Replies to post #59742 on NorthWest Biotherapeutics Inc (NWBO)

[flipper44]

Doc logic,

That may be the case, but my point in the thread we are discussing is this.

IMHO.

1. TIL count does not correlate with survival when standard of care is used. -- UCLA
2. TIL count does correlate with survival when DCVax-L is used.
3. ALC does not correlate with survival when SOC is used.
4. ALC does correlate with additional survival when immunotherapy (CI) is used, but we are waiting to see if this is an additional biomarker for DCVax-L.

The point is that with TIL, Dr. Prins states that, as a simple explanation, DCVax-L helps reactivate an immune response in tumors that are immunogenic but previously suppressed an immune response.

With regard to absolute lymphocyte count (peripheral blood lymphocyte count), patients in the DCVax-L trial have an absolute lymphocyte count ≥1,000/mm3. This means they do not start DCVax-L treatment in patients with lymphopenia. In other words, patients are more likely to still be able to mount an immune response, which may, we shall see be exploited by DCVax-L to fight the cancer.

You are taking it a step further and assuming I'm saying the ALC means there is an active response against the tumor -- prevaccination. I'm not saying that is necessarily the case. I'm just saying the inclusion criteria used patients that are more likely to have immune systems against the cancer activated and/or reactivated by DCVax-L and/or made more robust.

(This is not a black and white issue, because even where there is lymphopenia, the chemoradiation may have simultaneously temporarily compromised regulatory immune cells and thus allowed DCVax-L time to get a foothold -- sometimes. That is an area where there is controversy in the literature, and I believe the phase III trial might provide more data on that issue.)

Now add the recent UCLA paper, it's not just TIL count, but also, "significant overlap in sequence between T cell receptors in the tumor and in the peripheral blood was correlated with extended survival." This additional correlation was found when DCVax-L was used. Interestingly, even some patients that did not have overlap prior to DCVax-L treatment, developed it afterwards.

[Doc logic]

flipper44,

I forgot to mention that with proneural those older targets are basically still the same and they are protected from an immune response much better which is why the checkpoint inhibitors are needed. If at crossover patients are also receiving checkpoint inhibitors we have a secondary endpoint issue because all patients might be living longer right? Maybe that is why there has been talk about collaborations?

[Doktornolittle]

DOC: If a tumor manages to hide a number of mutated / non-self antigens I understand that the DCVax-L lysing + DC exposure would sniff those out. What I don't understand is how the resulting T-Cells would then find their targets?

Is the reasoning that the T-Cells don't need antigen match at the surface of the tumor cell in order to do damage. Ie that they penetrate better than DC's ?

It seems the T-Cells do infiltrate the tumor... but that is interstitial, is it not? So if the antigens are not presented... the T-Cells don't actually penetrate the Tumor cells looking for antigen do they? Could they do that and then get back out without damaging the cell? I wouldn't guess so, but it sounds like you likely know, and do not have to guess.