NorthWest Biotherapeutics Inc (NWBO)

[The Danish Dude]

I dove into the Merck/Moderna+BioNTech mRNA cancer vaccines. Looked into the trials ongoing. When they can be EARLIEST completed. How they are manufactored compared to DCvax-L. What they target. How inferior the mRNA are compared to DCvax-L. In terms of time to manufacture as well as how little they target.

It just reaffirmed what I already know, but still .... it's the closest to getting an imaginary boner.



No wonder they need to fud the hell out of it as long time they can.

The whole ChatGBT conversation with sources (links) here.

Question:
Both Merck / Moderna and BioNTech are having trials regarding researching mRNA cancer vaccines. Can you please tell me about these?

ChatGPT

Merck and Moderna, as well as BioNTech, are actively involved in developing mRNA-based cancer vaccines, which represent a promising new approach to cancer treatment.

Merck and Moderna

Merck and Moderna are collaborating on an investigational personalized mRNA cancer vaccine known as mRNA-4157 (or V940). This vaccine is designed to be used in combination with Merck's PD-1 inhibitor, Keytruda (pembrolizumab), for the treatment of high-risk melanoma following surgical resection. The combination therapy aims to improve recurrence-free survival rates by inducing a robust immune response against tumor-specific antigens identified from the patient's tumor profile.

The Phase 2b trial, KEYNOTE-942, showed that the combination reduced the risk of recurrence or death by 44% compared to Keytruda alone. This positive result led to the initiation of a larger Phase 3 trial (V940-001), which began in August 2023. This trial will enroll over 1,000 patients and aims to further assess the efficacy and safety of the vaccine combination in a broader patient population, including those with stage IIB to IV melanoma? (Merck.com)?? (Fierce Biotech)?? (Nature)?.

BioNTech

BioNTech, in collaboration with Genentech, is developing an mRNA vaccine named autogene cevumeran for pancreatic ductal adenocarcinoma (PDAC). This vaccine encodes up to 20 neoantigens personalized for each patient and is administered alongside the immune checkpoint inhibitor atezolizumab and standard chemotherapy. The Phase II trial, which began recently, aims to evaluate the vaccine's efficacy in preventing cancer recurrence and improving survival rates in PDAC patients, a particularly challenging cancer to treat due to its high relapse rate? (BioSpace)?.

BioNTech is also testing autogene cevumeran in Phase II trials for colorectal cancer and melanoma, reflecting the broad potential of this personalized mRNA approach across various cancer types? (BioSpace)?.

These mRNA cancer vaccines represent a significant advancement in oncology, leveraging the body's immune system to target cancer cells more effectively and potentially offering new hope for patients with difficult-to-treat cancers.

Question:
When is it expected that these trials have finished their Phase 3 trials and are ready for marketing approval?

ChatGPT

The Phase 3 trials for the Merck and Moderna mRNA cancer vaccine (mRNA-4157, also known as V940) are currently underway. These trials are expected to provide crucial data on the efficacy and safety of the vaccine in combination with Keytruda (pembrolizumab) for the treatment of high-risk melanoma and non-small cell lung cancer (NSCLC).

Melanoma Trial (V940-001)
The Phase 3 trial for high-risk melanoma (INTerpath-001) began in August 2023. This study aims to enroll 1,089 patients and will measure recurrence-free survival (RFS) as its primary endpoint. The estimated primary completion date for this trial is October 2029? (Home - ClinicalTrials.gov)?? (PharmExec)?.

NSCLC Trial (INTerpath-002)
Another Phase 3 trial (INTerpath-002) is evaluating the same vaccine combination in patients with completely resected Stage II, IIIA, or IIIB non-small cell lung cancer. This trial also started in 2023 and aims to enroll 868 participants, with a primary focus on disease-free survival (DFS). The completion date for this trial has not been explicitly stated but will likely align closely with the melanoma trial's timeline? (PharmExec)?.

