Expert Financial Analysis and Reporting

Reason for this Note

I was prompted to write this note after listening to a July 2017, You Tube segment in which Dr. Keyoumers Ashkan spoke about his belief that DCVax-L could be a major advance in the treatment of brain tumors. Here is the link to this approximately 13 minute video. His comments on DCVax-L begin about 8 minutes into the video. Dr. Ashkan is the chief investigator in the European segment of the phase 3 DCVax-L trial in newly diagnosed glioblastoma. I have also included comments from Dr. Linda Liau who is lead investigator on the trial; her remarks are not new as I previously have reported on her views. These highly respected, key opinion leaders may be the two most knowledgeable physicians on the planet about DCVax-L.

Summarizing Dr. Ashkan’s Remarks

Dr. Ashkan is the clinical lead for neuro-oncology at King's College Hospital in the UK. He has an active research interest in brain tumors and movement disorders and heads the Neuroscience Clinical Trial Unit.  Dr. Ashkan is one of the most respected neurosurgeons in the UK and Kings College is the premier teaching hospital in the UK. For more background on Dr. Ashkan, click on this link.

Dr. Ashkan believes that immunotherapy is the way forward in the treatment of brain tumors. He believes that DCVax-L, which is a personalized immune therapy, may be an important advance in the treatment of brain tumors. He says that there is nothing more clever than the ability of the immune system to cope with variation. He goes on to say that brain tumors are notoriously hard to treat because they are extremely heterogeneous. Because of rapid mutations that characterize GBM, no tumor in one individual is the same as a tumor in another person. Indeed, the mutations in one part of a tumor in the same person may make it a different type of cancer from another part. He is very hopeful on DCVax-L because it picks up the several antigens specific to each patient’s tumor. It them primes the immune system to attack the cancer cells characterized by these different mutations.

Background on DCVax-L

DCVax-L is an individualized treatment for brain tumors. During the surgical procedure that is the beginning step in the current standard of care for GBM, the surgeon removes as much of the tumor as possible. After providing some tumor tissue for pathology, the rest is saved for manufacturing DCVax-L. The other important procedure in producing DCVax-L is to obtain monocytes (a type of white blood cell) from the patient through leukapheresis (blood draw). Monocytes are precursor cells that go on to differentiate into dendritic cells.

The dendritic cell is at the very center of the adaptive immune response. Their critical role is to pick up and display to the immune system antigens (molecules) that are associated with cancers; antigens are foreign molecules that do not occur in normal cells. This biological activity of dendritic cells is usually done through phagocytosing (eating) cells or components of cells and then processing them internally to sort out antigens. Molecules containing these various antigens are then transported to the surface of the dendritic cell and through the major histocompatibility complex, they are displayed to the regulatory T-cells circulating in the blood. When these T-cells recognize an antigen, they trigger an immune response against cancer cells that display that antigen. Just as an aside, this mechanism of action is also the major defense system against bacterial, viruses and other pathogens.

DCVax-L is comprised   of living cells. The monocytes obtained in leukapheresis are cultured outside of the body and through a manufacturing process in which they go through a number of differentiations, they ultimately become dendritic cells. These are intended to be the same as dendritic cells occurring naturally in the body. At some point in the manufacturing process (the timing is a manufacturing art), these cells are exposed to lysed tumor tissue. They ingest the tissue and as in the case of dendritic cells in the body display the antigens. The resultant cells are frozen at cryogenic temperatures to be later injected back into the body at various points in time. Like dendritic cells produced naturally, they stimulate an adaptive immune response. This is highly individualized therapy as the dendritic cells are derived from the patient’s monocytes and the tumor are antigens specific to that patient’s tumor.

Dr. Ashkan describes this process as extremely clever. It is the elegant biology behind DCVax-L that long ago attracted my investment interest in DCVax-L.

Summarizing Dr. Linda Liau’s Views on DCVax-L

Dr. Liau is the discoverer of DCVax-L and the principal investigator for the pivotal phase 3 trial of DCVax-L in newly diagnosed glioblastoma multiforme. She has been working on DCVax-L for nearly 20 years and has vastly more experience with the drug than anyone else on the planet. Her credentials are extremely impressive as one might expect from a skilled brain surgeon. She is currently

• Chair, Department of Neurosurgery, UCLA School of Medicine
• Professor, Department of Neurosurgery, UCLA School of Medicine
• Director, Brain Tumor Program, UCLA School of Medicine

Her clinical expertise is in intra-operative functional brain mapping and use of intra-operative imaging for resection of brain tumors (gliomas, meningiomas, and metastatic tumors). Her research efforts are focused on the molecular biology of brain tumors, gene therapy, immunotherapy, and brain cancer vaccines. She has treated many patients with DCVax-L over 2o years.

