NorthWest Biotherapeutics Inc (NWBO)

[Pyrrhonian]

Hey Rk:

1) vaccines patients need to have > or = 1000 so those with < 500 who then become 200 (49 % loss) after 6 weeks radiation and chemo would have been denied entry into the study

It seems you mixed CD4 counts with total lymphocyte counts. The latter includes the former, and is always the greater number.

In the study from which NW got their 40% figure (http://clincancerres.aacrjournals.org/content/17/16/5473.full.pdf), even if we only considered baseline data (cell counts BEFORE receiving SOC), the % that would have been able to enroll in the DCVax-L trial would drop from 40% to 16%. Criteria states:

Patients must have adequate bone marrow function.. absolute lymphocyte count >/= 1,000/mm3

However in the study, those who had CD4 cell counts below 200 two months after receiving SOC had a median lymphocyte count of 1,044, but a range of 331-2,790. About half of these would have been denied entry into the DCVax-L trial if using baseline figures. Those of greater than 200 CD4 counts two months after SOC had a median lymphocyte count of 1,645 with a range of 672-4,736. About 25% of THESE would have been excluded from the trial just from their baseline cell counts.

However, those who seek to enroll in the DCVax-L trial must have a blood draw to determine eligibility between 2-4 weeks after having gone through SOC. Their cell counts will have already fallen off 30-50% over that time.

Based on this, and considering many in that study above that NWBO quoted which found 40% to have CD4 counts below 200 had biopsy only with more extensive RT and steroid use, and used Gliadel wafers, etc., the number of patients, by default, that have entered the DCVax-L study with CD4 cell counts below 200 will be very few to none. In fact, there shouldn't be many with CD4 counts below 400, as in the study the median lymphocyte count of 1,044 correlated with a CD4 median of 401. Remember, a 1,000 lymphocyte count is the minimum requirement for entering the trial, and 2-4 weeks AFTER SOC.

1a) those denied, either fall in the 99 category (additional open study) or the 55 compassionate use arm

The up to 99 expanded access is for ePD/psPD and those with insufficient vaccine only. The 55 was an information arm enrolled during 2011-2012, and is no longer enrolling. There may be some compassionate use available for those with lymphopenia, but they may just have to try a different trial.

1b) but because the research was of mostly biopsy patients, the 40 percent is also a blown figure, as most of these 96 research paper patients would have also been excluded from the dc vax trial, either due to improper tumor resection, use of steroids, and ...

Not mostly, rather there were more biopsy only patients found to also be low CD4 than high CD4, due most likely to more extensive chemoradiation and steroid use. But yeah, these would be excluded from NW's trial.

1c) these depressed 200 level die due to disease progression, essentially before poor immune system kills them

Yep

1d) these overall numbers seen in this research paper were on steroids so their CD4 level likely isn't indicative of DCVax screening group.

I think the control group of the DCVax-L trial will have a higher PFS and OS than IMUC's control and the more recent Avastin ND-GBM trial's control. But not A LOT more. At best, the healthiest in the study achieved an upward bound of 23 months OS. Nothing crazy. Shooting from the hip I'd say the control in the DCVax-L trial might have 10 months PFS and 19-20 months OS. Median. Probably not any better than that.

2) of those screened with > 1000 who do make it into the DC Vax trial, on average their CD4 drops around 500 points after radiation/chemo, and some as much as 79 percent (generally the higher the CD4 the greater the hit), which brings our group will clearly be above the 200 depleted state.

See my former note on CD4s and total lymphocytes.

2a) if they make it in, they need to be off steroids for at least 10 days before beginning the vaccine and have up to 14 days after SOC radiation ends to begin trial vaccine, which means some patients will only have a 4 day window if they don't taper off the steroids sooner, and could have ended up post screened in the 99 denied portion of the study.

You can take steroids for a while after SOC. The trial criteria limits this. Basically, you could complete SOC, continue on steroids for 4 more days, stop for 10 days, get a blood draw between THEN and two weeks FROM THEN (the 2-4 week window) to get into the trial. It's tight. Two week window.

2b) very small percentage of severely depressed state would have made it into our study

Imo, true.

My own thoughts and assumptions:
1) If DC Vax trial screening is removing the low CD4 candidates, then our placebo group will likely also fair better.
2) this cd4 depressed state shouldn't reduce our PFS numbers. At most, it could potentially affect OS years down the road, as a depressed state below 400 still resulted in hospitalization from varying systems.

I agree with 1). But I think it will affect PFS, as it seems most of the deaths were due to progression after all. However, imo DCVax-L will perform better in patients with the following very well thought out inclusion criteria:

-Patients must have a KPS rating of =70 at the baseline visit (Visit 3).

-Primary therapy must consist of surgical resection with the intent for a gross or near total resection of the contrast-enhancing tumor mass, followed by conventional external beam radiation therapy and concurrent Temodar chemotherapy. Patients having a biopsy only will be excluded. These primary treatments must be completed at least two weeks prior to first immunization.

-Patients may have received steroid therapy as part of their primary treatment. Steroid treatment must be stopped at least 10 days prior to leukapheresis.

-Patients must not have progressive disease at completion of radiation therapy.

-Patients must be willing to forego cytotoxic anti-tumor therapies except temozolomide essentially according to the schedule of the Stupp Protocol (Stupp et al. N Engl J Med 352: 987-96, 2005) while being treated with DCVax-L. DCVax-L treatment must be given as described and temozolomide/Temodar treatment schedules must be given essentially according to the Stupp Protocol.

-Patients must have adequate bone marrow function (e.g., hemoglobin >10 g/dl, white blood count 3600-11,000mm3, absolute granulocyte count =1,500/mm3, absolute lymphocyte count =1,000/mm3, and platelet count =100K/mm3.

These will respond best to DCVax-L. Including a minimum of around 400 CD4 cell counts (by extension).