Emerging Tissue and Serum Markers

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1 Emerging Tissue and Serum Markers for Immune Checkpoint Inhibitors Kyong Hwa Park MD, PhD Medical Oncology Korea University College of Medicine

2 Contents Immune checkpoint inhibitors in clinical practice Biomarkers for immune checkpoint inhibitors - Tissue or blood based multi-level assays Immunotherapy in breast cancer: recent signatures Emerging biomarkers

3 Atezolizumab (Genentech/Roche)

4 Current Approval Status of ITA by USFDA

5 Immunologic Armaments in Oncology Clinic Anti-CTLA4 Anti-CD137 agonist Anti-OX40 agonist Anti-CD27 agonist IL-2 IL-12 Anti-VEGF Vaccine IFN-alpha GM-CSF Anti-CD40 agonist TLR agonist CARs Chemotherapy Radiation therapy Targeted therapy Anti-PD1 Anti-PD-L1 IDO inhibitors Nat Rev Genetics Aug 2016

6 Combination immunotherapy : More trials, Better targeted 2017 Nature

7 PD-1/PD-L1 Blockades in MBC

8 Response rate: 18.5% No response in LDH > 2X UNL Pembrolizumab in TNBC :Phase Ib KEYNOTE-012 Study J Clin Oncol May 2

9 Avelumab in Metastatic Breast Cancer All MBC Patients (N=111) ORR: 3% TNBC Patients (N=46) ORR: 5% PD-L1+ PD-L1-

10 Hyperprogressors! Clin Cancer Res; 2017

11 Clinical Questions that you might have. Metastatic Cancer Remission Immune Targeted Agents Patient selection? Still immune response? Retreat? Anti-tumor immune response? How long treat? Combination approach? Toxicities?

12 KEYNOTE-001: Phase Ib study of Pembrolizumab for the Treatment of NSCLC PD-L1 expression status by IHC: anti PD-L1 antibody clone 22C3 (Merck) Cells counted: neoplastic and intercalated mononuclear inflammatory cells N Engl J Med 2015;372:

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14 Mechanisms of PD-1 Expression Nature Immunology 14, (2013)

15 PD-1/PD-L1: Exhaustion of T cells 1) Antagonizing TCR signaling 2) Decreased survival, proliferation, altered metabolism 3) Reduced proliferation via RAS path 4) Altered transcription 5) Altered T cell motility Trends in Immunology April 2015, Vol. 36, No. 4

16 Technical Complexity With PD-L1: Different Thresholds for Expression There are no harmonized criteria to define PD-L1 positivity by IHC 1 Various PD-L1 IHC assays differ in terms of the cells assessed, scoring methods, and thresholds used: Cells assessed Nivolumab Dako Assay 2 Tumour cells Pembrolizumab Dako Assay 3,4 Tumour cells and immune cells Atezolizumab Ventana Assay 5,6 Tumour cells and immune cells Durvalumab Ventana Assay 7 Tumour cells Ab clone C3 SP142 SP263 Scoring method Tumour score: P ercentage of cell s with membran e staining at any intensity Proportion score: Percentage of cells with membrane st aining at any inten sity Tumour cell (TC) score: staining percentage of tumour cells Immune cell (IC) score: staining percentage of tumour ar ea Percentage tumour c ells with membrane staining PD-L1 Expression Levels <1% or 1%, <5% or 5%, <10% or 10% 50% TC3 or IC3: TC 50% or IC 10% TC2/3 or IC2/3: TC or IC 5% TC1/2/3 or IC1/2/3: TC or IC 1% TC0 and IC0: TC and IC <1% 25% Ab, antibody; IHC, immunohistochemistry; PD-L1, programmed death ligand Heskamp S et al. Cancer Res [Epub ahead of print]. 2. Phillips T et al. Appl Immunohistochem Mol Morphol doi: /pai Dolled-Filhart M et al. Poster presentation at ASCO Rizvi N et al. Poster presentation at ASCO Spira AI et al. Oral presentation at ASCO Spigel DR et al. Poster presentation at ASCO Rebelatto MC et al. Poster presentation at ASCO

17 PD-L1 as a Biomarker?: Issues Tumor heterogeneity Interval between biopsy and treatment Primary vs metastatic disease Ab and staining conditions Defining a positive result (cut-offs) - Immune cells vs tumor cells - Location of expression: intracellular vs surface vs stroma - Intensity, percent of positive cells - Distribution

