The renaissance of immunotherapy is a revolution for cancer patients

Ira Mellman, Ph.D. Vice President, Cancer Immunology, Genentech

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The renaissance of immunotherapy is a revolution for cancer patients

Early data suggests that anti-PD-L1/PD-1 is active across a wide range of tumor types

•  Melanoma: FDA approval •  NSCLC (squamous): FDA approval, 2nd line •  Renal cell carcinoma •  Breast cancer (e.g. TNBC) •  Metastatic bladder cancer •  Head & neck cancer •  Hodgkin's lymphoma

Response rates are modest, at ~10-30%

Broad activity but most patients do not benefit from single agent therapy

Using patient data to understand cancer immunity cycle

MPDL3280A Phase 1 Data: Urothelial Bladder Cancer Patients Progressive Disease (PD)

Why do many patients not respond? •  No pre-existing immunity?

Stable disease (SD) What combinations will promote PRs & CRs? •  Insufficient T cell immunity? •  Multiple negative regulators?

Monotherapy durable responses (PR/CR) What are the drivers of single agent response? How can PRs be enhanced to CRs? •  Insufficient T cell immunity? •  Multiple negative regulators?

Chen & Mellman (2013) Immunity

The cancer immunity cycle Immunosuppression as the rate limiting step to effective anti-tumor immunity

α-CTLA4 (ipilumumab)

Immuno- suppression

α-PD-L1/PD-1 (multiple)

Chen & Mellman (2013) Immunity

Combinations of immunotherapeutics Increasing response rates by keeping cancer immunity cycle turning

α-PDL1*/PD1 α-LAG-3 α-TIGIT* α-KIR

α-CTLA4* α-OX40* α-CD27* α-CD137 α-GITR

vaccines* α-CD40*

α-VEGF-A*

* = Genentech/Roche programs

α-OX40* (Treg) α-CTLA4* (Treg) α-CSF1R* IDO inhibitor*

IFNγ-­‐mediated  up-­‐regulation  of  tumor  PD-­‐L1  

Shp-2

Adaptive expression of PD-L1

MAPK"PI3K

pathways"

IFNγ-­‐mediated  up-­‐regulation  of  

tumor  IDO  

Inhibition  of  effector  T  cell  

function  

Shp-2

MAPK"PI3K

pathways"

Adaptive expression of IDO

IDO  

Georgia Hatzivassiliou, Yichin Liu

IDO (indoleamine di-oxygenase) Another suppressor of effector T cells

IDO mediates T cell suppression by reducing extracellular tryptophan and increasing kynurenine

mTOR

Promote translation

high

Enhance T reg

arylhydrocarbon receptor

FoxP3

Kynurenine

IDO*

Tumor cells

IFNg activates IDO expression

Suppress T effectors

ñ Uncharged Tryptophanol-tRNA

GCN2 kinase

Stress response

low

suppressive cytokines

Dendritic cells Macrophages

*TDO (tryptophan dioxygenase) is a second related target to IDO

Free tryptophan

Early combination data shows promising efficacy Phase I/II study of INCB024360 plus ipilimumab in melanoma

Best

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Gibney et al. ASCO 2014

TIGIT Model of TIGIT regulation of T cell responses

•  Human and murine tumor-infiltrating CD8+ T cells express high levels of TIGIT

•  Antibody coblockade of TIGIT and PDL1 elicits tumor rejection in preclinical models

•  TIGIT selectively limits the effector function of chronically stimulated CD8+ T cells

•  TIGIT interacts with CD226 in cis and disrupts CD226 homodimerization

Tumor cell or DC

PVR

ITIM

Competes  with  CD226  for  PVR  

100nm 1nm

TIGIT CD226

ITIM ITAM

Disrupts  CD226  ac7va7on   Directly  inhibits  T  cell  in  cis  

1

2 3

T cell

TIGIT TIGIT and PD-L1 combination effective in PD-L1 non-responsive model

Tumor cell or DC

PVR

ITIM

Competes  with  CD226  for  PVR  

100nm 1nm

TIGIT CD226

ITIM ITAM

Disrupts  CD226  ac7va7on   Directly  inhibits  T  cell  in  cis  

1

2 3

T cell

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anti-PD-L1 �+ NME1�

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Control Anti-PD-L1

OX40 function and potential in oncology Promote antigen dependent effector T cell activation and T regulatory cell inhibition

Adapted from Nature Rev Immunol. 4:420 (2004).

Effector T cell

TCR

Antigen Presenting Cell

OX40

OX40L

IFN-γ

OX40 engagement on Treg cells

Treg

OX40L

OX40L

OX40

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(mm

3 ) ControlAnti-mouse OX40

Treatment

Primary Tumor Challenge (EMT6)

day

Chen & Mellman (2013) Immunity Jul 25;39(1):1-10

anti-OX40

anti-PDL1 CD8 T cell

receptor

HLA

PD-1

PD-L1

Tumor cell

T cell

IFNγ

PD-L1 increase

Increase in Teff cells by anti-OX40 may create need to combine with anti-PDL1

IFN-γ"

OX40L

OX40

Anti-OX40 combined with anti-PDL1 in the MC38 model

Tumor

Myeloi

d

Granu

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CD4+T

CD8+T

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Exp

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control*

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anti%OX40*+*anti%PD%L1*

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2500

day

Tum

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e (m

m3 ) !!!!!!!!!!!!!!!!!!!!!!!anti&OX40!

!!!!!!!!!!!!!!!!!control!

