DCVax®-Direct
A Novel Dendritic Cell Therapy
For Inoperable Solid Tumors
ASCO Industry Expert Showcase
May 30, 2015
Marnix L. Bosch, MBA, PhD
Chief Technical Officer
Northwest Biotherapeutics
Disclaimer
Certain 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 10-K. 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.
2
DCVax®-Direct
• Partially activated autologous (personalized) dendritic cells for
tumoral injection in any type of inoperable solid tumors ≥1 cm.
intra-
• Administered with any form of image guidance, can reach any tissue
• Dendritic cell precursors (monocytes) obtained through leukapheresis,
differentiated and partially activated ex vivo
• 7-day manufacturing process using a highly controlled, cost-effective,
proprietary manufacturing system
• Single manufacturing run for patient’s whole course of treatment. Frozen in
single doses until needed. Off-the-shelf for that patient.
3
DCVax®-Direct Phase I Trial
• 40 patients enrolled; 39 patients evaluable
• Late stage patients with multiple inoperable tumors (average of 3)
• Patients had failed other treatments; had poor prognosis
• Conservative treatment regimen:
 Only 1 tumor injected
 Treatments widely spaced (1-1/2 to 2 months apart, after first 2 weeks)
4
DCVax-Direct Phase I Trial: Factors Evaluated
• A dozen different cancers treated
• 3 dose levels tested: 2M, 6M and 15M cells
• 2 different activation methods for dendritic cells tested
• Feasibility of image-guided injections tested
• multiple imaging methods
• Both imaging and biopsies used to monitor responses, correlate
with clinical outcomes and evaluate treatment schedule
• Both local and systemic responses evaluated
• Potential endpoints evaluated, including tumor responses (“bulge”)
• Safety evaluated
5
DCVax-Direct Phase I Trial -- Highlights
• 27 of 39 patients still alive, at up to ~18 mos. after first injection
• Treatment effects observed in diverse cancers
• Survival & Stable Disease correlate with DC activation regimen used
• 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
6
Survival to Date from First Injection
Pancreas
mCRC
Sarcoma
Sarcoma
mCRC
Lung
Sarcoma
mCRC
Pancreas NET
Breast
Other
Melanoma
Melanoma
Melanoma
mCRC
Lung
Ovarian
Sarcoma
Sarcoma
NET
Lung NET
Pancreas
mCRC
Sarcoma
Sarcoma
Sarcoma
Bladder
Melanoma
Pancreas
Desmo
Melanoma
Melanoma
Pancreas
mCRC
Lung
mCRC
Pancreas
Pancreas
Breast
0.0
Alive
Dead/Method A
Dead/Method B
2.0
4.0
6.0
8.0
10.0
Months
12.0
14.0
16.0
18.0
20.0
Survival By Dose Level
16
14
Dead
12
Alive
10
8
6
4
2
7
10
4
15
1
2
0
2 million
6 million
15 million
8
Survival by Number of Injections
12
10
8
Alive
6
Dead
4
2
0
2 injections
3 injections
4 injections
5 injections
6 injections
9
Survival By DC Activation Regimen
p=0.035
18
16
14
12
10
8
6
4
2
9
9
3
18
0
Method A
Method B
The DC activation regimen influences survival
10
Tumor Control and Survival
• Stable disease (SD): <25% increase in sum of longest diameters of tumor
• Initial tumor control evidenced by SD at Week 8 after first injection
• 21 of 35 patients achieved SD by Wk 8 (progression data n/a for 4 patients)
Patients treated with DC activation
Method B are more likely to have SD at Wk 8
SD at week 8 is significantly
correlated with survival
p<0.001
p=0.002
20
18
16
14
12
10
8
6
4
2
0
16
14
12
SD week 8
10
PD week 8
alive
8
dead
6
4
19
2
5
9
2
4
12
16
3
0
SD week 8
PD week 8
Method A
Method B
11
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
Day 0
Example:
clear cell
sarcoma
CD3
CD4
CD8
Day 7
TILs sharing sequences with peripheral T cells also increased, indicating a
systemic response
12
Immunological Responses: Intra-tumoral Responses
Day 0
CD3+ T cells
Interferon gamma
Tumor necrosis factor
α
Week 8
Expression of T cell cytokines demonstrate anti-tumor activity of
infiltrating T cells following DCVax-Direct administration
13
Induction of Immune Checkpoint Expression
• Expression of immune checkpoint molecules in tumor tissue modulates antitumor 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
Example:
De novo PDL-1 staining on
sarcoma tissue, 8 weeks after
initiation of DCVax-Direct
treatment
14
Scientific Background: Dendritic Cells and Cancer
• Dendritic cells (DC) are professional antigen-presenting cells
which are required for inducing any adaptive immune response
• In cancer subjects, factors produced by the tumor block
functional maturation of DC
• The tumor microenvironment is highly immuno-suppressive,
and hampers induction of de novo immune responses as well as
the function of effector cells
• Thus, to generate an effective immune response in cancer
subjects, DC must be generated ex vivo and the tumor
microenvironment must be modified
15
Scientific Background: DC Maturation
• Immature DC take up and process antigen
• Mature DC present antigen and activate the immune system,
mainly through interaction with T cells
• DC maturation (the transition from immature to mature DC) is a
time-dependent process that takes 48 – 72 hours
• Activated, or partially matured, DC have been exposed to
maturation agents, and have been arrested in the maturation
process by cryopreservation
• If done correctly, the DC will continue the maturation process
after thawing
16
Scientific Background: Activated DC
• Activated DC:
– Still pick up and process antigen (especially dead and
dying tumor cells)
– Continue the maturation process upon thawing, as the
required signal transduction pathways have been
activated
– Are less susceptible to the suppressive effects of the
tumor microenvironment
– Produce high amounts of cytokines to modulate tumorbased immunosuppression
17
Phase I Trial Overview
• 39 evaluable patients out of 40 patients enrolled in >12 different indications
– Soft tissue sarcoma, pancreatic cancer, neuroendocrine tumors,
non-small cell lung cancer, melanoma, colorectal cancer, ovarian cancer, etc.
