New biomarkers for response to immunotherapy

Transcription

1 WIN Paris, 14:15-14:40, June 26, 2017 New biomarkers for response to immunotherapy Antoni Ribas, M.D., Ph.D. Professor of Medicine, Surgery, Molecular and Medical Pharmacology Director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center (JCCC) Director, Parker Institute for Cancer Immunotherapy (PICI) Center at UCLA University of California Los Angeles (UCLA) Chair, Melanoma Committee at SWOG

2 Disclosures of Relevant Relations with Industry Antoni Ribas, MD, PhD Consultant Honoraria: Amgen, Astra-Zeneca, BMS, Celldex, Chugai, Genentech, Merck, Novartis Scientific Advisory Board Stock: Advaxis, Arcus, BioOncoTech, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Kite Pharma, Lutris, Rgenix Co-founder Stock: Acteris, PACT, Tango Unapproved drugs: Atezolizumab, durvalumab

3 Outline Mechanism of response to single agent PD-1 blockade Combination therapies to improve PD-1 blockade Intralesional therapy Combination with BRAFi/MEKi targeted therapy Resistance to PD-1 blockade therapy

4 Melanoma response to PD-1 blockade is mediated by pre-existing infiltrates of CD8s inhibited by reactively expressed PD-L1 PD1/PDL1 1 IHC Analysis of CD8+ T-cells in samples obtained before and during anti-pd1 treatment Tumeh et al. Nature 2014

5 Inhibiting PD-1-mediated adaptive immune resistance Anti-PD-1 Anti-PD-L1 Melanoma cell or tumor macrophage IFN-g Pardoll, NRC 2012 Taube et al. STM 2012 Tumeh et al. Nature 2014

6 Inhibiting PD-1-mediated adaptive immune resistance Anti-PD-1 Anti-PD-L1 Melanoma cell or tumor macrophage IFN-g Tumeh et al. Nature 2014

7 Adapted from Tumeh et al. Nature 2014 PD-1 blockade induces responses by inhibiting adaptive immune resistance CD8 PD-1 PD-L1 Response Progression Melanoma cell or tumor macrophage Melanoma cell or tumor macrophage Interferon gamma Hypothesis formulated based on quantitative IHC analyses of 46 cases from UCLA

8 The cancer immunogram Tumor foreignness Mutational load Tumor sensitivity to immune effectors MHC expression IFN-g sensitivity General immune status Lymphocyte count Absence of inhibitory tumor metabolism LDH, glucose utilization Immune cell infiltration Intratumoral T cells anti-pd-1/l1 Absence of soluble inhibitors IL6->CRP/ESR Absence of Checkpoints PD-L1 Blank, Haanen, Ribas, Schumacher. Science 2016

9 Mutational load as a foreignness recognition of cancer Mutational load and response to anti-pd-1 in NSCLC Mutational load and response to anti-pd-1 in MSI high colon cancer Mutational load and response to anti-pd-1 in melanoma Mutational load and response to anti-ctla4 in melanoma Rizvi et al, Science 2015 Le et al, NEJM 2015 Hugo et al, Cell 2016 Van Allen et al, Science 2016 McGranahan et al. Science 2016

10 ome S100 Trichrome Trichrome SE 3 CASE CASE 3 S100 S100 Trichrome CASE 2 Trichrome Trichrome CASE CASE 2 S100 S100 S100 CASE 1 CASE CASE 1 Desmoplastic melanoma: Defined by a dense collagenous fibrous tissue a) DM1 DM2 b) Baseline 2-3 months later Tumor (S100) a) a) DM1 DM2 b) b) Baseline Baseline 2-3 months after anti-pd1 2-3 months therapy later Collagen (Trichrome) CM1 CM1 CM2 A rare subtype of melanoma (less than 4%) CM2 blue collagenous stroma, red cytoplasm and brown nucleus A dense fibrous reaction A known relationship to UV light damage High NF1 mutation rate and no known actionable genes for targeted therapies. Zeynep Eroglu Siwen Hu-Lieskovan Jesse Zaretsky (submitted)

