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 Program

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 Program

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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Manufacturing Established At Logistics Hubs In US & Europe

• Memphis, TN: worldwide hubfor both FedEx & UPS

• 80,000 sq ft facility; capacity for up to 5,000 DCVax patients/year

• Leipzig, Germany: Europe-wide hubfor DHL, Lufthansa Cargo, others