Immuno-Oncology Biomarkers:Progress UpdateJosep M. Piulats, MD, PhDDepartment of Medical Oncology, Institut Català d’Oncologia–IDIBELL, Barcelona, Spain
IOES18NP02971-02
Date of preparation: October 2018
Advisory board Astellas, BeiGene, Bristol-Myers Squibb, Clovis, Janssen, Merck KGaA/EMD Serono, Merck, Sharp & Dohme, Novartis, Roche and VCN Biosciences
Research funding
AstraZeneca, Bristol-Myers Squibb, Incyte, Merck KGaA/EMD Serono, Merck, Sharp & Dohme and Pfizer
Clinical trial participation (principal investigator)
Astellas, AstraZeneca, BeiGene, Bristol-Myers Squibb, Clovis, Immunocore, Janssen, Lilly and Merck, Sharp & Dohme
Disclosures
• The discovery of RELIABLE biomarkers to predict the efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research
• No efficient study designs to identify promising candidate biomarkers have been established
• This has led to a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated
• Many anticancer drugs are developed below their potential, due to failure to identify predictive biomarkers
– Unnecessary toxicities and costs
– Inability to identify the specific patient populationin which they are active
Biomarkers in Melanoma: BRAF Mutations—Are We There in I-O?1
EGF = epidermal growth factor; EGFR = EGF receptor; FGF = fibroblast growth factor; FGFR = FGF receptor; HRG = heregulin; I-O = immuno-oncology; PDGF = platelet-derived growth factor;
PDGFR = PDGF receptor.
1. Perez-Gracia JL et al. Cancer Treat Rev. 2017;53:79-97. 2. Pratilas CA et al. Clin Cancer Res. 2010;16:3329-3334.
Adapted from Pratilas CA et al. 2010.2
Images provided by JM Piulats.
HLAI = human leukocyte antigen-I; TCR = T-cell receptor.
Images provided by JM Piulats.
HLAI = human leukocyte antigen-I; PD-1 = programmed death 1; TCR = T-cell receptor.
Images provided by JM Piulats.
HLAI = human leukocyte antigen-I; IFN-γ = interferon gamma; PD-1 = programmed death 1; TCR = T-cell receptor.
Images provided by JM Piulats.
HLAI = human leukocyte antigen-I; IFN-γ = interferon gamma; PD-1 = programmed death 1; PD-L1 = programmed death ligand 1; TCR = T-cell receptor.
Images provided by JM Piulats.
HLAI = human leukocyte antigen-I; IFN-γ = interferon gamma; PD-1 = programmed death 1; PD-L1 = programmed death ligand 1; TCR = T-cell receptor.
Images provided by JM Piulats.
Primary Tumors Metastasis
AIS = adjusted inflammation score; TIL = tumor-infiltrating lymphocyte.
Adapted from Taube JM et al. Sci Transl Med. 2012;4:127ra37.
Fig 1 in Taube
source file
Colocalization of Inflammatory Response With PD-L1 Expression in Human Melanocytic Lesions Supports an Adaptive Resistance Mechanism of Immune Escape
Tx = treatment.
Adapted from Tumeh PC et al. Nature. 2014;515:568-571.
PD-1 Blockade Induces Responses by InhibitingAdaptive Immune Resistance
Spatiotemporal Dynamics of CD8+ Releasing the PD-1 Checkpoint Led to:
2. Intratumoral infiltration
3. Increased effector function
1. T-cell proliferation
Adapted from Tumeh PC et al. Nature. 2014;515:568-571.
PD-1 Blockade Induces Responses by InhibitingAdaptive Immune Resistance
TCR Clonality:
Low Diversity
High Clonality
High Diversity
Low Clonality
Images provided by JM Piulats.
Spontaneous
Treatment Induced
Images provided by JM Piulats.
Spontaneous
Treatment Induced
Images provided by JM Piulats.
Spontaneous
Treatment Induced
Images provided by JM Piulats.
Biomarkers in I-O
Neoantigens
Antigen presentation machinery
IFN-𝛄 signatures
IFN-𝛄–related proteins
Immune-staining cell populations
Adapted from Clancy S et al. Nature Education. 2008;1:101.
ALL = acute lymphoblastic leukemia; CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma.
Adapted from Lawrence MS et al. Nature 2013;499:214-218.
Somatic Mutation Frequencies Observed in Exomes From 3083 Tumor-normal Pairs
MMRd = mismatch repair–deficient; MMRp = mismatch repair–proficient; NSCLC = non-small cell lung cancer.
