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DCVax® Novel Personalized Immune TherapiesFor Solid Tumor Cancers
SMi 4th Annual Cancer Vaccines ConferenceSeptember 16, 2015
DisclaimerCertain statements made in this presentation are “forward-looking statements” of NW Bio as defined by the Securities and Exchange Commission (“SEC”). All statements, other than statements of historical fact, included in this presentation that address activities, events or developments that NW Bio believes or anticipates will or may occur in the future are forward-looking statements. These statements are based on certain assumptions made based on experience, expected future developments and other factors NW Bio believes are appropriate in the circumstances. Such statements are subject to a number of assumptions, risks and uncertainties, many of which are beyond the control of NW Bio. Investors and others are cautioned that any such statements are not guarantees of future performance. These forward-looking statements could cause actual results and developments to differ materially from those expressed or implied in such statements, including our ability to raise funds for general corporate purposes and operations, including our clinical trials, the commercial feasibility and success of our technology, our ability to recruit qualified management and technical personnel, our ability to scale up the manufacturing of our product candidates for commercialization, the success of our clinical trials and our ability to obtain and maintain required regulatory approvals for our products. Furthermore, NW Bio does not intend (and is not obligated) to update publicly any forward-looking statements. The contents of this presentation should be considered in conjunction with the risk factors contained in NW Bio’s recent filings with the SEC, including its most recent Form 10K. This communication is neither an offer to sell nor a solicitation of an offer to buy any securities mentioned herein. This publication is confidential for the information of the addressee only and may not be reproduced in whole or in part; copies circulated, or disclosed to another party, without the prior written consent of Northwest Biotherapeutics (NW Bio) are strictly prohibited.
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DCVax®: A Fully Personalized Immune Therapy
Personalized Product: autologous (personalized) dendritic cells Allows repeat doses, ongoing treatment
Personalized Targets: tumor antigens from patient’s own tumor Avoids “Russian Roulette”
Broad Scope of Targets: full set of tumor antigens Not just 1 or a few pre-selected, standardized antigens Maximize obstacles to tumor escape
Excellent safety profile Some flu-like symptoms; no additional drugs, no hospital stays
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Cancer Is A Personalized Disease
• Significant variations within a single patient as disease progresses
• Extensive heterogeneity even within a single tumor
• Extensive variation among cancers
• Extensive variation among patients, even with “same” cancer
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Cancer Is A Personalized Disease
LB Alexandrov et al. Nature 000, 1-7 (2013) doi:10.1038/nature12477
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Two Key Issues With Existing Cancer Treatments
The patient’s tumor may or may not express the targets.(e.g., EGFRvIII mutation in GBM – only expressed on ~30% of GBMs)
Tumors can and do stop expressing 1 or a few targets.But tumor cells cannot stop expressing all targets.
“Russian Roulette”
Tumor escape
Current treatments are largely standardized, not personalized.This raises 2 key issues…
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“Personalized” Treatments Vary Across A Spectrum
Standardized Product Standardized Targets Personalized Profiling
Personalized Product Standardized Targets
Personalized Product Personalized Targets
Peptide vaccinesDNA vaccinesCheckpoint inhibitors
CAR-TsDC vaccines withpre-selected peptide antigens
DCVax®
Dendritic Cells Mobilize Overall Immune System
INNATE IMMUNE SYSTEM ADAPTIVE IMMUNE SYSTEM“First-responders” (within hours/days)
Response is automatic
Response is non-specific(not tailored to each particular threat)
Follow-on defense (within week or weeks)
Response is triggered by exposure to particular threat (activation + “education”)
Response is specific & creates memory(tailored to each particular threat)Natural Killer Cells, Neutrophils,
Granulocytes, Macrophages
DENDRITIC CELLSthe master
immune cells
Signals activate & biomarkers “educate”
Dendritic Cells
B Cells AntibodiesHelper T CellsKiller T Cells
CELLULAR IMMUNITYHUMORAL IMMUNITY
