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I had partially transcribed Dr. Bosch's ASCO presentation

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sentiment_stocks Member Level  Tuesday, 11/03/15 04:57:32 PM
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I had partially transcribed Dr. Bosch's ASCO presentation but never was able to finish it. Below is the portion I was able to transcribe that some may want to read through. He speaks very fast in the presentation and some may find it helpful to read this while listening or just read through it. It takes you from almost minute 9 through the 14th slide. This information presented was key to what they had found with Direct at the time... so that's where I started. I've sent this privately to a few posters, hoping to get back to it and complete it... but I doubt I'll be able to find the time any time soon to do that.

So for those interested, here it is...


Beginning at 8:52

We looked at dose number. The numbers aren’t really large enough to allow statistical analyses. But because of the small numbers, there is, at this point, no more than a trend and we’ll see how that plays out when we get to phase two.

This is also an interesting slide. This is looking at the number of injections that patients received and in each of those cohorts, how many patients are alive at this time. And it’s quite clear, the red bars are the patients that have passed away. The green bars are the patients that are still alive. It’s quite clear that if you move to more injections, patients have a greater chance of being alive. We think that might actually be a quasi dose effect but we need to investigate that in greater detail.

So here is where we get to the activation regimens… and I know somebody is going to ask, and I’ll tell you right now, we will not be able to tell you what the two activation regimens are. But just remember there are two, and we have Method A and Method B. In our minds, B stands for Better.. that’s how we remember it.

Here you can tell (slide 10), of the 18 patients treated with Method A, 9 have passed away and 9 are still alive. But the 21 patients treated with Method B… I apologize, there should be numbers here, but there aren’t… of the 21 patients, 18 are still alive, and 3 have passed away. And like I said, in this way, the trial becomes it’s own internal control. It’s almost like we tested two products… one which is potentially inactive or less active, and one which then compared to this one, shows a great level of activity in keeping patients alive.

Then the question is… okay, why is that happening?

Slide 11
Let me first draw your attention to this panel here on the right. This looks, the color code is a little different because this looks at stable disease first as progressive disease at week 8. Stable disease is measured by less than 25% increase in some of the longest diameter of the tumor.

Let me digress here a little bit… what we see in a lot of these patients is an initial increase in tumor size. We think that may be due to infiltration of immune cells or initiation of an inflammatory response. We have some evidence for that in some patients where we do a biopsy at that point in time and indeed we see large numbers of T-cells infiltrating. But that’s just a correlation at this point in time. We don’t really know what the cause is. So that’s why we said at less than 25% increase… because we see that initial bulge. But those patients that were treated with Method B… in this case… 16 of 19 control their disease at week 8. Whereas with Method A, only 4 of 16 control their disease.

And then we look at the correlation between stable disease and survival, and you can see that the patients that control their disease, 19 of 21 are still alive at this point in time. This is not at week 8, this is measured at this point in time… whereas the majority of the patients that had progressive disease at week 8, have actually passed away.

So, this ties together everything quite nicely. The Method B activated dendritic cells, when injected into the tumor, are able to control tumor growth, and thereby appear to extend survival in those patients. And of course, I’ll have a slide about plans for phase two, but of course, we will only use Method B in the phase two trial.

12:21 Slide 12

This is a little bit about mechanism. It’s more sort of postulation about mechanisms… trying to find out what is going on in these tumors, and trying to understand whether we see systemic effects, whether we see local effects, or whether we maybe see a combination of the two, and my personal conclusion is that we see a combination of the two.

And here’s evidence in and of itself of whether it’s almost a combination of the two. This is a clear cell sarcoma patient at day 0… we biopsy before injections… and I know it’s very hard to see, especially from the back and the pictures don’t come across as well because if it was darker in the room, you’d be able to see it better.

There are a few CD3 positive cells, t-cells in the tumor at day 0. There’s also some CD4 positive cells. There’s almost no CD8 positive cells at day 0. Seven days after the first injection, we see massive infiltration of CD8 cells, as well as CD4 cells. CD3 cells have concomitantly increased. What this suggests to me as an immunologist is that a response was already there, but that we’ve dramatically increased the number of T-cells present, but more importantly, we’ve broken down the barriers of the tumor that allows these T-cells now to infiltrate in to fight the tumor.

We all know that tumors put up a lot of defenses to make sure it doesn’t get attacked by T-cells, and so what this treatment appears to be doing is… one of its effects, is breaking down the barriers allowing these T-cells that already exist to both multiply and get attracted to the tumor.

