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Dendritic Cell-Based Cancer Vaccines Could Be a Major Advance

In October of 2011, Dr. Ralph Steinman was post-humously awarded one-half of the Nobel Prize in Physiology or Medicine for his discoveries of the dendritic cell and its role in adaptive immunity. His discoveries have made possible the development of therapeutic cancer vaccines that are produced by removing living cells (monocytes) that are precursors to dendritic cells, loading them with cancer antigens that stimulate the immune system to fight cancer and then re-injecting them into the body, a process called autologous immunotherapy.

 

There is a great unmet medical need for better ways to treat cancer. Chemotherapies that are the cornerstones of cancer therapy are essentially poisons dosed at low levels to destroy rapidly dividing cells like cancer. At the same time, they also kill normal rapidly dividing cells in the body and this gives rise to devastating, life-threatening side effects. With a few exceptions, they offer modest survival benefits at the price of a severe impact on quality of life. More recently monoclonal antibody and targeted therapy technologies have gained widespread usage in treating cancer. However they also offer only modest improvement in outcomes, with a few notable exceptions like Glivec for chronic myelogenous leukemia and they come with side effects.

 

To achieve a major advance in treating cancer, dramatically different approaches are needed. Why not look at what nature has created? All of us develop precancerous cells in our life, but the immune system is able to eradicate them or wall them off before they become full blown, uncontrollable cancers raging widely in the body. The dendritic cell is a powerful and central player in activating the immune system to attack cancerous cells. The goal of dendritic cell-based cancer vaccines (and cancer vaccines based on different approaches) is to boost and restore the inherent effectiveness of the immune system. 

 

Autologous, dendritic cell-based cancer vaccines are based on elegant biology. They hold the promise of being that sought after advance in cancer treatment and, if so, they could become one of the most innovative new biotechnology drug categories over the next decade.

I have written extensively about Dendreon (DNDN) which introduced Provenge for treating prostate cancer in 2010; it is the first dendritic cell-based cancer vaccine and indeed the first ever cancer vaccine of any type to be approved for medical use in the US. This report is intended to give investors a rudimentary understanding of the role of the dendritic cell that will hopefully help in following the dialogue about and developments with Provenge, other dendritic cell-based cancer vaccines and other types of cancer vaccines.

 

This report also provides a brief introduction to two small companies, Northwest Biotherapeutics (NWBO.OB) and ImmunoCellular Therapeutics (IMUC.OB) which are in the late stages of developing dendritic cell-based cancer vaccines for glioblastoma, the most severe type of primary brain cancer. Along with Dendreon, they are currently at the forefront of this technology.

 

Investment Perspective on Dendritic Cell-Based Cancer Vaccines

Even though it is potentially a paradigm shifting drug, Provenge has been received cautiously by the pharmaceutical, medical and investment establishments. All three disciplines are debating whether Provenge is an important therapeutic advance or just an over-hyped biotechnology dream. I believe this is in large part due to its being so different from current cancer drugs.

 

Provenge’s effects on cancer are very different from chemotherapy. Oncologists have been trained to judge the effectiveness of chemotherapy by how much the tumor shrinks and how long it takes the tumor to start to grow again. In prostate cancer, decreases in PSA are also closely monitored to determine effectiveness. Provenge in its clinical trials often didn’t shrink tumors, didn’t reduce PSA and indeed some tumors continued to grow after treatment. Judged by the standards that have long been used by physicians to gage the effectiveness of chemotherapy in prostate cancer, Provenge doesn’t work. 

 

Clinical trials, however, have demonstrated a clinically meaningful improvement in median overall survival for Provenge of 4.1 months with enormous safety advantages over chemotherapy. This was achieved even though the design of the trial allowed control patients to cross over to Provenge when their cancer progressed. This may have understated the survival benefits of Provenge as it was being compared to the control group in whom some patients were also on Provenge. Despite these pronounced positive attributes, Provenge’s role in treating metastatic prostate cancer is a subject of hot debate and there is considerable skepticism and uncertainty about its role in prostate cancer.

