Northwest Biotherapeutics, Inc. · OTC:NWBO
Northwest Biotherapeutics — ASCO 2023
44 slides from Northwest Biotherapeutics's conference presentation, Jun 3, 2023
Slide 1: DCVax-L: Mechanism of Action, Immunological Effects, and Clinical Trial External Controls Methodology
DCVax®-L: Mechanism of Action, Immunological Effects, and Clinical Trial External Controls Methodology Marnix L. Bosch Northwest Biotherapeutics, Inc. June 3, 2023 1
Slide 2: Disclaimer
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 tha
Slide 3: Overview
Overview 1. Introduction to DCVax®-L 2. Mechanism of Action 3. Immune Monitoring 4. DCVax®-L Phase III Trial -- External Controls 5. Compassionate Use -- Observations 6. Conclusions 3
Slide 4: DCVax-L Introduction
DCVax®-L Introduction • DCVax®-L is comprised of autologous dendritic cells (DCs) loaded with autologous tumor cell lysate – Uses dendritic cells, which are the master cells of the immune system • DCs instill both targeting and direction of the response – Uses tumor cell lysate to ensure a broad-spe
Slide 5: Mechanism of Action
Mechanism of Action NORTHWEST BIOTHERAPEUTICS
Slide 6: DCVax-L: Mechanism of Action
DCVax-: Mechanism of Action Multiplier effect activated anti-cancer T cells travel to tumor site Dendritic Dendritic Cell Cell tumor target proteins anti-cancer T cell activated resting anti-cancer activated anti-cancer T cell attaches to DC T cells divide rapidly and acquire cytotoxic capability 6
Slide 7: Antigen Uptake and Presentation
Antigen Uptake and Presentation Proteomics analyses were conducted on the following materials to determine protein content and diversity: Tumor lysate Unpulsed DCs DCs pulsed with tumor lysate Peptides eluted from pulsed DCs Example findings from a single sample: • 25,109 MHC class I-associa
Slide 8: DCVax-L Immunopeptidomics: MHC Class I
DCVax-L Immunopeptidomics: MHC Class I 399 tumor-associated peptides (~9 mers) presented by MHC Class I Examples of peptides highly enriched post lysate pulsing: 8
Slide 9: DCVax-L Immunopeptidomics: MHC Class II
DCVax-L Immunopeptidomics: MHC Class II 220 tumor-associated peptides (~16 mers) presented by MHC Class II Examples of peptides highly enriched post lysate pulsing: 9
Slide 10: DCVax-L Immunopeptidomics
DCVax-L Immunopeptidomics Examples of peptides in pulsed DCs that were previously identified in GBM: Absent from normal tissues ‐ known to be present in GBM. Marker Tubulin beta‐4A chain of progression in multiple cancers. Known hyper expression in CaPro Dematin Inhibitory protein in GBM Dihydropyri
Slide 11: DCVax-L Immunopeptidomics
DCVax-L Immunopeptidomics Examples of peptides in pulsed DCs that were previously known to be associated with other tumors (TAA) but not previously identified in GBM: E3 ubiquitin‐protein ligase TRIM68 Expressed in multiple cancers. Spermatogenesis‐associated protein 2 Associated with poor prognosis
Slide 12: Proteomic Analyses - Observations
Proteomic Analyses - Observations The DCVax-L lysate preparation process releases multiple cancer- related proteins from which immunogenic cancer-specific peptides can be processed. DC Vax-L preparations pick-up, process and present hundreds of tumor-specific peptides to T cells through MHC clas
Slide 13: T cell Stimulation by DCs
T cell Stimulation by DCs • Lysate-loaded DCs induce a primary T cell response through a combination of different signals: – Interaction of the T cell receptor (TCR) with multiple peptide antigens associated with MHC molecules – Costimulatory signals such as CD40, CD80, CD86 – Cytokine production 13
Slide 14: Costimulatory Molecules
Costimulatory Molecules The dendritic cells in DCVax-L express the following (co-)stimulatory molecules (among others): - CD40 – interacts with CD40-L on the T cells - CD141 – involved in antigen presentation - CD82 – stabilizes DC-T cell interactions - CD86 – interacts with CD28 in the stimulation
Slide 15: Induction of CTL Activity
Induction of CTL Activity Killing of target cells is observed if T cells were stimulated by DCs loaded with tumor cell lysate Franz and Lowdell, 2022 15
Slide 16: Enhanced T Cell Stimulation