Adapted from Yarchoan M et al. N Engl J Med. 2017;377:2500-2501.
Correlation between Tumor Mutational Burden and Objective Response Rate with Anti–PD-1 or Anti–PD- L1 Therapy
Seq. = sequence.
Adapted from Snyder A at al. N Engl J Med. 2014;371:2189-2199.
Defects in DNA-repairing Genes as a Source for DNA Mutations: Do They Predict Response to Checkpoint Inhibitors?
DCB = durable clinical benefit; NDB = no durable benefit; NR = not reached; PD = progressive disease; PFS = progression-free survival; PR = partial response; SD = stable disease; V = validation.
Adapted from Rizvi NA et al. Science. 2015;348:124-128.
Defects in DNA-repairing Genes as a Source for DNA Mutations: Do They Predict Response to Checkpoint Inhibitors?
HR = hazard ratio; ITH = intratumor heterogeneity.
Adapted from McGranahan N et al. Science. 2016;35:1463-1469.
Defects in DNA-repairing Genes as a Source for DNA Mutations: Do They Predict Response to Checkpoint Inhibitors?
PD-1 Blockade in Tumors With Mismatch-Repair Deficiency
Adapted from Le DT et al. N Engl J Med. 2015;372:2509-2520.
Defects in DNA-repairing Genes as a Source for DNA Mutations: Do They Predict Response to Checkpoint Inhibitors?
INDEL = insertion and deletion; nsSNV = nonsynonymous single nucleotide variant; Pt = patient; WT = wild type.
Adapted from Hugo W et al. Cell. 2016;165:35-44.
Defects in DNA-repairing Genes as a Source for DNA Mutations: Do They Predict Response to Checkpoint Inhibitors?
Small INDELs
Frameshift Mutations:
Not All Genetic Alterations Are the Same…
Image provided by JM Piulats.
Not All Genetic Alterations Are the Same…
Adapted from Turajlic S et al. Lancet Oncol. 2017;18:1009-1021.
Not All Genetic Alterations Are the Same…
Adapted from Davoli T et al. Science 2017;355:eaaf839.
LOH = loss of heterozygosity; MHC = major histocompatibility complex.
Adapted from Chowell D et al. Science. 2018;359:582-587.
Patient HLA Class I Genotype Influences Cancer Response to Checkpoint Blockade Immunotherapy
Adapted from Hugo W et al. Cell. 2016;165:35-44.
Genomic and Transcriptomic Features of Response to Anti–PD-1 Therapy in Metastatic Melanoma
1. Non responding tumors expressed higher:
– Mesenchymal transition genes (AXL, ROR2, WNT5A, LOXL2, TWIST2, TAGLN, FAP).
– Immunosuppressive genes (IL10, VEGFA, VEGFC).
– Monocyte/macrophage chemotactic genes (CCL2, CCL7, CCL8, CCL13)
– Genes associated with wound healing and angiogenesis.
2. CDH1 was down-regulated in non-responders.
3. Genes with putative roles in modulating immune-checkpoint sensitivity were not differentially expressed.
4. GZMA, PRF1, PDCD1LG2, and CTLA-4 were expressed higher in patients who derived benefit from ipilimumab.
5. GZMA, PRF1, PDCD1LG2, CTLA-4, CD8A/B, PD-L1, LAG3, and INFG did not present higher expression in responders.
6. Expression levels of HLA class I genes trended higher among responding tumors.
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Adapted from Ayers M et al. J Clin Invest. 2017;127:2930-2940.
IFN-g–related mRNA Profile Predicts Clinical Response to Anti–PD-1 Blockade
Adapted from Ayers M et al. J Clin Invest. 127;2017:2930-2940.
IFN-g–related mRNA Profile Predicts Clinical Response to Anti–PD-1 Blockade
GEP = gene expression profile; TMB = tumor mutational burden.
Adapted from Cristescu R et al. Science. 2018;362:eaar3593.
TMB and GEP were independently
predictive of response and
demonstrated low correlation,
suggesting that they capture
distinct features of neoantigenicity
and T-cell activation
Pan-Tumor Genomic Biomarkers for PD-1 Checkpoint–Blockade-based Immunotherapy
PF
S
Time to progression (days)
MSI-h = microsatellite instability high; MSS = microsatellite stable; SCC = small cell carcinoma; TNBC = triple-negative breast cancer.