Jeong Kim et al. AACR 2015

Chen & Mellman (2013) Immunity

Combination with Avastin Increasing response rates by keeping cancer immunity cycle turning

α-VEGF-A

Increases in CD8+ T cell infiltration and vasculature changes with treatments in RCC

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Pretreatment Post Avastin Post Avastin + aPD-L1

CD8 (T cells)

CD31 (vasculature)

Sznol et al. ASCO GU 2015

Anti-PDL1 in combination with Avastin

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Anti-VEGF combination: preclinical data

a-VEGF

a-PD-L1

a-PD-L1 + a-VEGF

Control

Cloudman melanoma

Combination of anti-PDL1 and Avastin (Ph1 data in renal cancer)

Sznol et al. ASCO GU 2015

Chen & Mellman (2013) Immunity

Combinations with chemotherapy Induced inflammation & antigen release may enhance anti-PDL1 efficacy

Chemotherapy

20-30% patients •  T cells present in tumor •  Chemokines present

(attract leukocytes)

70-80% patients •  Lack lymphocytic infiltrates

Non-responsive to single agent immunotherapies

Tumor phenotype by T cell staining

Inflamed Non-inflamed

Responsive to single agent immunotherapies

Can we convert these to responsive?

Can responses be improved?

Inflammation is necessary for response

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Combinations with chemotherapy extend the benefit of anti-PDL1

•  Platinum chemo increases number of CD8+ cells in animal models

•  Compelling chemo+PD-L1 combination efficacy observed in phase 1 studies

•  Broad phase 3 combination program initiated in 1L NSCLC and TNBC

oxaliplatin

Dosing

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α-PDL1

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Control

Pre-clinical data

Phase 1 chemo combination data to be presented at ASCO 2015

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Recognition of cancer cells by T cells (CTLs, cancer cells)

ImmTACs Bispecifics

Not all patients may have pre-existing immunity: monitoring & promoting T cell responses ImmTACs and bispecific antibodies

Immune-mobilizing mTCR Against Cancer*

*In colalboaration with Immunocore

T-cell Dependent Bispecific

TCR

Tumor antigen

Cancer cell

T cell Knob into holes full-length IgG

Targeting intracellular tumor markers Targeting extracellular tumor markers

Recruiting T cells to cancer cells ImmTACs and bispecific antibodies

Chen & Mellman (2013) Immunity

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Cancer antigen presentation

(dendritic cells/APCs) Vaccines: •  Endogenous •  Exogenous

Not all patients may have pre-existing immunity: monitoring & promoting T cell responses Vaccines

Anti-PDL1 Phase Ia: indication response rates correlate with mutation frequency

Schumacher and Schreiber (2015) Science

Structural analysis suggests that only some mutations will be accessible to T cell receptors

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A

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REPS1! AQLPNDVVL!

ADPGK! ASMTNRELM!

FLU-NP! ASNENMETM!

Copine-1! SSPDSLHYL!

H60! SSVIGVWYL!

PàA RàM DàY

Immunogenic solvent-exposed mutation

Non-immunogenic mutation in MHC groove

Yadav et al (2014) Nature

Promise for a PHC vaccine? Immunization with antigenic peptides regresses growth of established MC38 tumors

Dose Groups● 01 − untreated control

02 − d1: anti−CD40 50µg + pIC 100µg, IP injection. d10: anti−CD40 50µg + pIC 100µg, IP injection. (n=10)03 − d1: anti−CD40 50µg + pIC 100µg + 3Xpeptide mix 100µg, IP injection. d10: 3Xpeptide mix anti−CD40 50µg + pIC 100µg, IP injection. (n=10)

Control

Adj

Adj+ Peptides

Immunization

14−0584: mutated MHCI MC38 peptide vaccine; MC−38 Raw and LME Fit Tumor Volume

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Control Adj

Adj+peptides

14-0584: mutated MHCI MC38 peptide vaccine; MC-38 Overlay Fits Tumor Volume

14-0584: mutated MHCI MC38 peptide vaccine; MC-38 Raw and LME Fit Tumor Volume

Yadav et al (2014) Nature

Strategic vision: lead by developing best in class combination therapies

Combinations with immunotherapies aCD40 ✔ Vaccines, Oncolytic Viruses ✔ ✔ aCTLA-4 ✔ aOX40 ✔ aCD27 ✔ aCEA-IL2v ✔ T Cell Bispecifics ✔ ImmTACs Planned IDOi ✔✔ aCSF1R ✔ aTIGIT Planned Cytokines, anti-cytokines ✔ Combinations with other agents aVEGF ✔ aCD38 ✔ FGFR1 ✔ EGFRi ✔ ✔ ALKi Planned BRAFi ✔ MEKi ✔ BTKi ✔ aCD20 ✔ aHER2 ✔ Chemo ✔ ✔ HDAC ✔ A2V ✔

Internal combo ✔ ✔

Partnered external combo

Chen & Mellman (2013) Immunity

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Priming & activation anti-CEA-IL2v anti-OX40 anti-CTLA4 anti-CD27* anti cytokine CD38*

Antigen presentation anti-CD40 IMA942 vaccine* oncolytic viruses*

Antigen release EGFRi ALKi BRAFi MEKi Chemo FGFR1* BTKi HDAC

T cell infiltration aVEGF

Cancer T cell recognition anti-HER2-CD3 anti-CD20-CD3 ImmTAC*

T cell killing anti-OX40 anti-CSF-1R anti-CEA-IL2v IDO inhibitor* TIGIT IDO1/TDO inhibitor*

T cell trafficking

Clinical development Preclinical development

* Partnered projects

Immuno- suppression

Doing now what patients need next