Dr. Liau’s academic credentials are extremely impressive:

• Undergraduate degree from Brown University with B.Sc. in biochemistry and B.A. in political science
• MD degree from Stanford University.
• in neuroscience from UCLA
• MBA from UCLA

Like Dr. Ashkan, she is very hopeful that DCVax-L will be a major therapeutic advance. My December 21, 2016 report- DCVax-L Viewed through the Eyes of Dr. Linda Liau, Lead Investigator on the Phase 3 Trial of DCVax-L-summarized some of her thinking. See this link.

Key Takeaways

1. The lead European and US investigators on the DCVax-L phase 3 trial in newly diagnosed glioblastoma are both on record as being extremely positive on the mechanism of action of DCVax-L and its potential to be a major advance in the treatment of glioblastoma multiforme and other brain tumors. It could change the paradigm in brain tumor treatment.
2. Both Dr. Ashkan and Dr. Liau are highly respected neurosurgeons and key opinion leaders in neurosurgery. Their endorsement of the elegance of the DCVax-L technology can be taken as a major validation by investors.
3. The mechanism of action of DCVax-L, like checkpoint inhibitors and CAR-T therapy, is based on activating the immune system to attack cancers. All three therapies are based on provoking a more profound T-cell attack against cancer cells. DCVax-L could be the first of a very promising new category of immune therapy drugs.
4. A major problem in treating cancers is that they rapidly mutate and in Dr. Ashkan’s and Dr. Liau’s view, no two tumors are alike even if they occur in the same organ system. Dr. Ashkan states that DCVax potentially could be a major new advance in treating brain tumors because it addresses this heterogeneity issue; it is a personalized medicine that targets the specific cancer mutations that occur in each patient.
5. At this point, there is no question that dendritic cell cancer vaccine therapy has the potential to be a major medical advance. However, this potential must be validated by clinical trials. There is certainly reason to hope that we will soon see this validation. Data from the phase 1/2 trials were extremely encouraging as was the data from the information arm of the phase 3 trial, but obviously these are only suggestive of efficacy.
6. Key investigators in the phase 3 trial have remarked that patients in the trial appear to be living longer than would be expected. Northwest has told us that investigators in the trial are preparing a manuscript based on blinded data from the trial. See my recent report- Issues to Focus on in Pending Manuscript Dealing with Blinded Data from Phase 3 Trial of DCVax-L in Newly Diagnosed Glioblastoma- for more detail. Here is the link.
7. Hopefully, this highly anticipated manuscript will provide investors further encouragement that DCVax-L is an approvable drug. It could give investors a very meaningful insight into whether the elegance of the mechanism of action translates into a profound therapeutic effect.
8. Northwest has been the subject of a vicious social media campaign that along with aggressive, illegal naked shorting came close to bankrupting the company. Because, NWBO was a small (indeed obscure) company without venture capital or investment banking backing, it had little meaningful analyst support. This made the company vulnerable to social media bloggers who were able to create the myth that NWBO was nothing more than a stock promotion. Their arguments were given credence by a massive illegal naked shorting attack on the Company that often coincided with the publication of incendiary reports. The downward pressure on the stock validated the specious reports and created a devastating downward spiral in the stock price.
9. If DCVax-L eventually becomes a major therapeutic advance as we all hope (well the social media bloggers and short sellers don’t) this could well be one the most amazing success stories in the history of biotechnology.
10. The optimism of Drs. Liau and Ashkan while highly encouraging, does not assure that the phase 3 clinical trial will be a success. Biology can be a cruel goddess and elegant biological hypotheses do not always result in the development of therapeutic advances.
11. The mechanism of action of DCVax-L is applicable to all solid tumors. In the best (euphoric) case, treatment of glioblastoma multiforme would only be the first in a broad range of applications for colorectal, non-small cell lung cancer and possibly all other solid tumors.