BioNTech's Cancer Vaccine
BioNTech is conducting a Phase 2 trial for its mRNA vaccine, autogene cevumeran, targeting pancreatic ductal adenocarcinoma (PDAC). This trial, which started in late 2023, aims to recruit 206 patients and is expected to be completed by 2029? (BioSpace)?.

Given the complexity and duration of these trials, marketing approval for these vaccines is not expected until the trials are completed and the data thoroughly analyzed, likely by the early 2030s if the results are favorable and regulatory approvals are granted.

Question
Can you tell me about their manufactoring process, how long time it takes to make a personalized cancer vaccine for 1 person?

ChatGPT

The manufacturing process for personalized mRNA cancer vaccines involves several intricate steps designed to tailor the vaccine to the specific mutations present in an individual's tumor. Here’s an overview of the process:

1. Tumor Sample Collection and Sequencing
Tumor Biopsy: A sample of the patient’s tumor is collected through a biopsy.
Sequencing: The tumor’s DNA is sequenced to identify unique mutations or neoantigens that are specific to the cancer cells.
2. Neoantigen Identification
Bioinformatics Analysis: Using advanced bioinformatics tools, the sequencing data is analyzed to identify neoantigens – proteins that arise from tumor-specific mutations and are not present in normal cells.
3. Vaccine Design
mRNA Design: The identified neoantigens are used to design synthetic mRNA sequences that will be encoded in the vaccine. Each mRNA sequence corresponds to a specific neoantigen.
4. mRNA Synthesis
Synthesis: The designed mRNA sequences are synthesized in the laboratory. This step involves transcribing DNA templates into mRNA molecules.
Purification: The synthesized mRNA is then purified to remove any impurities and ensure the integrity of the vaccine.
5. Formulation
Lipid Nanoparticles (LNPs): The mRNA is encapsulated within lipid nanoparticles to protect it from degradation and facilitate its delivery into cells.
Formulation: The mRNA-loaded LNPs are formulated into the final vaccine product.
6. Quality Control
Testing: The final vaccine undergoes rigorous quality control testing to ensure its safety, potency, and purity.
7. Administration
Injection: The personalized vaccine is administered to the patient, typically via intramuscular injection.
Timeframe
The entire process from tumor biopsy to vaccine administration typically takes several weeks. The exact timeframe can vary but generally spans around 4-8 weeks. This includes the time needed for sequencing, neoantigen identification, mRNA synthesis, and quality control.

Manufacturing Scale and Efficiency
Advances in mRNA technology and manufacturing processes have made it possible to produce personalized vaccines more rapidly than traditional methods. Companies like Moderna and BioNTech have developed scalable manufacturing platforms that can expedite the production of personalized mRNA vaccines. These platforms leverage high-throughput sequencing and automated bioinformatics pipelines to streamline the process.

Key Considerations
Personalization: Each vaccine is unique to the individual, tailored to the specific genetic makeup of their tumor.
Flexibility: mRNA technology allows for rapid adjustments if the tumor evolves or new mutations are discovered.
Storage and Distribution: The vaccines typically require cold storage to maintain stability, which can be a logistical challenge.

Conclusion
The personalized mRNA cancer vaccine manufacturing process is a cutting-edge approach that leverages the body's immune system to target cancer cells more precisely. The process is complex but has the potential to revolutionize cancer treatment by offering highly individualized therapies.

Question
Northwest Biotherapeutics have filed for marketing approval in the UK for DCvax-L. They have been manufactoring the personalized vaccine in clean rooms, but are almost ready with the Flaskworks manufacturing system Eden and a GMP-grade unit, which will take care of the manufactoring and scaling of DCvax-L in the future.

https://nwbio.com/northwest-biotherapeutics-moves-from-optimization-of-flaskworks-prototype-to-fabrication-of-gmp-compliant-units-for-installation-validation-and-final-testing-prior-to-regulatory-certification/

Can you please explain the difference in manufactoring of these personalized vaccines, the mRNA versus DCvax-L and how long time it takes for NWBO to manufacture DCVax-L with Flaskworks Eden?

