Was the Renaissance just an Artistic Revolution? Did the Renaissance lead to other revolutions?
The renaissance of immunotherapy is a revolution
Transcript of The renaissance of immunotherapy is a revolution
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
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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
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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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Primary Tumor Challenge (EMT6)
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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
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!!!!!!!!!!!!!!!!!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
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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
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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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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
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Immunization
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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
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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