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Northwest Biotherapeutics (NWBO) announced today that the phase I/II trial of DCVax Direct has been initiated at M.D. Anderson Cancer Center in Houston, Texas; this is one of the premier centers for cancer drug development in the US. Additional sites in the US and UK should open soon. I view the lead role of M.D. Anderson in this trial as important credibility check for NWBO and the potential for its dendritic cell cancer vaccines. As readers of my past reports will understand very well, there are vociferous skeptics of both the technology and the company. We can certainly exclude M.D. Anderson from that group. Some details on the DCVax Direct trial are as follows.

DCVax Direct has sprung out of nowhere, but it has the potential to capture investors' interest as much as DCVax-L. Past experience with products using a similar concept to DCVax Direct, i.e. introducing autologously derived dendritic cells not pre-loaded with antigens directly into inoperable tumors, have produced disappointing results. Dendritic cells in the body go through a maturation process in which they differentiate from monocyte precursors through various stages of maturation until they become mature dendritic cells. During the maturation process, immature dendritic cells pick up antigens from the tumor. They then migrate to the lymph nodes and differentiate into mature dendritic cells that are capable of displaying the antigens to other cells of the immune system. This activates the adaptive immune system which launches an attack on the cancer.

Northwest believes that it understands the reasons for past failures. It believes that the key to efficacy is identifying at what point the immature dendritic cells are most capable of both taking up antigens and displaying them. The cells in DCVax Direct are partially mature dendritic cells somewhere in the maturation stage between monocytes (which are obtained in a blood draw) and mature dendritic cells. The company believes that prior development efforts used cells that were either too immature or too mature. It believes that it has identified a dendritic cell maturation stage that will work. This requires both precision and control of the manufacturing process in order to consistently replicate this batch after batch. The company has issued patents that address this technology.

The DCVax Direct trial is a multi-center Phase I/II trial. It is an open label trial and efficacy will be measured in terms of tumor regression (shrinkage or elimination) that is expected to occur fairly rapidly (within a month or two following administration) if regression is going to occur. Since the trial is not blinded, the company can release data from this trial in any way that it determines -even on a patient by patient basis. This may mean that there could be some meaningful, if anecdotal, data released in 2H, 2013

This is a Phase I/II trial which will begin with a Phase I component that will escalate the dose of DCVax Direct. For most oncology drugs, Phase I is intended to determine the maximum tolerable dose that can be given before unacceptable, dose limiting side effects occur. If DCVax Direct is comparable to the three other dendritic cell therapies - Dendreon's (DNDN) Provenge, ImmunoCellular's ICT-107 and Northwest's DCVax-L, it will have very modest side effects so that the evaluation of different dose levels will be mainly focused on determining therapeutic efficacy rather than the maximum tolerated dose.

The primary goal of Phase I will be to determine the correct number of cells to administer. Dosing will start at 2 million cells per dose and will subsequently be escalated to 6 million and ultimately 15 million cells. In conventional drugs, there is usually an increase in efficacy with increased dose, but this may or may not be the case with immune therapies. In the case of DCVax-L, doses of 1 million, 5 million and 10 million cells were tested. Efficacy resembled half of a bell shaped curve in which the 1 and 5 million doses were about equally effective and efficacy actually decreased at 10 million cells. There are several views about why this may be the case, including that administration of larger numbers of cells all at once creates a crowding effect in the area of the injection site, which interferes with optimal functioning of the cells.

The cornerstone of curative cancer treatment is surgical excision of the primary tumor often followed by radiation or drug therapy. Phase I will enroll patients having a number of different types of inoperable solid tumors (these are desperate patients) and will go through cohorts of about six patients each. Most of these patients will be ones whose cancers have metastasized to the point that surgical excision is not feasible or is thought to be futile. These patients will be given escalating doses of cells going from 2 million to 6 million and then 15 million. The treatment regimen calls for treatment on day 0, week 1, week 2, week 16 and potentially week 32 depending on the tumor response. The company believes results in most patients can be determined by week 8 or 16.

The company has indicated that it is aiming to enroll at least a minimum number of patients for each of four cancers, plus an additional group of patients with miscellaneous diverse cancers. So, the trial will aim to treat six patients with liver cancer, six with melanoma, six with pancreatic cancer, and twelve with colon cancer plus six miscellaneous. There will be two key variables in the trial, the number of cells received by the patients and the type of cancer they have. The dose of dendritic cells given for each cancer will have a degree of randomness.

The Phase II stage of the trial will proceed as soon as the Phase I stage is done - the company does not have to go back to FDA to start Phase II. The Phase II stage as now planned will focus on 24 patients with colon cancer who will be given the most effective dose as determined in Phase I. The endpoint of the trial will be tumor regression which has been the most frequent basis upon which accelerated product approvals have been given by FDA. The injection of cells is image-guided directly into a lesion of the cancer. Bear in mind that these tumors are inoperable so that they may have widely metastasized throughout the body, including to the brain. The injection can be given at sites of primary tumors or at metastases or both.
There will be two valuable observations that can be made at the end of the trial. One will give a glimpse into or perhaps proof of principal as to whether DCVax Direct works in various solid tumors. The other will be a meaningful amount of data in 36 colon cancer patients that could be the basis for a Phase III trial design.

The company believes that it will see some initial patient results on an ongoing basis in Q3 and Q4 of this year from the Phase I component of the trial and could have results for the Phase II component by 2Q, 2014. Enrollment of patients with inoperable tumors is expected to be relatively rapid. Indeed, the company says that it has been flooded with patient and physician requests to participate in the Phase I stage. They anticipate rapid enrollment and tumor shrinkage could be seen a month or two after treatment begins in some patients.

The company and apparently M.D. Anderson are very excited about results seen in pre-clinical mouse studies, but there have been no studies as of yet in humans. Based on past experience, investors are very cautious or even cynical about extrapolating animal data into humans. As everyone readily acknowledges, curing cancer in mice has been much easier than curing cancer in men. Skeptics and even optimists will ask why the experience with DCVax Direct could be different.

The pre-clinical studies were done in mice which were injected with tumor cells to cause cancers. When treated with DCVax Direct, very consistent and impressive performance was seen across multiple tumor types; 80% to 100% of the animals in the various test groups eradicated all of the tumors in their body. These included large tumors relative to body weight. After these mice were successfully treated, 60 days later they were re-injected with tumor cells and interestingly the cancers did not re-establish which suggests that there was immune memory. If human results approach what was seen in pre-clinical, it would be extremely encouraging.