11 E s tim a te d O v e ra ll S u r v iv a l (% ) High response rate and high mutational load in Desmoplastic melanoma 70% overall response rate 18% complete response rate n=57 (out of 1054 cases Reviewed*) 1 siiic 3 M1a 20 M1b 35 M1c *Retrospective Review o s e (M o n th s ) B) % Overall survival (OS), median not reached Estimated 2 year OS 73% (CI 62-88) Time (months) T im e S in c e F irs t d o s e (M o n th s ) Non-Desmoplastic Melanoma Desmoplastic Melanoma = Progressive Disease = Response (RECIST1.1) Zeynep Eroglu Siwen Hu-Lieskovan Jesse Zaretsky (submitted)

12 What differentiates anti-pd-1-responsive from non-responding melanomas? ORR: 33% ORR in previously untreated: 45% Pembrolizumab Keynote 001 trial. Central radiology review by RECIST v1.1 Ribas et al. JAMA 2016

13 Management of cancer in the anti-pd-1/l1 era Anti-PD-1/anti-PD-L1 Bring T cells into tumors: Generate T cells: + anti-ctla4 + immune activating antibodies or cytokines + TLR agonists or oncolytic viruses + IDO or macrophage inhibitors + targeted therapies Vaccines TCR engineered ACT CAR engineered ACT Modified from Ribas, Cancer Discovery 2016

14 Adding BRAF targeted therapies to anti-pd-1/l1 Anti-PD-1/anti-PD-L1 BRAFi+MEKi Wilmott et al. CCR 2013 Frederick et al. CCR 2013 BRAFi+MEKi + anti-pd-1/l1

15 Combination of BRAFi+MEKi+Anti-PD-1 NIH Director s Blog* Knocking Out Melanoma: Does This Triple Combo Have What It Takes? Posted on March 31, 2015 by Dr. Francis Collins Comment on: Hu-Lieskovan S, et al. Sci Transl Med. 2015;7:279ra41. Hu-Lieskovan et al. Sci Transl Med Mar 18;7(279):279ra41 *Available at: Accessed on August 18, 2016.

16 Change From Baseline in Sum of Longest Diameter of Target Lesion, % Change From Baseline, % Clinical trials combining BRAFi+MEKi+anti-PD-1/L1 dabrafenib+trametinib +durvalumab 100 dabrafenib+trametinib +pembrolizumab vemurafenib+cobimetinib +atezolizumab Time, weeks Ribas et al. J Clin Oncol (Meeting Abstracts) May 2015 vol. 33 no. 15_suppl 3003 Ribas et al. J Clin Oncol 34, 2016 (suppl; abstr 3014). Hwu et al. Annals of Oncology 27 (Supp 6); 2016: Abstract 1109PD.

17 JAK1/2 and other IFN-g pathway LoF mutations Shin et al. Cancer Discovery 2016 Gao et al. Cell 2016 Sucker et al. Nature Communications 2017 JAK1/2 LoF mutations Zaretsky et al. NEJM 2016 Sucker et al. Nature Communications 2017 T cell exclusion by WNT signaling Spranger et al. Science 2015 Loss of neoantigen expression Anagnostou et al. Cancer Discovery 2017 JAK1/2 LoF mutations Zaretsky et al. NEJM 2016

18 How does the cancer sense IFN-gamma and reactively expresses PD-L1? PD1/PDL1 1 Melanoma cell or tumor macrophage Interferon gamma Tumeh et al., Nature 2014

19 IFN-gamma receptor signaling pathway controlling PD-L1 inducible expression Type I IFNs Alpha/Beta Type II IFN Gamma IFNAR1 IFNAR2 IFNGR1 IFNGR2 TYK2 JAK1 JAK1 JAK2 STAT1 and STAT2 Others IRS CRKL STAT4 STAT5 STAT6 STAT1 STAT1 STAT1 STAT3 STAT3 STAT3 STAT1 STAT2 IRF9 IRF1 ISRE??? STAT4 STAT5 STAT6 GAS1 GAS2 GAS3 - p21 - CDK - CSFR1 - GTPase - TRAIL - Caspases - Mx and 2-5 -OAS - FASL - Viperin - MHC I - PDL1 - PD1 - Antigens Chemokines Antiproliferative Antiviral apoptosis or survival Immunoregulation Migration Nucleus Modified from Angel Garcia-Diaz et al. Cell Reports 2017