8Tumor Cell Death
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Dendritic Cell
resting anti-cancerT cell attaches to DC
anti-cancerT cell activated
Dendritic Cell
Large Multiplier: Each Dendritic Cell Activates Hundreds of Anti-Cancer T Cells
tumor target proteins
activated anti-cancerT cells divide rapidly
activated anti-cancerT cells travel to tumor site
DCVax Potentially Applicable to All Types of Solid Tumors(Both Operable & Inoperable)
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Market Product Composition Lead Program
All OperableSolid Tumors
DCVax®-L Dendritic cells + biomarkers from tumor tissue sample surgically removed
Brain cancer348-patient Phase III trial underway
Small ovarian cancer Phase I/II trial completed
All InoperableSolid Tumors
DCVax®-Direct
Dendritic cells injected directly into tumor(s) + biomarkers picked up onsite in tumor
All solid tumor cancers60-patient Phase I/II trial underway
OtherHormone independentprostate cancer
DCVax®-Prostate*
Dendritic cells + recombinant prostate cancer biomarker (PSMA)
Prostate cancer600-patient Phase III trial previously cleared by FDA
* The Company will seek to out-license this program
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DCVax Is Expanding the Reach of Immunotherapy
Front line treatment for newly diagnosed disease DCVax-L for newly diagnosed GBM, with SOC (Phase III)
Front line treatment for lower grade cancers DCVax-L for all grades of gliomas, with SOC (Hosp. Exemp., Germany)
Treatment for patients with very heavy tumor burdens DCVax-L for late stage, metastatic ovarian cancer DCVax-L for “rapid progressor” GBM DCVax-Direct for 4-5+ inoperable metastatic tumors DCVax-Direct for very large tumors (10 cm. lung; 15x19x17 cm. sarcoma)
Long tail of Overall Survival
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Potentially Complementary With Checkpoint Inhibitors
• Large number of “checkpoints” built into the immune system
• Response rates (%s) to single checkpoint inhibitors limited to date
• T cells must be activated, to express checkpoints
• DCVax activates T cells
• DCVax mobilizes diverseT cell populations againstdiverse tumor antigens (targets)
Source: Allison, J. (2014). Targeting Immune Checkpoints in Cancer Therapy: New Insights and Opportunities , http://www.sitcancer.org/sitc‐meetings/sitc2014/primer
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Potentially Complementary With T Cell & Targeted Therapies
T cell therapies (CAR-Ts, TCR, etc.)• Focus on a particular tumor antigen (CD-19, EGFR, etc.)• Designed to boost T cell numbers, affinity, etc. for that antigen• Durability not yet clear• Addressing diverse antigens may be more important in solid tumors
Targeted therapies• Focus on a particular cellular pathway• Alternate/redundant pathways, tumor escape are an issue
DCVax offers broad spectrum anti-tumor actionwhich can complement key “rifle shots”
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Robust Pipeline of DCVax Programs
DCVax®- Direct:
Brain cancer – Phase III under way (348 pts)
All solid tumor cancers – Phase I/II underway
Additional Phase II trial(s) -- pending
DCVax®- L:
Metastatic ovarian cancer – Phase I completed
Pre-clinical Ph I Ph II Ph III
Brain cancer – “Info Arm” outside trial (51 pts)
Brain cancer – Hospital Ex./Other Early Access
Compassionate use – diverse cancers
DCVax®- ProstateHormone indep. -- Phase I/II completed (36 pts)
DCVax-Direct: Underlying Biology
Immature DCs will effectively take up antigens (biomarkers)in situ in tumors, but will not activate T cells. Also, immatureDCs are highly susceptible to suppression by the tumor.
Mature DCs will not effectively take up antigens in situ in tumors, but will present antigens to T cells and activate them.
****************************** Partially mature, activated DCs…. at a certain stage….
will effectively take up antigens (biomarkers) in situ in tumors, and will effectively present antigens to T cells and activate them.
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DCVax-Direct: Activated DCs
CD1a: DC-specific marker involved in antigen presentation (not on all DCs, and large patient-to-patient variability)CD209: DC-specific marker involved in binding pathogens (also found on macrophages)pSTAT-1: phosphorylated STAT-1 signal transduction pathway molecule required for IL-12 productionMHC-I, II: MHC molecules involved in antigen presentationCD83: DC activation markerCD40, CD80, CD86: surface molecules involved in T cell activation
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DCVax Direct: Potential Clinical Effects
Possible Clinical Effects
Causes Seen in Pre‐ClinicalStudies?
