NorthWest Biotherapeutics Inc (NWBO)

[Pyrrhonian]

Good stuff long, thanks for highlighting that. I remember looking at it, but didn't look deeply enough. However, this time through I saw certain things that would make me think those found to have low CD4s in the study would have been excluded from the DCVax-L trial. Here are some:

The range for CD4 counts was "90-2010." Also those with CD4s below 200 had a baseline median of 400. The lowest at baseline in this study were also the below 200 CD4's. Inclusion criteria would seem to prevent these lower bound patients from entering the DCVax-L trial. The study notes:

Subjects who developed grade III–IV CD4 count depression had significantly lower CD4 counts (458 vs. 887 cells/mm3, P 0.0001) and total lymphocyte counts (1,044 vs. 1,645 cells/mm3, P 0.001) before beginning radiation and temozolomide treatment than those who did not.

The study notes further:

The reduction in CD4 counts paralleled changes in total lymphocyte counts but was not related to changes in the white blood cell counts, neutrophil counts, platelet counts, or hematocrit.

However, criteria states:

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

Which is actually tabulated after SOC in the DCVax trial.

Also in the study, they may or may not have had Gliadel wafers post-surgery. That would exclude them from the DCVax-L trial. This may also have contributed to low CD4 levels.

Eligible patients were permitted to have had prior surgery with or without placement of Gliadel wafers..

Further, in the study it appears a number of them had prolonged steroid use (how many for how long is undefined, however). That may have had an effect (although perhaps not very large) on CD4 counts, and is an exclusion criteria for this trial:

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

Also of note is how many were "biopsy only," and required higher doses of steroids. The low CD4 group had an imbalance of them (although not quite stat sig):

Instead, patients died early from progressive growth of their HGGs. One potential explanation for this finding is that highly immunocompromised patients were poor prognosis patients with the largest postoperative tumor burden who required higher doses of glucocorticoids. Although this would be consistent with data in Table 1 showing that patients with lower CD4 counts at 2 months were older (60.9 vs. 56.6 years) and more likely to have been biopsied than resected (26% vs. 16%), these differences are not statistically significant. As noted in Table 1, patients with lower CD4 counts were more likely to be on glucocorticoids when beginning radiation and temozolomide treatment (92% vs. 79%, P 0.04)

The criteria states:

-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.

As noted, blood draws are taken at the time of leuk to determine eligibility, and of course low lymphocyte count would show up then if significantly affected by SOC.

However, it does seem clear that early progression was indeed the main factor behind shortened OS (not the result of other illnesses as the other study suggested):

Remarkably, the cause of death in these study subjects was early tumor progression and was unrelated to opportunistic infection.

and

Our initial hypothesis was that the addition of temozolomide would result in more highly immunosuppressed patients who would be at risk to develop severe opportunistic infections that might shorten their lives. However, we found that with appropriate PJP prophylaxis serious infections were not a significant cause of death. Instead, patients died early from progressive growth of their HGGs.

I also found this interesting, because we know that DCVax-L + Temodar > DCVax-L alone:

Temozolomide administered to patients with melanoma
as a single agent, without glucocorticoids or radiation,
produces profound lymphopenia and a striking reduc-
tion in CD4 counts that lasts for months after temozo-
lomide is discontinued (15). Thus, it is plausible that
the combined use of glucocorticoids, radiation, and
temozolomide in patients with HGGs results in signifi-
cant and long-lasting reductions in CD4 and total lym-
phocyte counts that can lead to clinically significant
immunologic impairment

and

Our observations suggest that severe immunosuppression is associated with poor outcomes, whereas other investigators have recently reported that temozolomide treatment–related lymphopenia might enhance the results of immunotherapy in patients with glioblastoma.

In summary, and imo, I still think there will be a lower % of low CD4 patients in the DCVax-L trial than this study suggests, and when considering all factors (Gliadel wafer use, extensive steroid use from biopsy only patients, possible prolonged steroid use across the board, and especially excluding low lymphocyte patients from the DCVax-L trial), it may even be below 24% (as the other study I quoted found was representative of the population).

What was most interesting to me was the discussion section on the pure counter-effectiveness of immuno-suppressive treatments. Time for change?