Enhanced T Cell Stimulation Multiplier Effect 1.4 Accumulation of late generation T cells 1.2 1 0.8 0.6 0.4 0.2 0 No lysate DCs Lysate‐loaded DCs Number of divisions DCs stimulate T cell proliferation leading Addition of tumor cell lysate to the DCs to multiple ‘generations’ of T cells results in mo
Slide 17: DCVax-L Mechanism of Action: Summary
DCVax-L Mechanism of Action: Summary • The DCs in DCVax-L express the requisite co-stimulatory molecules for productive interaction with T cells • The DCs also express CD141, a molecule involved in effective antigen presentation to T cells • Incubation of the DCs with tumor cell lysate adds addition
Slide 18: Conclusions
Conclusions • Mechanism of action studies demonstrate uptake and presentation of a broad range of antigens, which is important to prevent tumor escape • Immune monitoring data demonstrate activation of a wide repertoire of T cells, which can travel to the brain to attack tumor cells locally 18
Slide 19: In Vivo Immune Monitoring
In Vivo Immune Monitoring NORTHWEST BIOTHERAPEUTICS
Slide 20: In Vivo Immune Monitoring
In Vivo Immune Monitoring Consequential to our broad-spectrum approach, we use an analysis that allows monitoring of the entire T cell response (as opposed to monitoring the response to a single antigen), as follows: • Each T cell that emerges from the thymus during development has a unique T Cell R
Slide 21: Expanded T Cell Clones
Expanded T Cell Clones (compared to Baseline) Patient 1 Patient 2 Patient 3 # of Expanded Clones 1400 1200 1000 800 600 400 200 Background 0 Background Month 4 Month 8 Month 4 Month 8 Month 4 Month 8 • These bars represent the total number of newly expanded T cell clones (dark color) or further expa
Slide 22: T Cell Repertoire Dynamics
T Cell Repertoire Dynamics This is your brain blood This is your blood from an untreated person on DCVax‐L 22
Slide 23: T Cell Repertoire Dynamics
T Cell Repertoire Dynamics Expansion and Contraction of the T cell repertoire in response to DCVax-L (3 example patients) X-axis: Baseline Y-axis: 8 months 23
Slide 24: Prediction of (Tumor) Antigens
Prediction of (Tumor) Antigens • Existing databases allow us to predict which antigens the expanded T cells were possibly responding to • These algorithms are imperfect, and the databases are limited, so at this point predictions are only indicative • Within these limitations, we made the following
Slide 25: T cell Infiltration in GBM Post Vaccination
Mechanism of Action (3) T cell Infiltration in GBM Post Vaccination Infiltration of T cells in the tumor is observed in patients treated with DCVax-L Both CD4 and CD8 cells are seen L. Liau et al. 25
Slide 26: Immune Monitoring - Summary
Immune Monitoring - Summary • T Cell Receptor (TCR) sequencing demonstrated extensive expansion of specific T cell clones following immunization with DCVax-L • This expansion is responsive to a broad repertoire of antigens • “This level of clonal expansion, particularly of the newly detected clones,
Slide 27: DCVax-L Phase III Trial External Controls
DCVax-L Phase III Trial External Controls 27
Slide 28: Trial Design
Trial Design Primary Endpoint: OS in newly diagnosed GBM DCVax‐L arm (n=232) vs. External controls (n=1,366) (control arms of external studies) Secondary Endpoint: OS in recurrent GBM Placebo arm crossovers* (n=64) vs. External controls (n=640) *(Placebo arm patients received only SOC (control arms
Slide 29: Overall Survival in nGBM and rGBM
Overall Survival in nGBM and rGBM mOS of DCVax patients: mOS of DCVax patients: 19.3 months from randomization; 13.2 months from recurrence 22.4 months from surgery mOS of controls: mOS of controls: 16.5 months from randomization 7.8 months from recurrence 29
Slide 30: Landmark Survival Data
Landmark Survival Data nGBM Landmark survival rate ECP DCVax‐L Relative Rate 36 mo 15.5% 20.2% 130% 48 mo 9.9% 15.7% 159% 60 mo 5.7% 13.0% 228% rGBM Landmark survival rate post progression ECP DCVax‐L Relative Rate 6 mo 64.0% 90.6% 142% 12 mo 30.8% 54.1% 175% 18 mo 15.9% 31.8% 200% 24 mo 9.6% 20.7%
Slide 31: External Controls Drawn From Other Randomized Controlled Trials
External Controls Drawn From Other Randomized Controlled Trials 5 Other RCT nGBM 10 Other RCT DCVax‐L Trial rGBM Placebo Treated Placebo DCVax‐L SoC Treated nGBM crossover External Controls External DCVax‐L Controls rGBM 31