Local effects in tumors injected withDCVax-Direct
Tumor necrosis(tumor cell death)
Secretion of cytokines (e.g., TNFα, IL-6, IL-8)by activated DCs
Systemic effects in tumors not injected
Tumor shrinkage or elimination
Immune system activation
Immune memory Lack of recurrence even when re-challenged
Immune system activation
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DCVax-Direct Phase I Trial: Overview
• 40 patients enrolled; 39 evaluable• Patients had multiple metastases; had failed other treatments• 13 different cancers treated
• 3 dose levels tested: 2M, 6M and 15M cells• Only 1 tumor injected; treatments widely spaced
• Feasibility of image-guided injections tested (multiple methods) • Both imaging and biopsies used to monitor responses, correlate
with clinical outcomes and evaluate treatment schedule
• Both local and systemic responses evaluated
• Safety and potential endpoints evaluated
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DCVax-Direct Phase I Trial -- Highlights• Half of patients still alive, at up to ~22 mos. after first injection
• Treatment effects observed in diverse cancers
• Survival correlates with dose levels• Survival correlates with number of injections
• Survival correlates with absence of progression Stable disease (SD) at Wk 8 (4th injection visit) strongly correlates with survival 21 of 35 patients achieved SD at Wk 8 (progression data n/a on 4 pts)
• Encouraging immunological responses observed post treatment• Induction of immune checkpoint expression • Both local effects (in injected tumor) and systemic effects
(in non-injected tumors) observed
0.0 5.0 10.0 15.0 20.0 25.0
Breast
Pancr
mCRC
Pancreas
mCRC
Lung
Melan
Pancr NET
mCRC
Melan
Desmo
Pancr
Sarcoma
Melan
Melan
mCRC
Sarcoma
Sarcoma
Sarcoma
Sarcoma
Sarcoma
Sarcoma
Pancreas
NET
Bladder
Ovarian
Lung NET
Lung
mCRC
Breast
Melan
Lung
Other
Melan
Pancr NET
mCRC
Sarcoma
mCRC
Pancr
Months
DCVax-Direct Phase I Trial Update: Ongoing OSAs of Sept 2015
Alive
Dead
0
2
4
6
8
10
12
14
16
2 million 6 million 15 million
Dose Level Correlates With Survival
22
7 10 4 15 1 2
Alive
Dead
As of Feb 2015
Number of Injections Correlates With Survival
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0
2
4
6
8
10
12
2 injections 3 injections 4 injections 5 injections 6 injections
AliveDead
As of Feb 2015
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Tumor Control (Stable Disease At Week 8)Correlates With Survival
0
2
4
6
8
10
12
14
16
18
20
SD week 8 PD week 8
alive
dead
p=0.002
19 25 9
As of Feb 2015
Stable Disease at Week 8 Correlates With Survival
Months
0 6 12 18 24
Prop
ortio
n Al
ive
0.0
0.2
0.4
0.6
0.8
1.0
p=0.031
As of Sept 2015
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In a multivariate analysis, TNFα production is significantly associated with survival (p=0.018)
p<0.01
TNFα Correlates With SD vs. PD At Week 8As of Feb 2015
IL-8 Production Correlates with Survival
Months
0 5 10 15 20 25
Prop
ortio
n al
ive
0.0
0.2
0.4
0.6
0.8
1.0
IL-8 >1,000
IL-8 <1,000
As of Feb 2015
Immunological Responses: Tumor Infiltrating T Cells
TILs, including both CD4+ helper T cells and CD8+ killer T cells increased from baseline in 15 of 27 assessed patients
TILs sharing sequences with peripheral T cells also increased, indicating a systemic response
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Example: clear cell sarcoma
CD8
Day 0
Day 7
CD4CD3
Immunological Responses: Intra-tumoral Responses
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CD3+ T cells Interferon gamma TNF α
Day 0
Week 8
Expression of T cell cytokines demonstrate anti-tumor activity of infiltrating T cells following DCVax-Direct administration
Induction of Immune Checkpoint Expression
• Expression of immune checkpoint molecules in tumor tissue modulates anti-tumor immune responses
• Checkpoint inhibitors (CIs) can ‘unblock’ an existing anti-tumor immune response, but may be ineffective in absence of such pre-existing response
• 14 of 22 evaluable patients (64%) in DCVax-Direct Phase I trial, showed either de novo or significantly increased expression of the PDL-1 checkpoint molecule after DCVax-Direct treatment; potential candidates for CI treatment
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Example:De novo PDL-1 staining on sarcoma tissue, 8 weeks after initiation of DCVax-Direct treatment
PD-L1 On Macrophages In Tumor Correlates With Survival
M onths
0 6 12 18 24
Pro
