomonitoring studies
(….real life)
Chance to monitor at
different time points treatment
induced changesPeripheral blood biomarkers: a partial and dinamic
picture strongly indicative of tumor immune scenario. Modifications of the repertoire /function of circulating immune cells is
an
early
event
(
earlier
than
tumor
response
)
Circulating
cytokine
and
chemokine
can anticipate the
changes
in target
populations
, can be
alert
of
manifest immunesuppressive status, are indicators of activated recirculation and/or cross-talk of immune cells All data should have a longitudinal setting per patientWe need to
learn from our patients:….longsurvivors, excellent responders, off-label etc…Novel “mentality” in designing treatment protocols and clinical trials…Immunomonitoring guided trials
Slide37Botticelli , A. et al.2017
ALGORITHM of PATIENT SELECTION PARAMETERS FOR CANCER IMMUNOTHERAPY