NAM Annual Meeting: Cancer, can we beat the oddsPanel 2, Monday October 15, 2018

Resistance to Cancer 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

Disclosures of Relevant Relations with Industry:Consultant – Honoraria: Amgen, BMS, Chugai, Genentech, Merck, Novartis, Roche

Scientific Advisory Board – Stock: Advaxis, Arcus, Bioncotech, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Kite-Gilead, Merus, Rgenix

Co-founder – Stock: Lutris, PACT Pharma, Tango Therapeutics

Cancer immunotherapy: When the CD8 T cell is the drug

Baseline

Baseline

Day +180

Day + 90

Pre-CD8+ T-cell infiltrate

Post-CD8+ T-cell infiltrate

Cases from:Bartosz Chmielowski, MD, PhD, UCLAWen-Jen Hwu, MD, MD Anderson Cancer Center

Hamid et al. NEJM 2013Eroglu et al. Nature 2018

IHC Analysis of CD8+ T-cells in samples obtained before and during anti-PD1 treatment Tumeh et al. Nature 2014

PD1/PDL1

PD1/PDL1

Melanoma response to PD-1 blockade is mediated by pre-existing infiltrates of CD8s inhibited by reactively expressed PD-L1

Tumor cell

T cell

Role of the Interferon-gamma Receptor Signaling Pathway and Antigen Presentation/B2M

B2MMHC class I

TCR-α TCR-βIFN-γ

P P

IFNGR2

JAK2JAK1

PD-L1

PD-1

GASP

P

Anti-Proliferative Pro-Apoptotic Genes

TAP 1/2 LAMP PSMB 8,9,10

CXCL 9,10,11

MHC

ICAM-1

IFNGR1

STAT1STAT1

PD-L1IRF1

Graphics by Khriszha Quema-Yee

Tumor cell

T cell

Role of the Interferon-gamma Receptor Signaling Pathway and Antigen Presentation/B2M

B2M

TCR-α TCR-βIFN-γ

P P

IFNGR2

JAK2JAK1

PD-L1

PD-1

GASP

P

Anti-Proliferative Pro-Apoptotic Genes

TAP 1/2 LAMP PSMB 8,9,10

CXCL 9,10,11

MHC

ICAM-1

IFNGR1

STAT1STAT1

PD-L1IRF1

MHC class I

Timeline of clinical development of approved immune checkpoint inhibitors

Ribas and Wolchok, Science 2018Anti-PD-1/L1: 6 agents approved in 11 cancer indications in 4 years

Tumor cell

T cell

Role of the Interferon-gamma Receptor Signaling Pathway and Antigen Presentation/B2M

B2M

TCR-α TCR-βIFN-γ

P P

IFNGR2

JAK2JAK1

PD-L1

PD-1

GASP

P

Anti-Proliferative Pro-Apoptotic Genes

TAP 1/2 LAMP PSMB 8,9,10

CXCL 9,10,11

MHC

ICAM-1

IFNGR1

STAT1STAT1

PD-L1IRF1

PD-1 resistance biopsy data:Zaretsky… Ribas, NEJM 2016Sade-Feldman… Hacohen, Nature Comm 2017Gettinger… Politi, Cancer Discovery 2017

MHC class I

CRISPR screen:Manguso… Haining, Nature 2017Patel… Restifo, Nature 2017Pan… Wucherpfennig, Science 2018

Tumor cell

T cell

Role of the Interferon-gamma Receptor Signaling Pathway and Antigen Presentation/B2M

B2MMHC class I

TCR-α TCR-βIFN-γ

P P

IFNGR2

JAK2JAK1

PD-1

IFNGR1

PD-1 resistance biopsy data:Zaretsky… Ribas, NEJM 2016Shin… Ribas, Cancer Discovery 2017Sucker… Paschen, Nature Comm2017

CRISPR screen:Manguso… Haining, Nature 2017Patel… Restifo, Nature 2017Pan… Wucherpfennig, Science 2018

GASP

P

Anti-Proliferative Pro-Apoptotic Genes

TAP 1/2 LAMP PSMB 8,9,10

CXCL 9,10,11

MHC

ICAM-1

STAT1STAT1

PD-L1IRF1

PD-L1

Precision cancer immunotherapy

Anti-PD-1/anti-PD-L1

Generate T cells

+ anti-CTLA4 or other checkpoints+ immune activating antibodies or cytokines+ TLR agonists or oncolytic viruses+ immune suppressor cell inhibitors+ standard cancer therapies

Bring T cells into tumors

VaccinesTCR engineered ACTCAR engineered ACT

Modified from Ribas, Cancer Discovery 2016