Slide 32: External Control Population (ECP)
External Control Population (ECP) 4 Layers of Statistical Methods Used to: Closely match the ECP and DCVax‐L patients Address and minimize known and unknown biases 1. Matching of comparator clinical trials from which the ECP was drawn 2. Validation of this ECP approach: check that trial outcomes
Slide 33: 1. Matching of Comparator Trials
1. Matching of Comparator Trials Comparator trials selected by independent experts; no Company involvement Selection made using 14 criteria for matching (7 for nGBM and 7 for rGBM) nGBM: 1) contemporaneous study time period; 2) reported outcomes (including survival); 3) same standard of care used (r
Slide 34: 1. Matching of Comparator Trials (cont'd)
1. Matching of Comparator Trials (cont’d) Newly Diagnosed Glioblastoma Study Agent under study n Median OS (months) 95% CI (months) Gilbert et al 2013 dose‐dense tmz 411 16.6 14.9 – 18.0 Gilbert et al. 2014 bevacizumab 309 16.1 14.8 – 18.7 Weller et al. 2017 rindopepimut 374 17.4 16.2 – 18.8 Stupp e
Slide 35: 2. Validation of the ECP
2. Validation of the ECP Indication Study HR vs. ECP Lower bound Upper bound For each comparator trial, Gilbert 2013 1.01 0.89 1.14 the treatment arm was Newly Gilbert 2014 1.13 0.72 1.33 compared against the diagnosed Weller 2017 0.9 0.78 1.03 external controls (ECP) GBM Stupp 2017 0.73 0.65 0.83 d
Slide 36: 3. Sensitivity Analyses
3. Sensitivity Analyses Known bias: not all trials excluded patients with evidence of progression post chemoradiation. Removing those trials yields the following result: Studies removed n ECP HR 98% CI p None removed 1366 0.80 0.00, 0.94 0.002 Gilbert 2013, 2014 646 0.77 0.00 – 0.92 0.001 Unknown bi
Slide 37: 4. Adjustments for Individual Patient Characteristics
4. Adjustments for Individual Patient Characteristics Matching Adjusted Indirect Comparison: MAIC The MAIC methodology applies a weight to each individual patient in the DCVax‐L population in such a way that the sum of the weights for patients in each category for a characteristic achieves a match w
Slide 38: Phase III External Controls Conclusions
Phase III External Controls Conclusions • Survival of GBM patients participating in clinical trials as control subjects is remarkably consistent, creating a landscape in which ECPs can be used as synthetic control arms • Against this background, treatment with DCVax-L is associated with statisticall
Slide 39: Compassionate Use – Observations
Compassionate Use – Observations 39
Slide 40: Compassionate Case #2
Compassionate Case #2 46 yr. old female with GBM unusual Patient is alive headache First batch of DCVax‐L 2nd batch of DCVax‐L and doing well 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 Adjuvant temozolomide Resection: GBM diagnosis Chemoradiation Notes: ‐ Patient was diagnosed
Slide 41: Compassionate Case #1
Compassionate Case #1: 70 yr old male with GBM confusion Patient is alive and seizure First course of DCVax‐L Second course of DCVax‐L and doing well 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 First resection: Recurrence: Recurrence: GBM diagnosis 2nd resection 4th resection Chemoradiation +
Slide 42: Observations From Compassionate Use Cases
Observations From Compassionate Use Cases Anecdotal observations: • DCVax-L is well tolerated and can be effective in older patients, including patients with substantial co-morbidities, at least through late 80s ages • When patients experience recurrence, and have an additional resection, a new batc
Slide 43: Broader Perspective
Broader Perspective • DCVax-L induces a broad-spectrum immune response • DCVax-L suitable for combinations with wide range of other treatments (checkpoint inhibitors, oncolytic viruses, cytokines, chemo, etc.) • When a DCVax-L patient has recurrence(s), new batch(es) of DCVax-L can be made (treatmen
Slide 44: Acknowledgements
Acknowledgements • Patients and families • Clinical trial investigators • UCLA: Dr. Linda Liau and Dr. Robert Prins • King’s College: Dr. Keyoumars Ashkan • Advent Bioservices: Mike Scott, Alessandra Riva and team • Royal Free Hospital: Mark Lowdell and Daphne Franz • Flaskworks: Lekhana Bhandari an