|Traded as||NASDAQ: NWBO|
Northwest relies upon the contract manufacturing organization Cognate Bioservices for services supporting manufacture of product for clinical trials. The relationship with Cognate is long term, having begun before 2007 and slated to extend through the first quarter of 2016.:15 Due to cash flow issues common to development-stage companies, Northwest compensates Cognate through a combination of cash and stock payments.:16 Further, Cognate has provided Northwest with at least one short-term loan, provided and paid in mid-2013.:16 As of 2014, Northwest is undergoing an increase in activities as a result of expanding clinical trials, which has led to increasing reliance on Cognate for services, and subsequent renegotiation of the agreement with Cognate.:15,
The DCVax technology upon which NWBO's therapies rely involves injecting cancer patients with dendritic cells, which contain high levels of the same antigens found in tumor cells. The immune system, alerted by these antigens, attacks the cancer as well as the injected cells.
Northwest Biotherapeutics currently has three different cancer treatments in various levels of clinical trial. One thing in common to all three products is the use of dendritic cells, one of many types of white blood cells. The basic principle behind the DCVax line of products is that if one injects or creates a large enough number of dendritic cells carrying mutant proteins matching a cancer, these dendritic cells will excite enough T-cells and B-cells to overwhelm the cancer's many defenses.
DCVax-L is a solid-tumor cancer therapy currently in phase III clinical testing in the US, Canada, Germany, and the UK, for newly diagnosed GBM, a common and aggressive form of brain cancer. In Germany, it is being tested on all "gliomas" not just newly diagnosed GBM.
In this variation of the DCVax line, the tumor is removed through surgery, and some of the tumor presented to the aforementioned dendritic cells for the scavenging of tumor proteins. These dendritic cells, laden with tumor protein antigens, are then injected under the skin near lymph nodes. The dendritic cells then travel to the local lymph node where the dendritic cells present the proteins to the T and B Cells as previously described.
These dendritic cells are grown in the lab starting from stem cells extracted from the patient's blood. Only a sugar cube sized sample of the tumor is needed for subsequent presentation to the dendritic cells. The tumor sample is first broken down into constituent proteins using a caustic process known as lysing. (Thus the L in the name DCVax-L.) After the resulting "tumor lysate" is presented to the dendritic cells, they are ready for injection under the skin near the selected lymph node(s). Note that there are roughly 500 different lymph nodes in the body. Most are peripheral, some are internal.
DCVax-Direct is the latest addition to the DCVax line, and is currently in phase 1 trials in the US. With DCVax-Direct, there is no removal of the tumor, making DCVax-Direct ideal for inoperable tumors, if proven effective. For that reason, DCVax-Direct is currently in Phase 1 testing on patients with inoperable tumors for a very large range of cancer types.
In the DCVax-Direct procedure, the dendritic cells are developed as in the DCVax-L process, prior to antigen exposure / "pulsing". In Direct however, the subsequent exposure to tumor antigens does not occur in vitro, but rather in vivo. The prepared dendritic cells, along with adjuncts, are injected directly into one or more tumors.
At least two adjuncts are added to the dendritic cells. One adjunct excites a general aspect of the body’s immune response, while another excites a more tumor specific response. This mixture is then injected into the patient's tumor. There, the dendritic cells are expected to scavenge tumor proteins, and then find their way to the local lymph node for presentation of the tumor protein antigens to T-Cells and B-Cells. The activated T-Cells and B-Cells then travel to the tumor and kill tumor cells. Ruptured tumor cells would release more mutant proteins that are picked up by dendritic cells and other immune cells, and carried to the lymph nodes to excite still more B and T-Cells. This cycle repeats, spiraling upward and then leveling off at a high but safe level. Or, at least that is what is expected to be seen in the ongoing phase 1 trial, which finished enrollment in July, 2014.
DCVax-L + DCVax-Direct, if effective, could combine to address virtually all forms of solid tumor cancers, operable and inoperable. One exception might be prostate cancer.
Northwest completed phase II clinicals for DCVax-Prostate some time ago, and received permission from the FDA to move forward with a phase III. The phase III trial is expected to be quite large, and Northwest has been seeking partnering to take on that endeavor.
The DCVax-Prostate process is similar to DCVax-L, but rather than using the patient's tumor as the protein source, Northwest utilizes a synthetic protein that was determined to be a very common mutated protein located on prostate cancer cells. This method is very different, and is expected to be far more effective than the current approved immunotherapy for prostate.
Dendreon uses PAP, while NWBO uses PSMA. According to representatives at NWBO Dendreon’s target antigen (PAP) is not expressed on all prostrate cancers. They have to screen their patients to see the expression of their target. NWBO’s target antigen (PSMA) is expressed on all prostrate cancers. Additionally, with Dendreon’s target, the level of expression goes down as the cancer progresses. The level of expression on NWBO’s target goes up as the cancer progresses.
Another difference in the target antigens is NWBO’s target is bound to the membrane of the tumor cell. “If the DCVax® hits our target,” explains Linda Powers, “it hits the cell for sure. Dendreon’s target is secreted by the cell, so while the target is close by, it is not necessarily bound to the cell in every instance. Antibodies can come along and glom onto to the target and not hit the cell itself, which means accuracy is an issue."
The high cost of production for first generation dendritic cell therapies is often used as evidence that DCVax-Prostate and the other DCVax therapies will not be economically viable. These arguments consistently ignore the fact that Northwest Biotherapeutics has developed and regularly utilizes methods to freeze dendritic cells for transport and storage. This gives NWBO an enormous production cost advantage over these older therapies and over current would-be competitors, in part because it allows centralized processing of the patient samples at one enormous facility. Further, as mentioned, Northwest has developed and patented automated mfg processes that further reduce cost. The manufacturing processes are similar for all three of Northwest’s therapies. For each of the three, the production process is identical regardless of the patient, and even regardless of the solid tumor cancer type. Combined with centralized automatic mfg, this greatly simplifies large scale production, potentially allowing cost efficiency to reach levels unexpected for a product that is not a pill.
DCVax-L is now in Phase 3 trials in USA & Europe.
DCVax-Direct is a therapy to treat inoperable solid tumors in Phase 1 trials in the US.
DCVax-Prostate finished Phase 2 trials and has been approved for Phase 3 trials in the US.
Footnotes and references
- "Form 10-Q". EDGAR. U.S. Securities and Exchange Commission. 15 November 2013.
- "Northwest Biotherapeutics Gets Ready to Scale-Up Production". News: Bioprocessing. Gen. Eng. Biotechnol. News (paper). 34 (4). 15 February 2014. p. 24.
- Phase 3 trial of DCVax-L in GBM