We cannot, at this point, differentiate between the two, but proliferation typically takes a little bit longer than seven days, so I think we’re truly looking at a combination of proliferation and additional infiltration.

What this is showing is the shared T-cell receptor sequences between the tumor tissue and the blood. And if there are shared T-cell receptors, what that demonstrates is that the T-cells that are in the tumor, those same clones are actually represented in the blood as well. And we see after seven days… actually this is at a later time point… I think this is at week 8, that we see a quite significant increase in shared T-cell receptors from the early time point to the later time point, demonstrating that we have again induced an increase in tumor specific immune responses in terms of T-cells that are specific to the tumor that are also spreading to the periphery.

Slide 13
This is a different example. This is a patient where there truly were no CD3 cells and no cytokines. Here we’re not looking at looking at CD4 versus CD8. Here we’re looking at functional markers of the T-cells, interferon gamma and tumor necrosis factor. And here you see at week 8 from no T-cells infiltrating to about 40% of the total tumor tissue being taken up by T-cells so that would be almost doubling in mass of the tumor… purely because of infiltrating T-cells that are getting to the tumor tissue.

And again, it’s difficult to see, and I do apologize. But we did RNA scope… this was done by people at PhenoPath, a contract lab that we use in Seattle… and what you can see, if you’re close up, there’s little dots in these cells, little dark dots… RNA scope works different from immunochemistry, you get a different type of signal… but the background in the day 0 is completely blank, and then you see these dots appearing, and they co-localize with the T-cells demonstrating that the T-cells have infiltrated the tumor are functionally active. They produce cytokines that in and of themselves further enhance the immune response and that have anti-tumor effects… namely tumor necrosis alpha.

Let’s go back to the prior slide again (Slide 12). One thing that I didn’t highlight but that I will go back to when I talk about the scientific background… these dendritic cells produce enormous amounts of cytokines… namely TNF IL-6 and IL-8… and what that does, our hypothesis [is that it] converts the immunosuppressive environment to an immune conducive environment that can attract all these T-cells that are circulating, thereby allowing the immune system to attack the tumor.

This of course, we think, could be a function of dendritic cells taking up antigen at the time of injection, migrating to the lymph nodes, activating T-cell responses there, and those T-cells then find their way to the tumor, because in this patient, there was no pre-existing immune response.

The point that I would like to make from that is what that demonstrates is that potentially at least this treatment would work equally well in patients that do have a pre-existing immune response or patients that do not have a pre-existing immune response. And I’ll explain the relevance of that in a little bit.

Slide 14
Here we come to the new finding that I already mentioned. We know that tumors have these defense mechanisms, and one defense mechanism that these tumors throw up is that they mimic an immune regulatory mechanism that is already in place that dampens your immune responses so you don’t get autoimmune disease. In this case, what the tumor is doing is highjacking those pathways and starting to express these molecules that are capable of suppressing the immune response. And one of those checkpoints is called the PD-1-PDL-1 pathway; and we looked at tumor tissue before and after treatment in I think 22 of the patients, and we found that we either saw de novo expression of PDL-1… in other words, in tumors were there was no PDL-1 at the zero and probably at week 8, and at week 16, we have PDL-1 expression. That can either happen on the tumor cells or it can happen on tissue macrophages. Tissue macrophages are typically the ones that do dampen the immune response. What this suggests is that those macrophages are either recruited to the tumor by the tumor itself… because it wants to suppress the immune response that we’re inducing… or those macrophages are already there and they are up-regulating the PDL-1. We cannot distinguish between those two hypothesis.

There is brown staining here that again, may be difficult to see in the back of the audience because of the lighting. It’s very clear. I didn’t put a control slide in here because that would just be not informative because there is nothing to be seen there.

What we think is interesting here that follows a line of thinking that some people subscribe to, and I’m one of them, and that is that these checkpoint inhibitor molecules that we all know about and hear about and that have these wonderful response rates… there are still quite a few patients that don’t respond.

In lung cancer, single agent response rate hover between 20 and 30%… which is phenomenal and unheard of… but it still means that 70 to 80% of patients do not respond. And part of the hypothesis that would explain that is that those patients don’t have the pre-existing immune response, so you can’t take the brakes off… which is what these checkpoint inhibitors do.

So if we are able indeed to induce these immune responses that then lead to these checkpoint inhibitor expression, that makes these patients then subsequent candidates for checkpoint inhibitor therapy that they weren’t before. In other words, a combination therapy with dendritic cell DCVax Direct and PDL-1 could dramatically enhance the response rates to the checkpoint inhibitor molecules.

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