Adapted from Cristescu R et al. Science. 2018;362:eaar3593.
Pan-Tumor Genomic Biomarkers for PD-1 Checkpoint–Blockade-based Immunotherapy
PF
S
Time to progression (days)
PD-L1 < 1%
PD-L1 > 1%
aPD-L1 positive: ≥ 5% tumor cell surface staining. PD-L1 negative: < 5% tumor cell surface staining. Based on August 5 2014 database lock.
CI = confidence interval; IPI = ipilimumab; NIVO = Nivolumab; NR=not reached; OS = overall survival.
1. Robert C et al. N Engl J Med. 2015;372:320-330. 2. Wolchok JD et al. N Engl J Med. 2017;367:1345-1356.
Just One Slide About PD-L1 Staining…
Improved OS irrespective of PD-L1 status100
90
80
70
60
0
50
40
30
20
10
0 3 6 9 12 15 18Months
Nivolumab PD-L1+
Dacarbazine PD-L1+
Nivolumab PD-L1-
Dacarbazine PD-L1-
Patients at Risk
Dacarbazine PD-L1-
Nivolumab PD-L1-
Dacarbazine PD-L1+
Nivolumab PD-L1+
74
128
74
126
69
108
64
107
56
88
44
78
39
63
30
52
18
26
11
11
1
7
1
2
0
0
0
0
Pati
en
ts S
urv
ivin
g (
%)
OS by PD-L1 Statusa
Patients who died,
n/NMedian OS mo (95% CI)
1-Yr OS% (95% CI)
Nivolumab PD-L1+ 11/74 NR 82.1 (69.6–89.8)
Nivolumab PD-L1- 37/128 NR 67.8 (58.3–75.7)
Dacarbazine PD-L1+ 29/74 12.4 (9.2–NR) 52.7 (37.7–65.7)
Dacarbazine PD-L1- 64/126 10.2 (7.6–11.8) 37.4 (26.4–48.3)
Adapted from Robert C et al. 2015.1
Adapted from Wolchok JD et al. 2015.2
Lymphocytes in the Tumor
Lymphocytes in the Tumor
Primary Tumors Metastasis
AIS = adjusted inflammation score; TIL = tumor-infiltrating lymphocyte.
Adapted from Taube JM et al. Sci Transl Med. 2012;4:127ra37.
Fig 1 in Taube
source file
Colocalization of Inflammatory Response With PD-L1 Expression in Human Melanocytic Lesions Supports an Adaptive Resistance Mechanism of Immune Escape
AIS = adjusted inflammation score; TIL = tumor-infiltrating lymphocyte.
Adapted from DB Johnson et al. Clin Cancer Res. 2018;24:5250-5260.
Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma
AIS = adjusted inflammation score; TIL = tumor-infiltrating lymphocyte.
Adapted from DB Johnson et al. Clin Cancer Res. 2018;24:5250-5260.
Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma
AIS = adjusted inflammation score; TIL = tumor-infiltrating lymphocyte.
Adapted from DB Johnson et al. Clin Cancer Res. 2018;24:5250-5260.
Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma
AIS = adjusted inflammation score; TIL = tumor-infiltrating lymphocyte.
Adapted from M Sade-Feldman et al. Cell. 2018;175:998-1013.
Defining T Cell states Associated with Response to Checkpoint Immunotherapy in Melanoma
Adapted from Zitvogel L et al. Science. 2018;359:1366-1370.
…. And Last: The Microbiome
Gut Microbiome Modulates Response to
PD-1–based Immunotherapy in Melanoma PatientsGut Microbiome Influences Efficacy of
PD-1–based Immunotherapy Against Epithelial Tumors
1. Gopalakrishnan V et al. Science. 2018;359:97-103. 2. Routy B et al. Science. 2018;359:91-97.
The Microbiome and PD-1–based Immunotherapy
Adapted from Rouly B et al. 2018.2Adapted from Gopalakrishnan V et al. 2018.1
Conclusions:
• The perfect biomarker does not exist.
• Objective for a biomarker in I-O: Select patients that will benefit from anti-PD1 alone.
• We can divide biomarkers in:
– Genetic: Tumor mutation burden (TMB). Still margin for improvement…
– INF-g related:
• These biomarkers seems to work better when we combine:
- TMB + LOH loss for HLA locus.
- TMB + INF-g related biomarker.
• Importance of exploring more microbiota as single biomarker or associated with other.
Gene signatures.
Single gene (PD-1).
Imaging (new tools ).