DCVax®-L020221 Phase 3 Clinical Trial

Dendritic Cell Therapy for Brain CancerWhere Are We, and How Did We Get Here?

Marnix L. Bosch, MBA, PhDChief Technical Officer

Northwest Biotherapeutics

1. Fully personalized• Addresses complexity and heterogeneity

2. Uses ALL tumor antigens• Minimizes tumor escape

3. Uses the Master Cell of the immune system• Dendritic cells direct the immune response

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Key Characteristics of DCVax-L

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Large Multiplier: Each Dendritic Cell Activates Hundreds of Anti-Cancer T Cells

tumor target proteins

Dendritic Cell

resting anti-cancerT cell attaches to DC

anti-cancerT cell activated

Dendritic Cell

activated anti-cancerT cells divide rapidly

activated anti-cancerT cells travel to tumor site

First Clinical Trial

Autologous dendritic cells were pulsed with acid-eluted peptides from cultured autologous GBM cells to stimulate a class I – restricted CTL response

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Survival data from this trial are highly encouraging

Linda Liau et al., Clin. Cancer Res. 11: 5552. 2005

Process Optimization• Initial assessment identified GBM as an interesting target but

raised questions about scale-up of acid elution of cultured GBM cells– Culture of autologous GBM cells often requires months of culture time to

obtain sufficient numbers of cells– Acid-elution process proved difficult to standardize– Acid-elution resulted in cell death and release of a range of molecular

species, varying in mass from small peptides to large macromolecules, with no identifiable peak at 9 amino acids

• Use of tumor cell lysates developed as an alternative– Avoids need for long-term culture as lysate can be generated directly

from surgically resected tissue– Range of molecular species is similar to acid-eluted material

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Second Clinical Trial

• This trial used autologous DCs pulsed with autologous tumor cell lysate

• Overall survival data from this trial were similar to the first trial

• The survival benefit appears greatest in patients with mesenchymal subtype

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Robert Prins et al., Clin. Cancer Res. 17: 1603. 2011

T cell Infiltration in GBM Post Vaccination

7L. Liau et al.

Infiltration of T cells in the tumor is observed in patients treated with DCVax-L

Both CD4 and CD8 cells are seen

Phase III Trial• The trial was conducted at >80 sites in 4 countries:

– USA, Canada, UK, Germany

• Patients with possible GBM are consented prior to surgery– GBM confirmed through independent review

• Surgical tissue is used to generate tumor cell lysate• Leukapheresis to collect monocytes is conducted after recovery

from surgery, and before chemoradiation• Patients are randomized 2:1 after chemoradiation• Crossover option allows for DCVax-L treatment post progression,

without revealing original treatment assignment

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Crossover option(Every eligible patient will get the treatment)

• Patients with documented progression are allowed to receive DCVax-L – NWBio, the investigators and patients are kept blinded

• Patients originally assigned to placebo are eligible to ‘cross over’ to DCVax-L treatment

• Patients originally assigned to DCVax-L are allowed to continue immunizations, if sufficient material is still available

• Immunization schedule for all crossover patients is restarted, and the blind is maintained– Day 0, 10, 20, months 2, 4, 8, 12, 18, etc.

• As a result of the Crossover Option, almost 90% of patients have received DCVax-L at some point: ~67% received it at randomization, and the rest received DCVax-L after documented disease progression

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DCVax-L Phase III Trial in Glioblastoma MultiformeScreening Timeline

Screening based on symptoms and MRI

week 0 4 8 12

leukapheresisRadiation + temozolomide

Randomization and enrollment

Tumor lysate preparation

DCVax-L manufacturingand release

DCVax-Lfirst dose

Main Reasons for Screen Failure:- Not GBM- Tumor too small- Leukapheresis failure- Progressive disease

Recruitment, Inclusion, and Randomization of Patients

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1) Patients are screened prior to surgery, so glioblastoma (GBM) determination is made from pathological diagnosis after surgery.

2) Insufficient tumor lysate generated to meet threshold.3) Progressive disease or pseudoprogression (which are

indistinguishable at this point) based on central review of MRI imaging at baseline post-chemoradiation.

4) Patients who consented to tumor donation but then declined participation in trial prior to leukapheresis.

5) Includes deviations from standard chemoradiation protocol, history of prior malignancy, inadequate renal or bone marrow function, etc.

6) Includes drug product failure or insufficient drug or placebo manufactured to meet release criteria.

7) Includes clinical deterioration, declining Karnofsky performance status, or patient deaths.

8) Includes biopsy only, surgery canceled, or tumor tissue not processed after surgery

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month 0 12 24 36DCVax-L doses

Randomization & Enrollment

DCVax-L Phase 3 GBM Trial: Treatment Timeline

InductionPhase

(Day 0, 10, 20)

BoosterPhase

(Month 2, 4 8)

MaintenancePhase

(Every 6 mos.)

TMZ (approx.)

