NorthWest Biotherapeutics Inc (NWBO)

[CogDiss 1188X]

Here’s an attempt to translate the garbled audio transcription of the Ralph Moss’s interview with Nobel winner James Allison into English, given below. Bold text is my translation.

First, Sharpie, to take a stab at answering your question:

Can someone comment on Dr. Allison's answer to the question at the 14m10s mark? The question was "So would it make sense to give a dendritic cell vaccine in conjunction with the immune checkpoint inhibitors?"

He asserts that checkpoint inhibitors in conjunction with Dendritic Cell treatments (as opposed to those which are naturally occurring in the body) didn’t work any better n the past, in response to Moss’ question at 14:09. I believe that’s his answer.

Based on the context below, I believe it’s because he discovered that one of the main issues in immune system response to cancer isn’t necessarily antigen presentation to the T-cell by dendritic cells, naturally occurring or otherwise. The big issue is the inhibition of those cancer-recognizing T-cells’ activation (through B7 binding to CD28) by CTLA-4 and PD-1.

However, that doesn’t mean that prior attempts to use dendritic cells were optimized for complete cancer antigen presentation to T-cells. He doesn’t address this question.

Presumably antigen presentation can be improved, which is something we expect DC-Vax-L to provide.


ALLISON:
12:38 but what puzzled me you know is why
12:41 because there are all these ideas oh we
12:43 have cancer all the time and
12:45 the immune system exists you know that
12:47 whole idea was that
12:48 the immune system is designed to hit
12:51 cancer
12:52 and yet when we started working on (understanding)
12:54 co-stimulation (of T-cells) we
12:56 very really quickly realized,
12:59 using a three-cell assay that
13:00 you could do
13:02 you know where you have one (cancer) cell with an
13:03 antigen on it
13:05 and then another (cancer) cell that didn't have
13:07 antigen but had
13:09 what turned out to be a B7molecule
13:11 which binds to CD28 (on the T-cell)
13:14 and you could you know have a t cell
13:15 there and with those signals on separate (cancer)
13:18 cells sometimes you could
13:20 get t cells activated but without that
13:23 second (signal from B7 binding to CD28, you don’t get T-cell activation (while) dendritic cells can give
13:25 all the signals (antigen presentation to T-cells as well as B7 binding to CD28 to activate the T-cell)
13:26 but what we did was we took the ligands
13:29 for cd28, these b7 molecules, and put them
13:31 into tumor cells they got rejected
13:33 immediately (ie, the cancer cells were killed when costimulation of T-cell receptor and CD28 occurred)
13:35 so that proved to us that it wasn't lack
13:38 of antigens
13:39 it was because
13:43 the tumor cells were invisible to the
13:45 immune system those antigens were
13:47 invisible to the immune system
13:49 because they couldn't give that second
13:51 signal (via CD28) but when you
13:53 tumor cells die you know it enlarges the
13:56 innate immune system the dendritic
13:58 cells come in
13:59 and phagocytize the antigens from the
14:02 dying tumor cells
14:03 but on their (DCs) surface in the context of
14:05 those b7 (costimulatory) molecules,
14:07 that's when the immune response starts.

MOSS:
14:09 so would it make sense to give a
14:11 dendritic cell vaccine
14:13 in conjunction with the immune
14:15 checkpoint inhibitors

ALLISON:
14:17 yeah so because people did that quite a
14:19 bit and
14:21 that that has never worked particularly
14:22 well either i think because
14:25 what we realized uh you know when CTLA-4
14:28 came along (ie, when we figured out that there is a normal immune inhibitory signal mediated by CTLA-4 that prevents B7 from binding to CD28 on the T-cell, thus preventing T-cell activation).
14:29 is that you know if a t cell that's just
14:32 going around
14:33 it can bump into an antigen specific (to cancer). you
14:36 know a t-cell that would have a receptor specific
14:39 for something in the tumor.
14:41 without that second signal (from CD28 because it’s being inhibitored by CTLA-4)
14:44 there's no response
14:46 but once you get it started through this
14:48 cross-priming
14:50 when the t-cell gets the signals what
14:52 happens is there's two parallel pathways
14:54 that are turned on
14:56 when you get cd28 and t-cell receptor
14:58 one of them
14:59 is just a cascade of signals that tells
15:01 the cells to start dividing
15:03 really quick so you get clonal expansion
15:07 and then you know they differentiate and
15:09 start require effector (killing ability) functions but
15:11 the other thing is
15:12 you turn on the CTLA-4 gene because that
15:14 CTLA-4 is not expressed in a resting
15:17 T-cell so that you turn on the CTLA-4 gene
15:21 and that starts this
15:22 negative (inhibitory) process that is going to
15:24 terminate
15:25 the ability of cd28 to co-stimulate
15:29 because the immune system can’t just stop the clonal expansion of effector T-cells. It also has to regulate their activity with CTLA-4 (through competition with CD28) so the T-cells don’t go hog wild killing cells with unchecked abandon.