 

With living cell therapies like dendritic cell-based cancer vaccines, the manufacturing process largely determines the ultimate characteristics of the product. The processes used to grow the cells and alter them can lead to end products which may have the same general approach and therapeutic goal, but whose efficacy can be quite different. An important point to understand is that Provenge is a first generation product and as would be expected with a pioneering process, its manufacturing process is crude and inefficient. While Provenge is an effective product, future dendritic cell-based vaccines using improved manufacturing techniques may be much more effective, both against prostate and other cancers.

 

DCVax-L and ICT-107 are Second Generation Dendritic Cell Cancer Vaccines

In the course of doing research on Provenge, I came across two small publicly traded companies developing dendritic cell-based vaccines: Northwest Biotherapeutics’ DCVax-L and ImmunoCellular Therapeutics’ ICT-107. These vaccines address glioblastoma multiforme or GBM, the deadliest form of primary brain cancer. (Provenge is approved for prostate cancer.) In my judgment, the manufacturing technologies used by these companies to develop their vaccines are significantly more advanced than that used by Dendreon to produce Provenge and hold the promise of being more potent, albeit the cancers targeted are different.

 

In phase I trials, both DCVax-L and ICT-107 when added to standard of care produced impressive signals of efficacy in comparison to the current standard of care (which is surgical resection followed by a combination of radiotherapy and the chemotherapy drug temozolomide). I have compared the median progression free survival, median overall survival and three year survival for the phase I trials of DCVax-L and ICT-107 along with the pivotal phase III trial that established radiotherapy and temozolomide as standard of care in the following table:

Treatment of Newly Diagnosed Glioblastoma Patients
	Standard of care*	DC-Vax-L**	ICT-107**
Newly diagnosed glioblastoma patients	287	20	16
Median progression free survival (months)	6.9	24.0	16.9
Median overall survival (months)	14.6	36.0	38.4
Three year survival	16%	55%	55%
* NEJM, March 15, 2005 Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma
** Company presentations**

 

 

At face value, these results are striking suggesting that 55 of every 100 patients treated with DCVax-L and ICT-107 added to standard of care are alive after three years versus only 16 out of every 100 treated with standard of care. It is also extremely interesting that two possibly quite different products produced remarkably comparable results and for me provides meaningful validation of the power of the dendritic cell approach.

 

Seasoned biotechnology investors will quickly point out the inherent flaws of the comparisons in the preceding table. The phase I trials of DCVax-L and ICT-107 enrolled a small number of patients in non-randomized trials performed at one clinical site. Such trials are subject to investigator bias, albeit inadvertent, as investigators have a tendency to select for younger, healthier patients. They are reluctant to enroll older, sicker patients with poor prognosis who might die regardless of treatment. No one wants to see a new drug be judged ineffective because it is given to patients for whom there is very little hope for survival. In phase II and III clinical trials, however, such patients do find their way in. There is an axiom in cancer drug development that phase III results are never as good as phase II and phase II is never as good as phase I. Comparing results from different trials is also viewed suspiciously because protocols and the characteristics of the patient populations can vary widely, especially when comparing small phase I to large phase III trials.

 

Skeptics would also point out the large number of companies that have sought to develop cancer vaccines and experienced stunning failures.  CancerVax, Genitope, Favrille and Cell Genesys were all exciting companies that showed striking phase I results with their cancer vaccines (none of which were dendritic cell-based vaccines), but each failed to duplicate the promising early results in later trials. Investors suffered large losses and there is not surprisingly a lot of skepticism on Wall Street about cancer vaccine companies.  

 

Adding to investor caution is that these two companies are bulletin board companies, which are little followed by Wall Street. They are small, virtual and underfunded companies that outsource most of their clinical development and manufacturing. NWBO has only 8 full time employees and IMUC has just 4. They have been strapped for cash and have had to raise new capital at modest valuations, leading to significant dilution of existing shareholders.