Crossover at time of recurrence

DCVax®-L for Newly Diagnosed Glioblastoma Multiforme (GBM)Status report on Phase III Trial

Liau et al. 2017

First Interim Blinded Data

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DCVax-L administration• DCVax-L is shipped frozen to the hospital pharmacy

– each dose is drop-shipped to arrive 2-3 days prior to appointment

• Two vials are thawed at the pharmacy just prior to

administration

• DCVax-L is drawn up into syringes at the pharmacy

• Filled syringes are picked up by the nurse coordinator or

designee and taken to the treatment room

• DCVax-L is administered intradermally in the upper arm

(alternating by visit), in an outpatient setting

• Administration of DCVax-L must be as soon as possible,

not exceeding 1 hour post thawing

• Patients are observed for 2 hours following

administration and typically continue with their day

thereafter

Safety Overview in ITT Population

no SAE

Unrelated SAE

Possibly Related SAE

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Patient Demographics

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Patient demographics are comparable to other GBM trials, especially with regard to known prognostic factors.• 75% are over 50• more unmethylated than

methylated MGMT

The trial excluded early progressors and pseudoprogressors, similar to other large, published, recent GBM trials*

*Stupp et al. 2015, 2017; Weller et al. 2017.

Background Survival Data

Historical Data (Temodar + Radiation)

• Stupp et al. 2005: median* overall survival (mOS) = 14.6 months• Hegi et al. 2005: mOS in MGMT-methylated** patients = 17.0 months

Recent Clinical Trials (Temodar + Radiation groups)These trials have similar inclusion criteria to the DCVax-L trial

• Weller et al. 2017: mOS = 17.4 months from randomization***• Stupp et al. 2017: mOS = 16.0 months from randomization***

• Methylated MGMT: mOS = 21.2 months (from randomization***)• Unmethylated MGMT: mOS = 14.7 months (from randomization***)

*median means half lived longer, and half lived shorter** patients with a methylated MGMT gene promoter derive greater benefit from temozolomide chemotherapy***randomization in these trials took place 3 – 4 months post surgery

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Survival of Whole ITT Population From Surgery(interim data: 2017 vs. 2018)

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Population n Median OSsince surgery

Survival at1 year

Survival at2 years

Survival at3 years

2017 data 331 23.1 months 89.3% 46.2% 25.4%

2018 data 331 23.1 months 89.3% 46.4% 28.2%

Prognostic Factors in ITT Population of DCVax®-L Trial Comparable to Other Key Trials

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Months Stupp 20091

CelldexControls2

(Weller 2017)

CelldexTreated2

(Weller 2017)

OptuneControls2

(Stupp 2017)

OptuneTreated2

(Stupp 2017)

DCVax-L1

(updated 2018)

Age (median) 33% <50 58 59 57 56 56

mMGMT 44% 35% 33% 42% 42% 40%

Performance WHO 0,1: 86%WHO 2: 13%

ECOG 0,1: 95%ECOG 2: 6%

ECOG 0,1: 96%ECOG 5: 5%

KPS ≥90: 65%KPS <90: 32%

KPS ≥90: 66%KPS <90: 33%

KPS ≥90: 71%KPS <90: 29%

Complete resection 39% 56% MRD 53% MRD 54%

(13% biopsy)53%

(13% biopsy)63%*

* ~4 months difference in mOSwith full vs partial resection

Survival From Surgery by MGMT Methylation Status(interim data: 2017 vs. 2018)

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Data set n Median OSsince surgery

Survival at1 year

Survival at2 years

Survival at3 years

2017 methylated 131 34.7 months 94.5% 66.7% 46.4%2018 methylated 131 35.1 months 94.6% 66.6% 49.1%2017 unmethylated 162 19.8 months 86.4% 32.1% 11.0%2018 unmethylated 162 19.8 months 86.4% 32.6% 14.3%

Survival from Surgery: Impact of Prognostic Factorsin Blinded Interim Data (2017)

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Performance StatusAge

Lymphocyte CountSurgery

MGMT Status and DCVax-L

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The difference in mOS between MGMT unmethylated and methylated patients is typically around 7 months (e.g. Stupp et al. 2017: 14.7 vs. 21.7 months in the control population)

Ø In this trial, the difference is approximately 15 monthsØ This increase in the delta cannot be attributed to known prognostic factors or to patient selection

Unmethylated Methylated

Age <50 24.1% 19.8%

KPS >90 71.0% 70.2%

ALC >800 46.9% 50.4%

Complete resection 63.0% 63.4%

A DCVax-L treatment effect that differentially affects these two populations would explain this increased difference in survival between the two populations

Survival From Surgery of Top 100 Patients(interim data: 2017 vs. 2018)

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n KM- derived mOS 95% CITop 30% (2017) 100 40.4 mos 35.5-46.5Top 30% (2018) 100 58.4 mos 45.9-94.5

Extended survival not fully explained by known prognostic factors

Top 100% Patients: Demographics

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Prognostic Factor Top 100 ITTAge <50 + methylated MGMT + Complete resection 8% 6%

Median age and range 56 (21, 70) 55 (19, 73)

