Member Info for Burble

Chrome failed me, safari succeeded! Roll on Cliff.

Unfortunately, it seems I am unable to connect to the bloomin' broadcast! Don't know if it's my computer or something else.

Can somebody post an update once it's over. Ta

*news

Damnit! The one day I over sleep and this is the bees I wake upto wake up to!

Yeah that’s the one. I didn’t know whether it was against the board rules to use the TO word, hence my cryptic response to Bermuda.

Bermuda I definitely saw it, something about Red and an end game they might be playing.

C7

I'm sorry to hear both of your diagnosis and that your results have been delayed. That surprises me, especially if they have had two MDTs between then and now. If I were in your situation I would probably chase your consultant oncologist. I hope you get the results sorted soon - especially for your mental wellbeing!

But yes, disruption across the NHS is going to have long lasting implications on how we treat patients and sadly, it wouldn't surprise me in the slightest if this government point to this as a reason for introducing more and more privatisation across the NHS.

C7,

Based on what I see from the nurses we work with at 20 of the major NHS trusts, all non-covid trials were generally put on hold. It’s really only in the last two months or so that we have had some return to normal recruitment. Though two things to note, cancer diagnoses are down, a number of people are delaying going to hospital and so we are seeing patients presenting further along in their disease. Secondly, there is a knock on effect that many routine lists are delayed.

Data yesterday suggests 1/10 trials have stopped entirely and 7/10 have been delayed. SCLP may be lucky because they’re relatively early phase meaning they may have not got properly started before shutdown and so are one of the easier ones to resume. I definitely think it’s the more complex trials with more hands on time that will have been worst affected.

I also know that many of the Clinical Trials Units have been working solidly throughout lockdown to get all the regularly paperwork and stuff in place and actually have had more time to do this because they had less active trials going on. Though a caveat to that is that a large proportion of their resources were diverted to rapidly setting up Covid-19 trials. Some of these were done at lightning speed and it’s a real tribute to the integrated NHS structure and trials set up in comparison to other countries.

Bermuda

Is this the one that you were thinking about?
https://www.scancell.co.uk/Data/Sites/1/media/publications/posters/paris-lap-poster.pdf

Not a problem in the slightest.

I'm curious as to why Thursday's talk was pushed back. I wonder if there is news imminent and that will happily now coincide with this talk.

Knowlesi,

Bits and pieces. Background working for big pharma in early stage drug research (biologics and small molecule), then small biotech (biologics), then academia (cancer research) and now straddling the academic and cancer research sector (but not bench science any longer). My PhD was in antibody engineering and novel platforms with a focus on melanoma and cervical cancer. So bit of a mixed bag. Been invested in SCLP since 2012, though have hopped in and out a bit. I'm now in a more financially stable position to take a long term view of the company as I recognise the potential that the different platforms have.

Scrap that, I'm getting confused with SCIB2.

Ignore this 1253 post.

Yes - Modi-2.

I apologise, I should have been more specific. In a way, I wonder though whether this is part of the reason why CR UK have not progressed development of Modi-2 further, as they need to understand more about which groups would benefit over others before proceeding into the clinical trials setting.

Inanaco - 1227
When I say pan-indication, LD presented data of T-cell response from 7 lung cancer patients, 3 ovarian and a single breast cancer patient. 7/7 lung cancer patients had a T-cell repertoire against the three Modi-2 peptides (though in differing amounts), 1/3 ovarian responded to all 3 peptides and 1 other responded weakly to Aldo 74Hcit. The other ovarian and the breast cancer didn't respond at all to any of the three. My comment 'At the moment they don't know whether this is pan-indication' was whether this lack of response was across all ovarian or breast cancer patients or whether it is specific to an individual patient.

Inanaco - 1230
This was in peripheral blood mononucleocytes taken from control patients and patients in the above diseases, stained with carboxyfluorescein succinimidyl ester and measured by FACs.