 

I acknowledge and share all of these concerns, but I think that it is difficult to ignore the compelling survival data shown in these phase I trials. Investors get excited about phase I results for chemotherapy, monoclonal antibodies and new targeted therapies if they show meaningful tumor size shrinkage in phase I trials in 30% to 50% of patients without any evidence of a survival benefit. Viewed against this backdrop, the phase I results showing huge survival benefits for DCVax-L and ICT-107 are stunning.

 

I am extremely interested in NWBO.OB and IMUC.OB as I see dendritic cell-based vaccines as potentially a major breakthrough in treating cancer and these companies have products in advanced stages of development. Whatever reservations one may have in regard to phase I results; they can only be viewed as encouraging for both companies. There could also be important, product defining phase IIb results for both companies in late 2013 or 2014. Although these companies are being ignored by most of Wall Street, the history of biotechnology is replete with examples of small companies that were ignored or written off and then surprised investors with successful development of their products. Dendreon is an example as are Amgen (AMGN) and Genentech in their early years.

 

People who have followed my work are familiar with my research approach to new companies. I am very much attracted to companies with intriguing new products. When I find such companies, I rarely start with a buy opinion. I find that understanding a company takes a long time. My usual mode of operation is to issue an introductory report like this one and then follow with other reports. This approach lends itself to analysis of NWBO and IMUC as we are still a year or more away from clinical data in their defining phase IIb trials. I have previously written a report on ImmunoCellular and I am in the process of writing one on Northwest Biotherapeutics. If you are interested in this product space as I am, I would urge you watch for what I anticipate to be a series of future reports about these companies, dendritic cell-based vaccine technology and possibly new entrants that emerge in cancer vaccine development.

 

Historical Perspective on Development of New Technologies

In looking back at the history of biotechnology, I have found it often to be the case that innovations are viewed skeptically in their early years. Recombinant production of proteins- think Amgen (AMGN) - was labeled a manufacturing process and initially dismissed. It was thought that monoclonal antibodies- think Genentech- would remain a laboratory tool because the mouse protein components associated with the early products resulted in immune reactions that prohibited repeated use in humans. These issues, while legitimate, were overcome by human ingenuity and these technologies have become the bedrock of today’s biotechnology industry.

 

It is also important to note that important new innovations invariably seem to come from small, upstart companies rather than current industry leaders. This was certainly the case with Amgen and Genentech, but this phenomenon is not just related to biotechnology. Apple (APPL), Google (GOOG) and Facebook are examples of this in the technology space. Experience has taught me to be patient and not give up too quickly on new technologies. The early going is usually choppy and uncertain; they always take longer to develop than people think and the pioneers are not always the winners. However, perseverance and patience can lead to striking investment opportunities.

 

This note is an overview of the development of dendritic cell-based vaccines for treating cancer. I am intrigued by the underlying biological rationale and I give this technology an excellent chance of being a major advance. In order to follow the developing debate on dendritic cell-based vaccines, it is helpful to have a rudimentary understanding of the science involved and that is an important aim of this report.

 

The development of preventive vaccines which stimulate the immune system to launch an immune response to prevent disease has been one of the great triumphs of drug development and has led to preventive vaccines for smallpox, polio, measles, mumps and so forth.  The idea of using therapeutic vaccines to stimulate the immune system to fight an active disease like cancer dates to 1890 when Dr. William Coley injected a mixture of killed bacterial cells into cancer victims with the idea of stimulating the immune system to fight cancer. This approach was called Coley’s toxins and was actually used in medical practice until 1963. In the wake of the thalidomide controversy and the Kefauver Harris Amendment of 1962, Coley's toxins were designated as drugs by the FDA. This made it illegal to use them other than for clinical trials. Several small trials were conducted, but results were mixed and the drug never gained approval in the US.

