Replies to post #139837 on NorthWest Biotherapeutics Inc (NWBO)

[Virgilio]

EX, Chinatown, RKM, anyone?

[wavelengthy]

UCLA / Dr. Prins findings on the potency of combining DCVAX with a checkpoint inhibitor pertain to recurrent GBM;

Not newly diagnosed GBM.

You must watch the video from a few minutes before the point at which your link begins.

[jammyjames]

Actually it's quite positive for the trial (though not positive for patients unfortunately) as it is an explanation as to why dcvaxl alone doesn't work particularly well for rGBM...I.e. progressing SOC patients in the current p3 that elect to switch to dcvaxl...If he's right then the likelihood of crossover confoundment is low...It'll help give a clearer distinction between the test and control curves and a better pvalue

[sentiment_stocks]

You have to go back earlier in the video to get the context. He's first referencing those tumors that are actively progressing despite being on SOC treatment. So if you begin vaccination with a progressing tumor OR these patients were expressing immune inhibitor genes such as TGF beta or IL-10, these patients didn't mount a corresponding response to DCVax OR to a PD-1 blocking antibody.

So in these tumors... what Prins et al found in their murine models was when you have a well established tumor... you give the dendritic cell vaccine coupled with a PD-1 blocking antibody, the survival is recovery.

Here is the transcript of that presentation starting at minute 8:24.

8:24
Based on these early studies, we partnered with a company, Northwest Biotherapeutics, to kinda move this out beyond our single institution studies, where dendritic cells, which are not easily made, and you need a GMP suite, so while we have that at UCLA, not every institution has a good manufacturing suite where you can just manufacture monocytes that are GMP grade. So in collaboration with Northwest Biotherapeutics, we initiated multi-center clinical trials, one of which is ongoing right now in a randomized fashion.

9:00
This is the design of the study that’s going on right now and they’re still accruing patients so it’s not, we’re not going to talk about that.

With that background, I thought I would kinda provide some sort of additional thoughts and relevant issues about personalized immunotherapy and what this means. And I think there are essentially three issues that are pertinent, especially to you as clinicians. One, which subtypes of GBM should be treated by immunotherapy? So we’ll go through a couple of anecdotes. (Two) Why is vaccination in the setting of advanced disease, or patients that are progressively growing… why is it less effective? And (three), which target antigens should we be actually vaccinating against?

9:56
So here’s a Tale of Two Tumors. This was shared by Linda Liau, this are actually a couple of patients in our first phase one clinical trial. So both have tumors in the same basic location, and I assume the oncologists can help me out here if I need it. These are patients that got surgery by Linda. They got standard chemo and radiation. And they were vaccinated on our phase one clinical trial with an autologous tumor lysate pulsed dendritic cell vaccine. But you can see that the survival is obviously quite a bit different. And we started wondering why one patient survives, and one patient doesn’t survive as long?

So it became clear that, and you’ve heard a lot of this, that a GBM is not a GBM, even though it’s called a World Health Organization grade IV tumor, there’s a lot of heterogeneity. And awhile back, Stan Nelson and Paul Michel at UCLA began looking at gene expression profiling of all these tumors. And as you’ve heard, there are several different subtypes of glioblastoma, and some of the early studies that they published, and even though they say Type 1A, 1B, 2A, 2B… these are really the Proneural, the Mesenchymal, and the Proliferative groups. These were compared with survival and you can see that there’s some subtypes that definitely have different overall survival. This group right here (points to right side) is the Proneural group, which is the enriched with the IDH mutations. This was confirmed by Heidi Phillips with the UCSF group, and they named it more this Proneural, Mesenchymal, and Proliferative subtypes and those seem to have caught on. And they essentially are enriched for gene groupings that are associated with neuro development… Classical, Proliferative markers and invasion inflammation and (indecipherable ??) of the matrix, these are essentially what these groups are.

And we sorta began to wonder whether vaccines might be having more effective long term survival in different subtypes. So we did micro-ray gene expression profiling on the first 23 patients in our phase one trial, and looked to see which subtypes and how well they did on survival. So one thing that was clear is that when we looked at the patients that had proneural and classical subtype, that their survival was no different than what had been seen with standard chemo and radiation in a large group of patients that was shown here. However, if you looked at our patients that had a mesenchymal subtype, actually, their survival turned out to be highly significantly elevated than what you would normally see, or expect to see. And so we thought that was interesting.

Why mesenchymal? Mesenchymal often has the worst prognosis. Why would these patients have longer survival, especially on our dendritic cell trial?