Age >65 years 16% 17%

Age <50 years 28% 25%

KPS median (range) 90 (50, 100) 90 (40, 100)

KPS ≥80 95% 82%

Methylated MGMT 66% 39%

Complete resection (CR) 75% 63%

ALC ≥800 70% 60%

Long-Term Survivors

The top 100 patients (those with the longest survival times) were assessed for known prognostic factorsØ An average eligible patient has a 30% chance to fall into this groupØ Median KM-derived overall survival for this group is 58.4 months

What is the makeup of this group in terms of known positive prognostic factors?• 29% are ≤50 years of age (vs. 24.7% in the ITT population)• 65.9% have a methylated MGMT promoter (vs. 39.6% in the ITT population)• 71% had a complete resection (vs. 63.1% in the ITT population)• Only 8% had all 3 positive factors

Question: What other possible factors can explain the longevity of this group?• Other, unknown prognostic factor(s)• DCVax-L treatment• A combination of the above

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Survival Findings: Key Points

• Overall survival in the ITT population is longer than observed in historical and contemporary controls

• This extended survival is observed both in patients with favorable prognostic factors and in patients with unfavorable prognostic factors– Age ≥50 years and Age <50– Karnofsky performance status ≥90 and <90– Complete resection and incomplete resection– Lymphocyte count high and lymphocyte count low– MGMT methylated and MGMT unmethylated

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Take Home Messages/Conclusions

• DCVax-L is very well tolerated in patients with newly diagnosed GBM

• Blinded, interim data from the study population, in which ~90% of patients received the vaccine, either early or upon disease progression, suggest a possible survival benefit

• This potential survival benefit is observed in patients with both favorable and unfavorable prognostic factors

• Temozolomide chemotherapy and DCVax-L immunotherapy may cooperate

• A DCVax-L treatment effect may be responsible for some of the observed survival outcomes

• Long-term survival outcomes in the longest survivors cannot be fully explained by known prognostic factors

• ‘Life expectancy’ for patients in the trial increases substantially past a certain threshold of being in the trial

• The overall data suggest that DCVax-L immunization sets up a battle between the immune system and the tumor, and the immune system may win that battle in some/many cases

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(Near) Future Plans in Brain Cancer

• Unblinding and analyzing the Phase III data

• Combination trials of DCVax®-L with checkpoint inhibitor molecules

• Intratumoral injection of DCVax®-Direct (a related product) in brain metastases

• Intratumoral injection of DCVax®-Direct in diffuse intrinsic pontine glioma (DIPG)

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Acknowledgements (1)

• Patients and families• Investigators: Linda M. Liau, MD, PhD; Robert M. Prins, PhD; Jian Li Campain, MD, PhD;

John Trusheim, MD; Charles Cobbs, MD; Keyoumars Ashkan, MD; Lucy Brazil MD; Jason Heth, MD; Sarah Taylor, MD; Stacy D’Andre, MD; Fabio M. Iwamoto, MD; Yaron Moshel, MD, PhD; Kevin A. Walter, MD; Clement Pillainayagam, MD; Edward J. Dropcho, MD; RekhaChaudhary, MD; Samuel Goldlust, MD; Michael Gruber, MD; Tobias Walbert, MD; Paul Duic, MD; Jay Grewal, MD; Daniela Bota, MD, PhD; Kevin O. Lillehei, MD; Heinrich Elinzano, MD; Steven R. Abram, MD; Andrew Brenner, MD; Jana Portnow, MD; Simon Khagi, MD; Steven Brem, MD; Reid C. Thompson, MD; William G. Loudon, MD; Lyndon J. Kim, MD; Andrew E. Sloan, MD; Karen L. Fink, MD, PhD; David E. Avigan, MD; Julian K. Wu, MD; Scott M. Lindhorst, MD; Gabriele Schackert, MD; Jose Lutzky, MD; Hans-Jorg Meisel, MD, PhD; Minou Nadji-Ohl, MD; Arnold B. Etame, MD, PhD; Raphael Davis, MD; Christopher Duma, MD; David Piccioni, MD, PhD; David Mathieu, MD; Erin Dunbar, MD; Timothy J. Pluard, MD; Michel Lacroix, MD; David S. Baskin, MD; Victor C. Tse, MD; Sven-Axel May, MD; John Lee Villano, MD, PhD; James D. Battiste, MD, PhD; Michael Pearlman, MD, PhD; Paul Mulholland, MD; Michael Schulder, MD; Manfred Westphal, MD, PhD; Timothy F. Cloughesy, MD;

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Acknowledgments (2)

Northwest BiotherapeuticsMeghan SwardstromLinda PowersAlton BoyntonAnthony Maida

Cognate BioservicesMike StellaLori NoffsingerKyle Hendricks

NWBio Scientific Advisory BoardPhase III Steering Committee

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UCLALinda LiauRobert Prins

Biostats Solutions, Inc.Ena BromleyLaura GillisLin Li

SynteractCheryl JohnsonTed Preston

Fraunhofer IZIGerno Schmiedeknecht