 

Interest in cancer vaccines has not faded with the demise of Coley’s toxins. There continue to be many drug development programs based on various approaches that aim to stimulate the immune system and create a treatment for cancer. Dendritic cell-based vaccines are only one on many approaches. So far, this has not worked out well from either a medical or investor standpoint. Cancer vaccines have largely been an investment graveyard as companies such as CancerVax, Genitope, Favrille and Cell Genesys have all been spectacular failures. In 2010, Dendreon broke the string of failures when Provenge was granted approval for treating some forms of prostate cancer.

 

Overview of the Immune System

The first step in understanding dendritic cell vaccines is to have a rudimentary understanding of the immune system. Its function is to recognize and rid the body of abnormal cells and foreign substances. This is based on its ability to recognize markers on cells that identify them as normal (self) or abnormal (non-self); these markers are called antigens (short for antibody generating). The first thought that comes to mind for most people when the immune system is mentioned is fighting infectious disease. However, it is also geared to rid the body of abnormal cells like cancer. We all develop precancerous cells during our life, but most are eradicated by the immune system or walled off from the rest of the body rendering them harmless. It is when the immune system fails that recognizable cancers occur.

 

Each individual’s immune system springs from stem cells found in the bone marrow. These cells have the ability to differentiate into other cells which in turn further differentiate creating many types of cells with very different functions. The aggregate of immune cells that comprise the immune system are white blood cells which circulate through the blood and lymphatic systems. The same primordial stem cells also create red blood cells that carry oxygen and platelets that are integral in forming clots to stop bleeding.

 

The immune system is comprised of millions and millions of cells that are organized into specialized sets and subsets which work in concert. When launching and coordinating an immune response, they pass information back and forth that coordinates their activity like bees swarming around a hive. These cells interact with each other and pass information through numerous protein messengers called chemokines.  

 

Numerous chemokines are released by many different types of immune cells and serve to influence and direct other immune cells. Through following a signal of increasing chemokine concentration, immune cells can be guided toward the source of the chemokine resulting in migration of an immune cell though tissue and the lymphatic and blood systems. Some chemokines provide signals that are essential for cells to differentiate and mature. Others can promote development of new tissues such as angiogenesis (forming new blood vessels). Still other types release signals in response to events that cause physical damage and initiate an immune response to promote healing. It is generally believed that chemokine gradients are also responsible for the migration of dendritic cells to the lymph node where they interact with other cells of the immune system to initiate and direct an immune response.

 

The Innate Immune System

There are two elements to the immune response which are referred to as the innate and the adaptive immune systems. The innate system is non-specific and always on duty; it is the first line of defense reacting to an antigen within hours or days. Cells that comprise the innate system lurk in tissues or the blood and lymph systems and are continually on the alert for damaged cells like infected or cancer cells. Among these cell types are natural killer cells and granulocytes (predominantly neutrophils) which can recognize cells displaying antigens and launch an attack through engulfing and/or releasing toxic chemicals. These are complemented by phagocytic (literally cell eating) cells called monocytes. Phagocytic cells engulf and digest abnormal cells from their surroundings. They then process the antigen into fragments which brings the adaptive system into play; it launches a response that is specifically targeted at the antigen.

 

The Adaptive Immune System

The adaptive immune system is importantly based on two kinds of cell groups called T cells and B cells. Certain subsets of T cells (killer T cells) are programed to seek out and attach to cells displaying a particular antigen. An activation process gives killer T cells the ability to form receptors that recognize and hone in on an antigen present on the surface of targeted cells. They bind with that cell and release proteins which punch a hole in the cell surface causing it to leak cellular contents and die.

 

Helper T cells are another sub-set of T cells that are not directly involved in the killing process, but play a major role in activating and directing killer T cells and B cells through chemokine signaling. They are essential to the process that activates antigen specific killer T cells and antigen specific antibodies produced by B cells.

 

Regulatory T cells are a third sub-set. They dampen the responses of immune cells actively involved in killing. They settle the immune response after it has done its work because an overly activated immune system can do damage to the body causing autoimmune disease such as rheumatoid arthritis, asthma and psoriasis.