And if you actually look back, a lot of these patients were enriched for these sorta pseudo-progressor cases, which they look, you know, after therapy, you see what looks like to be progression but goes away on the T-1, T-2 flair. But if you think about the mesenchymal subtype, they actually are known to be associated with inflammation. So we began to wonder whether maybe these are more immunogenic types of cancer… or this subtype is more immunogenic. And it was clear that mesenchymal subtypes have more endogenous T-cells, even before therapy starts. And then after therapy, they have a significant higher T-cell content after therapy.

13:59
So what we think is that different subtypes of tumors have/are different immunogenicity, and have different endogenous immune responses. And by doing vaccine in these mesenchymal type patients, you’re actually just re-activating a response that had already been there. And it’s more effective that way. So one anecdote of what we’ve been working on.

Secondly, why is vaccination in the setting of advanced disease, or progressive disease, less effective? This has been sorta the achilles heel of any vaccination, in pre-clinical models and even in patients. If patients are actively progressing on treatment, they are almost uniformly do not respond. So why is that? Could we develop models to sort of test what’s going on? We notice certainly early on that in patients in our clinical trial that not only if they had progressive tumors at the time that we were beginning vaccination, or if they had expression of some genes that are known to be immune inhibitors, such as TGF beta, or IL-10, that these patients didn’t mount responses. They didn’t induce T-cell infiltration after the vaccination. So we began to just think about mechanisms by which this might happen, and see whether we could look more in pre-clinical models. So we set up and went back, back to our pre-clinical model. And this is just a mouse model. Alright? These are murine glioma cells injected into the brains of mice and looking to see whether different treatments work. What I’m not showing you is that if you vaccinate mice, and then challenge with tumors, you basically can cure mice. However, if you wait for a tumor to become well-established, meaning it’s progressively growing, and you give the same treatment, it doesn’t work. Alright? The survival of a dendritic cell vaccine tumor lysate pulsed, or even a PD-1 blocking antibody, which is in the news these days, it doesn’t work. So this doesn’t happen because you’re not inducing immune response. We can see a robust inflammatory T-cell response. We can get T-cells there and they’re even activated T-cells at the site. So why is it that we’re not getting extended survival in a mouse model?

16:37
What we did notice is that vaccination in the setting induces a significantly large proportion of early myeloid cells and macrophages. So this is a flow cytometry plots of different populations that are within tumors. And what we notice that they express is PDL-1. High levels of PDL-1. PDL-1 is an immunomodulatory agent that binds to PD-1 on T-cells and turns off their functional activity. So is wasn't the tumor cells that expressed PDL-1. It was actually macrophages. And myeloid cells. And others. So since they expressed such high levels of PDL-1, we reasoned that blocking the effects of PD-1 or PDL-1 on macrophages might actually be a strategy. So when you do the same situation… you wait for a well established tumor, you give a dendritic cell vaccine, and you couple that with an antibody, a blocking antibody to PD-1, the survival is recovery. We see the same survival here that we see in the prophylactic setting.

17:52
So, we actually think this is relevant in humans. We went back and looked at our patient population, that were treated on a dendritic cell trial, and looked at, this is hard to see here, but we’re doing multiplex staining for CD-8 T-cells that express PD-1. And it was clear that PD-1 was up-regulated after vaccination. And, if you did an ex-vivo assay to look at whether you took out of a tumor you grew T-cells out of that, and looked to see whether they would kill the autologous tumor if you blocked PD-1 right before you’re put on the tumor, the killing was significantly higher. So we think this is a strategy that’s based on mechanism.

18:40
And, we’re actually designing a new clinical trial right now in which dendritic cell vaccination is going to be combined with a PD1 blocking antibody. And the reason we think it’s going to… we hope it will… work is because this is the inherent biology of these types of tumors. In the no treatment situation, these tumors are not inherently immunogenic except for some subtypes. There is no anti-tumor immune response and the tumor progresses. If you give dendritic cell vaccination alone (note: the slide shows DCVax which is NWBO’s trademarked name), you can induce a T-cell response but you get this macrophage infiltration that basically inhibits what you just started in the environment. If you give PD-1 blocking antibody by itself, alright, it doesn’t work because there is no endogenous immune response. So there aren’t any T-cells within the tumor that you can activate their function. However, if you give, if you induce a T-cell response, and you block a negative regulatory molecule with an antibody, you can then get significant rejection of the tumor (note: visual shows “tumor eliminated).

So based on this, we’ve already negotiated with a couple of companies, with BMS and Merck, to partner with a dendritic cell vaccine. Hopefully a clinical trial will be starting up soon.