• All patients had stage 4, locally advanced or metastatic disease
• Patients had an average of 3 tumor lesions
• Patients had a median of 3.1 prior therapies
• Three dose levels tested
– 2 million (n=17), 6 million (n=19), or 15 million (n=3) live DC per injection
• Two different DC activation regimens tested
• Safety and feasibility are main endpoints
• Other endpoints include tumor response, survival
18
Administration of DCVax-Direct
• Injection of DCVax-Direct is typically done using image guidance
– Both ultrasound and CT are used
• A guide needle is placed at the injection site and the DCVax-Direct cell
suspension is delivered through a needle inside the guide needle
• Retracting and reinserting the injection needle allows for delivery of
the DC into multiple areas of the tumor
• Necrotic centers are avoided
• Injections were given at day 0, week 1, week 2, and then weeks 8, 16,
and 32.
19
Safety Findings
• 149 DCVax-Direct injections were given
• Administration of DCVax-Direct is generally well tolerated
• Transient fevers ≤39 °C, accompanied by chills and night sweats, are
typically following seen in days following the injection
• There were 2 SAEs considered related to the treatment:
– 1 patient admitted briefly for dehydration following injection-related fevers
– 1 case of systemic inflammatory response syndrome
• Other related, mostly mild and occasionally moderate AEs include fatigue
(n=11), anorexia (n=7), pain (including pain at the injection site) (n=6), and
other infrequent AEs (nausea, headache, decreased appetite, etc.)
• A maximum tolerated dose was not reached
• There were no obvious safety differences between dose levels
20
Imaging challenges
• Tumors can appear larger due to infiltration of inflammatory cells
and/or immune cells
• Tumors can appear larger due to accumulation of fluids
• Tumors can appear to maintain size, despite extensive necrosis
21
DCVax-Direct: Manufacturing (2)
22
DCVax-Direct: Manufacturing (2)
• Manufacture of DCVax-Direct entails the following critical steps:
– Purification of monocytes in our one-step automated process
– Differentiation of the monocytes into DC using GM-CSF only
• This combination of unique and proprietary steps ensures the
generation of truly immature DC (iDC)
– Activation of the iDC with a combination of factors that results in
DC-1 type properties
– Cryopreserved activated DC constitute the final product
– Extensive Quality Control is performed on each batch
23
DCVax-Direct Phase II Trial Plans
• Injections into multiple tumors
(only 1 tumor injected in Phase I trial)
• More frequent injections
• Better activation method
• Extensive imaging and biopsies
• Patient condition/quality of life measures
• At least 2 trials in parallel with 2 different cancers
• Expansion of trial sites
24
Conclusions (1)
• There are no safety or feasibility constraints for the intratumoral application
of DCVax-Direct in late-stage cancer patients
• Side effects observed to date are minimal, which is further reflected in an
overall (anecdotal) sense of improved quality of life
• The evidence gathered to date, based on tumor biopsies as well as bloodderived data, supports the hypothesis that DCVax-Direct induces systemic
anti-tumor immunity
• Extended survival is associated with a specific DC activation regimen
suggesting that DCVax-Direct treatment may be directly responsible for
increased life expectancy in late stage, unresectable cancers
• Stabilization of tumor growth predicts long term survival in patients treated
with DCVax-Direct
25
Conclusions (2)
• Several pieces of information gathered in Phase I point to the
mechanisms of action of DCVax-Direct:
– Rapid recruitment of T cells to the tumor suggest that DCVax-Direct
injection breaks down the barriers of the tumor that inhibit T cell
infiltration
– Emergence of de novo T cell infiltrates suggest induction of specific
anti-tumor responses
– Emergence of de novo PDL-1 staining of tumor tissue suggests
activation of immune checkpoints, and points to checkpoint inhibitors as
a logical follow on therapy
26
Phase II Trial Plans
• Several Phase II trials will be undertaken in parallel:
– Non-small cell lung cancer
– Soft tissue sarcoma
– Diverse cancers
• Lessons from Phase I will be applied to Phase II
• Enrollment planned in countries beyond the USA
27
Application of Phase I Lessons Learned to Phase II
• Injection of multiple tumors, as well as multiple injections into
larger tumors, at each visit
• More intense injection schedule
• Exclusive use of Activation Method B
• Initial focus on indications with promising activity
– Soft tissue sarcoma, non-small cell lung cancer
• Implement Quality of Life measurements
28
Acknowledgments
MD Anderson Cancer Center
Dr. Vivek Subbiah
Dr. Ravi Murthy
Northwest Biotherapeutics
Meghan Swardstrom
Linda Powers
Orlando Health
Dr. Omar Kayaleh
Cognate Bioservices
Mike Stella
Lori Noffsinger
Kyle Hendricks
Deepthi Kolli
Robert Morris
UCLA
Dr. Robert Prins
Dr. Tina Chou
Phenopath
Dr. Regan Fulton
Céline Jaquemont
PerkinElmer
Dr. Cliff Hoyt
UT Health, University of Texas
Dr. Robert Brown
Dr. Mary McGuire
29