ChatGPT

The manufacturing processes for personalized mRNA cancer vaccines like those from Moderna and Merck, and for DCVax-L from Northwest Biotherapeutics (NWBO), involve distinct methods due to the nature of the products.

mRNA Cancer Vaccine Manufacturing
Process:

Tumor Sample Collection: A tumor biopsy is performed to obtain a sample.
Sequencing and Neoantigen Identification: The tumor’s DNA is sequenced to identify specific mutations or neoantigens.
mRNA Design and Synthesis: mRNA sequences coding for these neoantigens are synthesized.
Formulation: The mRNA is encapsulated in lipid nanoparticles to protect it and facilitate delivery into cells.
Quality Control and Administration: The vaccine undergoes rigorous testing before being administered to the patient.
Timeframe:
This process typically takes around 4-8 weeks from the biopsy to the administration of the vaccine.

DCVax-L Manufacturing
Process:

Tumor Sample Collection and Dendritic Cell Isolation: A sample is collected, and dendritic cells are isolated from the patient’s blood.
Cell Culture and Activation: These cells are cultured and activated with tumor antigens.
Formulation and Cryopreservation: The activated dendritic cells are formulated into a vaccine and cryopreserved for storage.
Flaskworks Eden System:
The Flaskworks Eden system automates and closes the DCVax-L manufacturing process, addressing several challenges:

Closed System: Reduces the need for high-grade clean rooms by eliminating open steps.
Automation: Automates key steps like cell isolation, culturing, and extraction, which traditionally required skilled technicians.
Batch Production: The entire process for a patient’s treatment over several years can be completed in a single 8-day batch, after which the doses are cryopreserved.
Timeframe:
The automated Flaskworks system aims to mirror the manual process, which currently takes about 8 days to produce the full set of doses for a patient. The new system is expected to streamline production and reduce costs significantly, making it feasible to scale up for large numbers of patients? (Northwest Biotherapeutics)?? (Northwest Biotherapeutics)?? (Green Stock News)?.

Both manufacturing processes involve cutting-edge technology and significant automation to ensure precision, safety, and scalability, but they are tailored to the specific requirements of mRNA and dendritic cell-based therapies.

Question
Tell me about the vaccines how they target neo-antigens and cons and pros?

ChatGPT

Neoantigen-Targeting Vaccines: mRNA and Dendritic Cell-Based Approaches
mRNA Vaccines (Moderna and Merck)
Mechanism:

Tumor Sequencing: A sample of the patient’s tumor is sequenced to identify unique mutations or neoantigens.
mRNA Design: Synthetic mRNA sequences corresponding to these neoantigens are designed.
Immune Activation: The mRNA is encapsulated in lipid nanoparticles and injected into the patient. The mRNA instructs cells to produce the neoantigens, which are then presented on the cell surface.
Immune Response: The immune system recognizes these neoantigens as foreign and mounts a targeted attack against the tumor cells expressing them.
Pros:

Personalization: Highly personalized, targeting unique mutations specific to the patient’s tumor.
Rapid Production: mRNA vaccines can be designed and produced relatively quickly.
Versatility: Can be adapted to different types of cancers and mutations.
Cons:

Stability and Storage: Requires careful handling and storage at low temperatures.
Delivery Challenges: Effective delivery of mRNA into cells can be challenging and requires advanced nanoparticle technology.
Immune Response Variability: The effectiveness can vary based on individual immune system responses and the heterogeneity of tumors.
Dendritic Cell-Based Vaccines (DCVax-L by Northwest Biotherapeutics)
Mechanism:

Dendritic Cell Collection: Dendritic cells are isolated from the patient’s blood.
Tumor Antigen Loading: These cells are exposed to antigens from the patient’s tumor, either peptides or lysates, which they then present on their surface.
Activation and Injection: The activated dendritic cells are injected back into the patient, where they stimulate T cells to recognize and attack tumor cells expressing the target antigens.
Pros:

Personalization: Tailored to the patient’s tumor antigens, potentially increasing effectiveness.
Strong Immune Activation: Dendritic cells are potent activators of T cells, leading to a robust immune response.
Specificity: High specificity for tumor antigens reduces the risk of attacking normal tissues.
Cons:

Complex Manufacturing: The process of isolating, culturing, and activating dendritic cells is complex and labor-intensive.
Cost: Production costs are higher due to the personalized nature and complexity of the process.
Scalability: Scaling up production to treat large numbers of patients can be challenging.
Comparative Analysis
Effectiveness:

Both types of vaccines are designed to elicit strong, targeted immune responses against cancer cells. The success of these vaccines in clinical trials shows promise in extending survival and reducing recurrence rates in cancers like melanoma and glioblastoma.
Logistics:

mRNA Vaccines: Easier to scale up and faster to produce, but require stringent storage conditions.
Dendritic Cell Vaccines: More labor-intensive and costly, but potentially offer stronger and more specific immune responses due to the direct involvement of dendritic cells.
Safety:

Both vaccine types have shown acceptable safety profiles in clinical trials. However, the personalized nature of these therapies necessitates careful monitoring for any adverse effects related to the immune response.
Future Prospects:

mRNA Technology: Benefiting from advancements in nanoparticle delivery systems and rapid production capabilities, mRNA vaccines are positioned for broader application across various cancers.
Dendritic Cell Technology: Continued innovations in automation and closed-system manufacturing, like Flaskworks, are making these therapies more accessible and affordable.
Conclusion
Both mRNA and dendritic cell-based vaccines offer groundbreaking approaches to personalized cancer treatment, each with unique advantages and challenges. Ongoing research and technological advancements will continue to optimize these therapies, potentially transforming the landscape of cancer treatment.

Question:
How about the number of neo-antigens they target? It seems the mRNA ones target 20-34 specific neo-antigens, while DCVax-L uses tumor cell lysate to ensure a broad-spectrum immune response againnst multiple antigens and uses lysate from patient’s own tumor to ensure correct antigens targeted.

ChatGPT

Targeting Neoantigens: mRNA vs. DCVax-L Vaccines
mRNA Vaccines (Moderna and Merck)
Neoantigen Targeting:

Number of Neoantigens: mRNA vaccines typically target 20-34 specific neoantigens. These neoantigens are identified through sequencing the patient's tumor DNA and selecting the most immunogenic mutations.
Specificity: By targeting a defined set of neoantigens, these vaccines aim to elicit a strong and focused immune response. Each mRNA sequence corresponds to a specific neoantigen, ensuring precise targeting.
Pros:

Precision: High specificity for selected neoantigens potentially leads to a stronger and more efficient immune response against cancer cells.
Efficiency: The ability to rapidly design and produce the mRNA sequences for these neoantigens allows for quicker vaccine development and customization.
Cons:

Limited Scope: Targeting a specific set of neoantigens might miss other relevant mutations present in the tumor, potentially allowing some cancer cells to evade the immune response.
DCVax-L (Northwest Biotherapeutics)
Neoantigen Targeting:

Number of Neoantigens: DCVax-L uses tumor cell lysate, which contains a broad array of antigens from the patient’s own tumor. This means it can potentially target a wide range of neoantigens present in the tumor.
Broad Spectrum: By using the entire tumor lysate, DCVax-L ensures that the immune response targets multiple antigens, which can be advantageous in dealing with the heterogeneity of cancer cells.
Pros:

Comprehensive Targeting: The broad spectrum of antigens ensures that a wide array of tumor-associated antigens are targeted, reducing the likelihood of immune evasion by cancer cells.
Personalization: The use of tumor lysate from the patient’s own tumor ensures that the vaccine is highly personalized, targeting the specific antigens present in that individual’s cancer.
Cons:

Complexity and Cost: The process of creating a vaccine from tumor lysate is more complex and costly compared to synthesizing mRNA.
Variable Response: The effectiveness can vary based on the quality and composition of the tumor lysate, and it might not always lead to the strongest immune response against all neoantigens.
Comparative Analysis
Scope and Breadth:

mRNA Vaccines: Targeting a specific set of neoantigens allows for precise immune responses but may miss some antigens.
DCVax-L: Uses a broader approach by including multiple antigens from the tumor lysate, potentially offering a more comprehensive immune response.
Personalization:

Both types of vaccines are personalized, but mRNA vaccines are designed based on selected mutations, while DCVax-L uses the entire tumor lysate, capturing a broader antigen profile.
Manufacturing and Cost:

mRNA Vaccines: Generally quicker and more scalable but require advanced technology for delivery and storage.
DCVax-L: More complex and expensive to produce, requiring sophisticated facilities and processes.

Conclusion

Both mRNA and DCVax-L vaccines offer unique advantages in targeting cancer. mRNA vaccines provide precise, targeted responses against selected neoantigens, while DCVax-L offers a broad-spectrum approach by utilizing the entire tumor lysate. The choice between these approaches depends on various factors, including the type of cancer, the patient's specific tumor characteristics, and logistical considerations.

Question
The cons you describe for DCvax-L "More complex and expensive to produce, requiring sophisticated facilities and processes.", would you consider that hurdle "overcome", with the GMP grade production unit of Flaskworks Eden apparatus, if that can create a biosimilar of DCvax-L?


ChatGPT

The implementation of the Flaskworks Eden system for the production of DCVax-L represents a significant advancement in overcoming some of the traditional hurdles associated with the complexity and cost of producing dendritic cell-based vaccines. Here’s how the Flaskworks Eden system addresses these challenges:

Overcoming Complexity and Cost
Automation and Standardization:

Closed System: The Flaskworks Eden apparatus automates the manufacturing process and converts it into a closed system. This minimizes the risk of contamination and reduces the need for the most stringent cleanroom environments, thereby lowering the overall cost of the facilities required? (Northwest Biotherapeutics)?? (Northwest Biotherapeutics)?? (Green Stock News)?.
Reduction in Manual Labor: By automating key steps such as cell isolation, culture, and extraction, the system reduces reliance on highly skilled technicians who previously performed these tasks manually. This makes the process more scalable and less dependent on a limited pool of skilled labor? (Northwest Biotherapeutics)?? (Northwest Biotherapeutics)?.
Cost-Effectiveness:

Lower Grade Clean Rooms: The ability to use lower grade clean rooms (grade C instead of grade B) significantly cuts down on the infrastructure costs associated with maintaining high-level sterile environments. This can translate into substantial cost savings over time? (Northwest Biotherapeutics)?? (Green Stock News)?.
Batch Processing: The Flaskworks system enables the production of multiple patient doses in a single batch, further enhancing efficiency and reducing per-dose costs. This batch processing capability is crucial for scaling up production to meet larger patient demands? (Northwest Biotherapeutics)?.
Consistency and Quality:

Reproducibility: The automated system ensures consistent production of DCVax-L, maintaining the same composition, purity, and biological characteristics as the manual process. This consistency is essential for regulatory approval and patient safety? (Northwest Biotherapeutics)?? (Green Stock News)?.
GMP Compliance: The development of GMP-grade units for Flaskworks Eden ensures that the production meets the stringent regulatory standards required for clinical and commercial use. This is a critical step towards broader adoption and scalability of the vaccine production process? (Northwest Biotherapeutics)?? (Green Stock News)?.
Conclusion
The introduction of the Flaskworks Eden system marks a significant improvement in the manufacturing process for DCVax-L, addressing many of the previous challenges associated with complexity and cost. By automating the process and transitioning to a closed system, Flaskworks Eden makes it feasible to produce DCVax-L in a more efficient, cost-effective, and scalable manner. This advancement not only enhances the potential for broader accessibility of the vaccine but also aligns with regulatory requirements for consistent and high-quality production.