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Bernard A. Fox, PhDHarder Family Chair for Cancer ResearchMember and Chief,Laboratory of Molecular and Tumor ImmunologyEarle A. Chiles Research InstituteProvidence Cancer Center
CEO, UbiVac
Adjunct Faculty, Dept. Molec. Micro and Immunology, and Knight Cancer Institute, OHSUPortland, Oregon , USA
Cancer Vaccines and
Combination
Immunotherapy
@BernardAFoxIOM
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Bernard A. Fox, PhD
Aduro, research supportArgos, Scientific Advisory Board (SAB) Bristol-Myers Squibb, research support, SABDefiniens, research supportImmunophotonics, consulting - SABJanssen/Johnson & Johnson, research support, SABMedImmune/AstraZeneca, SAB, research support PerkinElmer, SAB, research supportPrimeVax, SAB, Peregrine, research supportUbiVac, co-founder, managing Member, SalaryVentana/Roche, SAB, Research Support Viralytics, research support
Presenter Disclosure Information
IOM
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Vaccines and Combination Immunotherapy
• to provide a high-level overview of the data.
• Identification of evidence gaps and Barriers to progress.
• pragmatic opportunities for action to advance the field of immunotherapy and improve patient care.
IOM
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Preclinical Models of Vaccines and combination immunotherapy
• Prime immunity–Prehn and Main – Unique antigen paradigm
- Has stood for 50 years
–Understanding tumor Immunogenicity
–Application of adjuvants (Dranoff)
IOM
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October 20, 1975, The Cancer Research Institute honored 15 scientists for their pioneering contributions to the field of cancer immunology
Edward J Foley, Richmond T. Prehn, and Ludwik Gross
Received awards for finding evidence that cancer cells have specific antigens that can elicit a cancer destructive response
IOM
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–Prehn and Main, J Natl Cancer Institute, 1957IOM
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Tumor Vaccines are Specific for Unique MCA-Induced Sarcoma
Each independently-derived chemically induced sarcoma expresses a unique mutation whose product serves as the dominant tumor rejection antigen.
– Prehn and Main, J Natl Cancer Institute, 1957
– Basombrio, et al., Cancer Res, 1970
Schreiber, Fundamental Immunology 5th ed.,Adapted from Basombrio, et al., Cancer Res, 1970
IOM
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Irradiated D5tumor cellsOr none 14d
Challenge w/ live D5 tumor (e3, e4 or e5)
Monitor tumor growth
Vaccination with B16BL6-D5 provides no protection from live D5 tumor.
Poorly Immunogenic
IOM
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IOM
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IOM
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Preclinical Models of Vaccines and combination immunotherapy
• What it takes to protect or “cure” mice in poorly immunogenic models
- At minimum: Role for CD4 and CD8 W/o CD4
- Potential role for B cell / Ab MOA?Role in preventing metastases?
IOM
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IOM
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IOM
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• Vaccination protects from challenge• Depletion of T cells does not affect
protection• Protection can be transferred by sera
- Ab against TRP2
Role for Antibodies
IOM
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Potential vaccine: vaccine combinations
Strategies that induce both T and B cell responses..
IOM
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Preclinical Models of Vaccines and combination immunotherapy
• Stragies to induce broad sterilizing immunity
– Why it’s important (tumor burden)
• Heterogeneity – Vogelstein
• “Triple E” Hypothesis - Schreiber
– Cancer Antigens
• NCI Prioritized - Cheever
• Her2/neu (mesothelin) – ML Disis / E Jaffee
• SLiPs and DRiPs – J Yewdell
IOM
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IOM
Cancer HeterogeneityMandates Broad Immunity
Vogelstein B, Science 339:1546, 2013
Hypothesis:
Effective treatment of metastatic cancer will require an immune response to many antigens
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Dealing with Immunoediting
In addition to heterogeneity add immunoediting.
Induce a strong immune response against an antigen and you put incredible pressure on tumor cells to escape.
R D Schreiber et al. Science 2011, IOM
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IOM
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IOM
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IOM
Prostate CR: Strong Antibody Response to HIBCH And HIBCH is Expressed in Patient’s Tumor
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IOM
Prostate CR: Strong Antibody Response to HIBCH And HIBCH is Expressed in Patient’s Tumor
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Two Protein Degradation Pathways
IOM
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Proteosome Blockade shunts DRiPS and SLiPS to Autophagy Pathway
Use as a Vaccine
IOM
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Proposed Model for AutophagosomeVaccine Cross-Presentation
• APC-Targeted vesicle• >100 antigens, 12 NCI prioritized cancer antigens • 15 DAMPs and agonists for TLR 2, 3, 4, 7 and 9.