20 Primary resistance to PD-1 blockade by disabling PD-L1 adaptive expression Would be useless to try to inhibit PD-1:PD-L1 Melanoma cell IRF-1 PDL1 Promoter PD-L1 Adapted from Shin et al. Cancer Discovery 2017 and Garcia-Diaz et al. Cell Reports 2017

21 Is JAK loss associated with primary resistance to PD-1 blockade? Responders Non-Responders JAK1 homozygous all heterozygous JAK1 homozygous 1/23 melanoma cases with high-allele frequency JAK1 mutation 1/16 colorectal cases with high-allele frequency JAK1 mutation data from Le DT et al. NEJM 2015 Shin et al, Cancer Discovery 2017

22 Summary of 4 Acquired Resistance Cases Lesion Size (mm 2 ) Lesion Size (mm 2 ) Lesion Size (mm 2 ) Lesion Size (mm 2 ) Baseline Relapse Baseline Max Response Relapse Genetic Alteration 6000 Case # Days on Therapy JAK1 LoF Case #1 Mutations VAF JAK1 loss of function mutation 1500 Case # JAK2 LoF Chromosomal Copy Number Days on Therapy * New small bowel lesion Left iliac lymph node #1 Left iliac lymph node #2 Copy Number Case # B2M LoF >=4 Loss of Heterozygosity Days on Therapy 2000 Case # Unkn Days on Therapy Zaretsky et al. NEJM 2016

23 Interferon-gamma Sensitivity Model: Initially, benefits of PD-L1 suppression outweigh immune sensitizing effects. PD-L1 expression is of no benefit after PD-1/L1 blockade; selective pressure is flipped. The cancer has an incentive to lose INF-γ sensitivity, avoid apoptosis, enhanced antigen presentation. Acquired Resistance JAKs Melanoma cell Growth inh/apoptosis PD-L1 APM Adapted from Zaretsky et al. NEJM 2016

24 Log2 RNA Counts 24 hours Post-Interferon gamma Loss of IFN-g transcriptional induction with JAK2 LoF Baseline cell line (M420) Case #2 ICAM1 ITK PD-L1 IRF8 CXCL 9/10/11 Tbx21 IDO1 IL6 IRF1 A2M STAT1/3 TAP1 CSF1 CCL2 Acquired resistance cell line (M464) Log2 RNA Counts Pre-Interferon gamma Angel Garcia-Diaz, PhD Zaretsky et al. NEJM 2016, 375,

25 Conclusions Inhibiting adaptive immune resistance is the mechanistic basis of the antitumor activity of PD-1 blockade therapies Combination therapies aimed at increasing T cell infiltration in tumors may improve the antitumor activity of PD-1 blockade Loss of function mutations in IFN-gamma receptor signaling or antigen presenting machinery mediate some cases of primary resistance and acquired resistance to PD-1 blockade therapy

26 R35 CA (Ribas) P01 CA (Ribas) P01 CA (Baltimore) P50 CA (Herschman) U54 CA (Heath) R01 CA (Heath-Ribas) Ressler Family Fund The Robert Vigen Memorial Fund Garcia-Corsini Family Fund Alexandra Cooper Memorial Fund Wesley Coyle Memorial Fund Louise Belley and Richard Schnarr Fund Bila Alon Hacker Memorial Fund Fred L. Hartley Family Foundation Ruby Family Foundation Al and Betsy Stronberg Samuels Family Fund Grimaldi Family Fund SU2C-CRI-AACR-DT1012 (Alison-Ribas)

27 Acknowledgments Roger S. Lo, MD, PhD Jesse Zaretsky Herlena Escuin-Ordinas, PhD Willy Hugo, PhD Paul C. Tumeh, MD Tom G. Graeber, PhD Ton Schumacher, PhD Siwen Hu-Lieskovan, MD, PhD Angel Garcia Diaz, PhD Daniel Shin, MD