 

Memory T cells can be either helper or killer T cells that have become experienced through a previous encounter with an antigen. It is this component of the immune system that preventive vaccines give rise to and is the basis for their effectiveness. At a repeat encounter with an antigen, memory T cells can quickly reproduce to mount a faster and stronger immune response than the first time the immune system is exposed.

 

B cells are activated with the aid of helper T-cells and work in concert with killer T-cells. They produce specific antibodies that bind to and attack the antigen expressed on targeted cells. They can sometimes act directly to destroy the targeted cell on their own or trigger further complementary responses from other components of the immune system which work in concert to destroy the targeted cell. 

 

Distinguishing Self from Non-Self

The essence of both the innate and adaptive immunity systems is the ability of immune cells to distinguish between self and non-self molecules. Both recognize antigens that mark cells as non-self and launch a powerful attack to destroy them while ignoring normal cells that do not express the antigen. The biological process for distinguishing between self molecules and antigens is based on proteins called major histocompatibility complex or MHC molecules that are found in every cell in the body that contains a nucleus.

 

The MHC molecules are integrally involved with proteasomes which are very large protein complexes located in the nucleus and the cytoplasm of cells. The main function of the proteasome is to degrade unneeded, damaged or foreign proteins that occur in cells. This is a process by which cells regulate the concentration of normal proteins in the cell and get rid of foreign or dysfunctional proteins. The proteins are degraded in the proteasome and then formed into small fragments called peptides. 

 

MHC class I molecules that are present on all nucleated cells in the body bind to peptides that are created when proteins are degraded in the proteasome. The resulting complex of the MHC I molecules and the peptides then travel to the cell wall. The peptide component is then displayed outside the cell while the MHC molecule stays within the cell membrane. In this way, the internally processed proteins of a cell can be displayed to cells of the immune system. A normal cell will display peptides from normal cellular protein which immune cells recognize as normal and ignore. However, the display of antigens (foreign proteins) that arise in virally infected cells, cells infected with intracellular pathogens or cancer cells can trigger an attack by killer T-cells and antibodies that have been trained to seek out and destroy cells displaying these antigens.  

 

MHC class II molecules are found only on a subset of immune cells involved in antigen processing. They function like MHC Class I molecules in displaying peptides resulting from degradation of substances in the proteasome. However, there is an important difference in that they only present proteins that are brought to the cell by ingesting bacteria or other extracellular organisms, another cell or cellular debris. These MHC II peptide complexes play an important role in activating helper T cells to spur antibody production against antigens.

 

MHC Class I MHC peptide complexes play a direct and well understood role in activating killer I-cells. The MHC Class II MHC peptide complex is only involved with activating helper T cells. The role of the activated helper T cells is much more complex and less well understood.

 

Dendritic Cells; the Key Messenger between the Innate and Adaptive Immune Systems

Dendritic cells are derived from monocytes, a phagocytic (cell eating) type of white blood cell. Monocytes leave the bone marrow and circulate through the blood. Depending on chemokine signals, they further differentiate into macrophages and immature dendritic cells. Both of these cell types phagocytose (engulf and then digest) foreign substances such as cellular debris, infectious microbes and abnormal, damaged cells like cancer. Both play a role in activating the adaptive immune system, but dendritic cells are more specialized and play a much more important role. They are referred to as the professional antigen presenting cell and can be considered the starting engine of any immune response.

 

Immature dendritic cells circulate through the blood to take up residence in tissue at potential sites where they may encounter cells displaying antigens. They are present in the blood, tissues in the inner lining of the nose, lungs, stomach and intestines. Immature dendritic cells are geared for antigen capture. They then migrate through tissues following a chemokine gradient into the lymphatic system and ultimately into lymph nodes where they develop into mature dendritic cells. As T cells in the lymph flow past the dendritic cells, there is an interaction that initiates and shapes the adaptive immune response.