porti
on A
live
0 .0
0 .2
0 .4
0 .6
0 .8
1 .0 Emerging or significantly increased PD-L1 expression
No emerging or significantly increased PDL-1 expression
As of Sept 2015
Phase II Trial Plans
• Injection of multiple tumors, as well as multiple injections into larger tumors, at each visit
• More frequent injection schedule
• Indications with promising activity, as well as diverse indications– Soft tissue sarcoma
• Include Quality of Life measurements
• Trials both in US and outside US
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DCVax-L for Operable Tumors: Newly Diagnosed GBM
• 20 newly diagnosed GBM; 14 recurrent GBM; 5 lower grade gliomas
• Standard of care (surgery & 6 weeks radiation & chemo) + DCVax-L
• Primary endpoint: safety; Secondary endpoint: progression free survival
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Standard of Care* Matched Concurrent Controls**
DCVax-L
Progression (Tumor Recurrence)
6.9 mos 8.1 mos 2 years
Overall Survival 14.6 mos 17 mos 3 years
Long Tail of Survival 2 – 3% aliveat 5 years
To date: 33% alive >4 yrs27% alive >6 yrs2 pts alive >12 yrs
PHASE I/II TRIALS
**matched for age, gender, Karnofsky score, extent of surgical resection,and same std of care treatment, at same hospital, in same time period
* N Engl J Med 352: 987-96, 2005
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International Phase III Trial With DCVax-L for GBM
• 348 patient, randomized (2:1), double blind, placebo controlledPhase III trial: the “gold standard” in clinical trial design
o Primary endpoint: PFS (progression free survival)o Secondary endpoints include OS (overall survival)o 3 DCVax-L treatments upfront (Day 0, 10, 20), then 3 boosters (months 2, 4, 8)
then 4 treatments twice/year for maintenance phase (months 12, 18, 24, 30)
• Newly diagnosed GBM; trial under way in both US & Europe
• Multiple protections built into trial design 4-month extension of PFS required to meet primary endpoint
(less than 1/3 as long as extension of PFS seen in Phase I/II trials) Trial designed to reach p value = 0.02 if 4-month difference in PFS shown Trial also powered for secondary endpoint of Overall Survival Multiple sub-group analyses were prospectively included
Information Armopen label, for patients with apparent PD post chemo-radiation
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51 patients had evidence (25% increase or new lesion) of apparent disease progression in imaging at Baseline Visit following 6 weeks’ chemo‐radiation
Patients re‐imaged at Month 2 after Baseline Visitto confirm actual disease progression (another 25% increase or new lesion)
(patients categorized by independent medical imaging company)
20 patients had further progression (another 25% increase or new lesion) at Month 2: Rapid‐Progressors
25 patients had stabledisease, or modest (<25%) progression or some (<25%) regression at Month 2 Indeterminate
1 patient had all original 25% increase gone at Month 2: Confirmed Pseudo‐progressor
5 patientsUnclassifieddue to lack of images
0 12 24 36 48
20 Rapid-Progressor Patients: OS in Sept. vs Jan. 2015
MonthsRecurrent GBMmedian OS 8.3 – 10.8 monthsin literature
Patient alive in Jan. 2015 remains alive; OS now > 3-1/2 years Overall, median OS 15.3 months (with Std of Care, 8.3 – 10.8 months)
Alive
Dead
25 Indeterminate Patients: OS in Sept. vs Jan. 2015
0.0 12.0 24.0 36.0 48.0 60.0
Alive Jan. 2015 **
Dead Sept 2015
Dead Jan 2015
Only 1 patient died during Jan. to Sept, 2015 40% of patients (10 of 25) now have OS ≥ approx. 3 years 20% of patients now have OS ≥ 3-1/2 years Median OS is 21.5 months (vs. 14.6 months with Std of Care)
Median OS of regular GBM patients with Std of Care: ~14.6 mos
Months
Alive Sept 2015 **
** (extension periodsvary based on timingof data collection)
DCVax®-L: Cost-Effective, Rapid Batch Manufacturing
•DAY 1: Tumor tissue & blood at manufacturing facility.
•DAY 2: Precursors of dendritic cells isolated.
•DAY 2-7: Precursors differentiated into dendritic cells.
•DAY 7: Dendritic cells “educated” by exposure to biomarkers from tumor tissue.
•DAY 8: “Educated” dendritic cells harvested & frozen. Manufacturing finished. (Release tests follow)
Single manufacturing run yields 3‐5 years of doses of DCVax‐L product. Only 2 grams of tumor tissue needed for full batch.
With <2 grams of tumor tissue, a partial batch can be produced.
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