18 HER-2 type Breast Cancer: PANACEA 2017 SABCS Loi et al

19 Genomic Signatures of TIL is Prognostic in HER2 Type Luminal low Luminal high HER-2 TNBC 2018 BCRT, doi: /s

20 Clinical Development in Cancers with High mutational burden Science 3 April 2015

21 Mutational Load Mutational Landscape of Melanoma according to the CTLA-4 blockade Response Survival in Discovery set Snyder A et al. N Engl J Med 2014;371:

22 Mutation burden, clinical response, and factors contributing to mutation burden: NSCLC Science 3 April 2015

23 Neoantigen burden & Intratumoral Heterogeneity (ITH) Science MAR 2016

24 Clonal Heterogeneity and Immune Signature in TNBC N=193 TNBC with follow up TCGA JAMA Oncol. 2017;3(12): doi: /jamaoncol

25 TIL Infiltration and Response to anti PD-1: Melanoma J Clin Invest. 2016;126(9): doi: /jci87324.

26 Tumoral CD8+ T cell Infiltration after Pembrolizumab Response (n=22) Proliferating T cells Progression (n=24) Nature 515, (27 November 2014)

27 Change in TCR Repertoire Theoretical repertoire of different TCRs that could be generated in humans Effective anti-tumor immunity increased TCR clonality Genes and Immunity (2016) Nature (2014)

28 T cell Diversity and Mutational Burden Science 3 April 2015 Nat Genetics 2016

29 What we should know for Rational application of Immune Targeted Agents (ITA) Immune responses with standard anti-cancer treatment Indicators to judge Immune-related Response - Pseudo-progression - Delayed but prolonged response, delayed K-M curve separation - Mixed responses Predictors for Immune-related Adverse Events Timing for Re-treatment: monitoring immunosuppressive TME

30 Best Information is in Tissue

31 Multiplex IHC NanoString Analysis : KEYNOTE-001 Peter Lee, 2016 SABCS

32 Assessment of Tumor Immune Microenvironment Static markers Dynamic markers Genomic analysis (WES, targeted seq) IHC for molecular & immune markers Flow/CyTOF for phenotyping RNA seq for profiling the transcriptome Single cell (TCR seq, RNAseq) Analysis of germline SNPs Flow/CyTOF for phenotyping (best if paired with tumor) Cytokine profiling in serum Exosome analysis (WES, RNAseq, paired with tumor) Single cell (TCRseq, RNAs eq)

33 Blood mirrors anti-tumor immune responses! - Immune cell profiles - Cytokines - PBMC Immunomics

34 F/81, Metastatic Breast Cancer (TNBC) Baseline Treatment week #18 Treatment week #16

35 Cell-based Analysis Flow-cytometry (FACS) Easy accessibility High-throughput High signal overlap ~16 parameters Mass Cytometry (Cy-TOF) No signal overlap >40 parameters High cost Low-throughput Limited availability

36 MDSC in Ipilimumab Treated Melanoma Patients MDSC with Treatment MDSC vs Response MDSC vs LDH MDSC vs M stage Cancer Immunol Immunother (2014) 63:

37 Change in circulating Lymphocytes after Ipilimumab Early change in ALC Delayed change in CD8 Delayed change in EØ Delayed change in CD4 *Early: 2-8 weeks after Tx, Delayed: 8-18 weeks after Tx CCR

38 Anti-PD1 Response : T cell invigoration & Tumor burden 2017 Nature doi: /nature22079

39 Anti-PD1 Response : T cell invigoration/tumor burden ratio Tumor burden (pre) Penn PD-1+CD8 (pre) MSKCC 2017 Nature doi: /nature22079

40 Gut microbiome influences efficacy of PD-1 based immunotherapy All cancer Frequency of Akkermansia NSCLC Science 05 Jan 2018: DOI: /science.aan3706

41 Dynamic immune monitoring is necessary in Development of new IO-based cancer treatment. : Best combination between ITA-ITA, SOC-ITA. Endpoint measures Decision for treatment, retreatment Public issue Neoantigen discovery & precision medicine Need collaborative effort in academic society!

42 Bio-specimens reflecting Anti-tumor Immune Responses Translational research for optimal immune monitoring Validation of immunoassays using clinical samples Establish the most feasible, standardized assays for immune monitoring Annu. Rev. Med :

43 AACR Tweeter

44 Smart Research Cures Cancer!