 

Mature dendritic cells process digested antigen fragments and present them on their surface though MHC peptide complexes to other cells of the immune system. The killer T cell becomes sensitized to an antigen by first encountering it on the MHC class I molecules on the surface of antigen presenting cells. This recognition of the antigen present on the MHC class I peptide complex is generally not enough to activate killer T cells and turn them into cancer cell killers. They need the support of helper T cells. Helper T cells recognize a different collection of peptides displayed as MHC class II molecules. When helper T cells come in contact with these MHC class II molecules containing antigen, they become activated and secrete cytokines that promote the expansion and maturation of killer T cells and B cells that produce antigen specific antibodies.

 

In addition to antigen presentation, mature dendritic cells also express on their surfaces co-stimulatory molecules such as CD 80, CD 86 and CD 40. These bind to the T-cell, keeping them in close proximity and producing a confirmatory signals needed for activation. In the absence of these signals, T cells do not respond to the antigen signal, a condition referred to as T cell tolerance.

 

Summary of How the Adaptive Immune System is Activated

The most important elements for activating the adaptive immune system’s response to cancer can be generally characterized by the following sequence:

 

Step 1:  Immature dendritic cells ingest cancer antigens.

 

Step 2: The immature dendritic cells follow chemokine gradients that enable them to migrate through tissue into the lymphatic system which carries them to lymph nodes where they differentiate into mature dendritic cells.

 

Step 3:  Mature dendritic cells in the lymph nodes present cancer antigen fragments in order to activate naive killer and helper T cells that are flowing past in lymph and which then become activated against that particular antigen.

 

Step 4: Activated helper T cells produce cytokines that greatly enhance the cell division of killer T cells and enhance their cancer killing properties. Helper T cells also help to activate B-cells which produce antibodies specific to an antigen to attack that antigen and also cause them to proliferate.

 

Step 5: Cancer cells presenting antigens on their MHC class I MHC peptide complexes are recognized by killer T cells and antibodies specific for that antigen which attack and try to destroy the cell.

 

Developing Cancer Vaccines

Cancer cells are mutations of healthy human cells so that they carry normal self markers as well as antigens.  Cancer occurs because the immune system is no longer able to properly recognize antigens and then control or eradicate the cells expressing them. This may be because of a flaw in the functioning of the immune system or something about the cancer that allows it to evade detection or blunt the attack of the immune system. It is probably the result of all of these factors and more; science really doesn’t really know.

 

The goal of dendritic cell cancer vaccines is to bolster the adaptive immune response in the hope that this will allow the immune system to regain its efficacy. In effect, drug developers are trying to replicate the action that in nature stems from the immature dendritic cell capturing antigens, migrating to the lymph nodes and differentiating into a mature dendritic cell that displays that antigen to T cells passing in the lymph. In nature, this is an incredibly complex process as I have alluded to in previous sections. Dendreon, Northwest Biotherapeutics and ImmunoCellular all have developed different manufacturing processes to do this

 

The manufacturing process involves three phases. The patient first goes to a leukapheresis center where white blood cells are collected. These are shipped to a manufacturing facility where monocytes are separated and given nutrients and cytokines that allow them to differentiate into immature dendritic cells. These are loaded with cancer antigens to produce the vaccine, which is then shipped back to the physician’s office or some other facility where it is given to the patient. In the case of dendritic cell vaccines, the manufacturing process can result in widely varying properties of the final drug product.

 

The manufacturing process for all three companies starts with leukapheresis in which a tube extracts blood from one arm and runs it through a machine that separates out white blood cells and then returns the blood, which now contains primarily red blood cells and plasma, through a tube in the other arm. Over a period of a few hours, the machine can extract a considerable number of white blood cells which are then shipped to the manufacturer.

 

The leukapheresis product contains monocytes, lymphocytes, granulocytes and other white blood cells. The manufacturer must then separate the monocytes and culture them to obtain immature dendritic cells. The cells are spun in a process that separates the different cellular components into gradient layers based on their density; one of these layers contains the concentrated lymphocytes and monocytes.