IOM
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Autophagosome Vaccine more Therapeutic than “Gold Standard” Vaccine in 3 Day-established 3LL
Li, Y., et al., Cancer Research 66:6889, 2008
IOM
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Tumor Vaccines are Specific for Unique MCA-Induced Sarcoma
Each independently-derived chemically induced sarcoma expresses a unique mutation whose product serves as the dominant tumor rejection antigen.
– Prehn and Main, J Natl Cancer Instit, 1957
– Basombrio, et al., Cancer Res, 1970
Schreiber, Fundamental Immunology 5th ed.,Adapted from Basombrio, et al., Cancer Res, 1970
IOM
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Autophagosomes from one unique sarcomacan prime an immune responses against other
independently-derived syngeneic sarcomas
Whole Cell Vaccine Autophagosome Vaccine
Twitty C., et al., Clin Can Res., 17:6467, 2011 IOM
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Combination Immunotherapy
Vaccination + anti-OX40: Three breast tumor models to
contrast allogeneic whole cell and DRibble vaccines
25,000 viable
4T1 tumor cells
100ug OX86 (i.p.)
Day 7+9Day 5Day 0
10ug DRibble (i.n.)or
10x106 tumors (s.c.)+
100ug OX86 (i.p.)
25,000 viable
C57MG tumor cells
100ug OX86 (i.p.)
Day 9+11Day 7Day 0
25,000 viable
FAT tumor cells
100ug OX86 (i.p.)
Day 11+13Day 9Day 0
10ug DRibble (i.n.)or
10x106 tumors (s.c.)+
100ug OX86 (i.p.)
10ug DRibble (i.n.)or
10x106 tumors (s.c.)+
100ug OX86 (i.p.)
4T1 Model
C57MG Model
FAT Model
IOM
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Therapeutic immunity in three allogeneic tumor models
using DRibbles but not whole cell vaccines
Therapy
Tumor Inoculation
4T1
4T1
C57mg
C57MG
FAT
FAT
Therapy
Tumor Inoculation
4T1
4T1
C57mg
C57MG
FAT
FAT
Whole Cell Vaccine DRibble Vaccine
Mouse Strain: BALB/c C57BL/6 FVBMouse Strain: BALB/c C57BL/6 FVB5d 7d 9d 5d 7d 9dTumor Est.: Tumor Est.:
IOM
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Identification of gaps and barriers to progress.
• Limitations– No high density ProtoArrays (Ab detection)
– A mouse with cancer is not a human with cancer • Time (tumor growth and age)
• Tumor burden
• Immune selection
• Microbiome / SPF
– Different models can give very different results.• Combination immunotherapy
IOM
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Anti-OX40/PDL1 Combo in MCA205 Tumor Model(Treating Larger Tumors)
Survival proportions: Survival of survival
Days (post tumor inoculation)
Pe
rce
nt s
urv
iva
l
0 20 40 60 800
50
100 Rat IgG
OX86
aPDL1
OX86 + aPDL1
C57Bl6:MCA205
p<0.0001
B6
.5e6 MCA205 tumor cells
10-12d (tumor ~50mm2)
a-OX40
3d
a-OX40
3d
Monitor tumor growth; sacrifice mice when tumors reach 150mm2
4d
3d
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Concurrent addition of anti-PD-1 and anti-OX40 reduces antitumor effect of anti-OX40 alone.
0 20 40 600
50
100
150
Day
Tu
mo
r S
ize (
mm
2)
OX40
OX40 + PD-1
PD-1
No Treatment
OX40PD-1
DM 1
0 20 40 600
50
100
150
Day
Tu
mo
r S
ize (
mm
2)
OX40
OX40 + PD-1
PD-1
No Treatment
OX40PD-1
DM 3
0 50 100 150 2000
50
100
Day
Perc
en
t S
urv
ival
OX40 (n=12)
OX40 + PD-1 (n=12)
PD-1 (n=10)
OX40 + PD-1d (n=10)
PD-1d (n=10)
No Treatment (n=10)
*
***DM 3
0 20 40 600
50
100
150
Day
Tu
mo
r S
ize (
mm
2)
OX40 + PD-1
OX40 + PD-1d
No Treatment
OX40PD-1
PD-1d
****
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Identification of gaps and barriers to progress.
• Pilot human studies: Combination Immunotherapy
– Small numbers of patients
– Well Studied for MOA
– Intratumoral?
IOM