 

Dendreon’s separation process stops at this point, but NWBO and IMUC go a further step. NWBO places the cells containing monocytes on a plastic dish to which the monocytes selectively adhere. They then wash away the other cells. IMUC separates the monocytes from the other cells using a density based centrifugation method called elutriation. The remaining cells in the case of IMUC and NWBO are roughly 80% monocytes while for Dendreon only 15% of the resulting mixture is monocytes. As I will discuss later, this is may be a very important point of differentiation.

 

The mixture containing monocytes is given nutrients to keep them alive and cytokines that stimulate their differentiation into immature dendritic cells. Mechanical factors such as rocking the culture are also used. Each company has a proprietary process for doing this so that there is the possibility that the immature dendritic cells they produce may have quite different properties. The Dendreon process is much less efficient and at the end of the process 85% of the cells are some other types of white blood cell other than monocytes as compared to 20% or less in the NWBO and IMUC processes.

 

The next important step is to induce these immature dendritic cells to capture antigens. Each company uses a different approach for obtaining the cancer antigens which are loaded into the immature dendritic cells. Dendreon’s Provenge is directed against prostate cancer so that its antigen is very different from those used by IMUC and NWBO. Provenge is a fusion protein that is a combination of prostatic acid phosphatase or PAP and granulocyte macrophage colony stimulating factor or GM-CSF and is produced recombinantly. PAP is an antigen that appears on about 75% of prostate cancer cells. GM-CSF is an immune system stimulator.

 

ImmunoCellular has selected six antigens which are widely expressed in glioblastoma: gp100, MAGE-1, IL13Rα2, Her2/Neu, AIM-2 and TRP-2. Each of these antigens is an off the shelf product that is produced synthetically. The company believes that the last four antigens are highly expressed on cancer stem cells and believes that this greatly enhances the efficacy of ICT-107. Cancer stem cells are not rapidly dividing and are often left untouched by chemotherapy which attacks the rapidly dividing cells that are the daughters of cancer stem cells. The cancer stem cells then regenerate the daughter cells and the cancer reemerges. This is a very interesting theory, but not yet confirmed. Because of HLA restrictions, this mix of antigens can only target 75% of glioblastomas

 

Northwest Biotherapeutics uses a tumor lysate to create antigens for its vaccine. When the surgeon removes the tumor, a small piece is sent to the pathology laboratory for analysis. The remaining tumor is washed with saline and placed in a premixed tube containing enzymes. It is then ground up into small pieces, placed in a container and shipped to NWBO by courier. Proponents of this approach point out that no two cancers are the same and that the character of the tumor changes over time and sometimes resulting in the suppression of antigens that are targeted by the immune system. They believe that this approach is more specifically tailored to that patient’s tumor, and that ‘immune escape’ is much less likely in the face of this more extensive antigen mixture.

 

After the NWBO and IMUC vaccines are produced they are cryopreserved and can be kept for three years of more. There is considerable art in this freezing process. DCVax-L and ICT-107 are more concentrated and frozen and because of this many more doses are available for usage. This means that DCVax-L and ICT-107 can be given as booster shots that maintain and expand T cell levels. To give a booster shot of Provenge, the whole manufacturing process has to be repeated. Clearly, long time storage of a single production lot allows for continued treatment at significant cost reductions.

 

The greater concentration of immature dendritic cells in the final product for NWBO and IMUC allows them to be given as intradermal injections. Provenge must be given as a one hour infusion. DCVax-L and ICT-107 can be administered in the arm near lymph nodes where immature dendritic cells that have ingested antigens naturally reside. They can then follow the normal chemokine gradient that takes them to the lymph node. Provenge is infused into the blood and has to exit the blood stream, migrate through tissue to the lymph system and then find its way to the lymph node. This is a much more indirect and complex route.

 

Disclosure: At the time this note was written, the author had no stock position in either Northwest Biotherapeutics or ImmunoCellular Technologies.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tagged as ImmunoCellular Therapeutics LTD, Northwest Biotherapeutics Inc. + Categorized as Company Reports