Bermuda

Modi-1 clinical trial was described as being in two parts.
Part 1 - dose comparison to look at high and low conjugate doses.
Part 2 - four tumour-specific expansion cohorts (triple neg. breast cancer, ovarian, renal and if selected for expansion, head and neck cancer as a combo with nivolumab).

Stage 2 monotherapy requires greater than 19% of patients to respond for further investigation.
Stage 2 combo therapy requires greater than 28% of patients to respond for further investigation.

This was presented at the end fo the Modi-1 section.

LD then went on to describe Modi-2 (homocitrullination) and how depleting Ly6G+ and Ly6C+ myeloid cells reduced the anti-tumour response to homocitrullinated peptides, demonstrating that MDSC are required for MPO to enable Modi-2 to work.

One of the final slides was titled 'is there a human T cell repertoire to homocitrullinated peptides'.
In normal patients LD said they (direct quoting here) 'see responses to all epitopes of Modi-2 and said that cancer patients respond - particularly the lung cancer patients, but there is some attenuation in the ovarian cancer patients. We see some response to the Aldo74Hcit epitope, but we have lost the response to the Aldo140Hcit and Vim116Hcit, suggesting that these epitopes are expressed by the tumour but there is attenuation of the response against these epitopes. The question remains about whether the vaccination will rejuvinate these responses or whether we should pick a group of patients where we do not see that attenuation'

LL

Exactly as RP says, Moditope only works in cells where there is stress and autophagy. This really only happens in select conditions and wouldn't generally be occurring together in normal cells. Hence, the potential for limiting off target effects is high and having a hyper targetted effect is also increased. It also is interesting too because a lot of cancers evade therapeutics by mutating (either spontaneous or selective pressure driven), whereas it's pretty difficult (read nearly impossible) for a cancer cell to not be metabolically stressed or have autophagy going on. Hence, moditope could be incredibly powerful, selective and cover a broad range of tumour types.

RP

The big take home I think from this (both Modi-1 and Modi-2) is that success in different cancer types is dependent entirely on the CD4+ response. Unfortunately in some cancers (in LDs presentation some ovarian and breast cancer patient samples) did not express a CD4+ response against the citrullated peptides. Hence, Moditope may not be appropriate for those as you are unable to induce a response. Thus 'continuing on and on as new cancers are added' is highly dependent on expression of these CD4+ cells. At the moment they don't know whether this is pan-indication, or whether subsets of patients with a disease respond and others won't. Understanding that is key to being able to design clinical trials to answer these questions.

RP

Unfortunately LD didn't say how many mice this was in, but I would assume to be able to draw conclusions they will have used a number that is appropriate for this experiment. The three R's of animal research (replacement, reduction and refinement) here will influence whether there is more work on the combo testing. I suspect that ethically this work may not be expanded much further due to this, though unsure as what the sample size for this was and so whether it needs expanding to give a firm answer.

If you look at the ****** meier chart you see the following:
Control
Day 22 - 70% survival
Day 29 - 20% survival
Day 55 - 10% survival continuing until Day 60 (end of graph)

PD1 only
Day 22 - 90% survival
Day 24 - 60% survival
Day 32 - 50% survival
Day 35 - 40% survival
Day 42 - 30% survival continuing until Day 60 (end of graph)

Modi-1 only
Day 22 - 90% survival
Day 29 - 80% survival
Day 38 - 60% survival continuing until Day 60 (end of graph).

Modi-1+PD1 combo
Day 42 - 90% survival continuing until Day 60 (end of graph)

Take home points - PD1 actually progresses relatively similarly to the control mice. Frustratingly there is no comparison between Modi1 alone and control, so we can't see whether this is statistically significant, but eyeballing the graph it looks as if it is (probably 0.01 I would guess). The fact that Modi-1+PD1 combo, vs Modi-1 alone is not significant is a plus as it suggests that Modi-1 is the driving force behind the survival of these animals. Hence actually improving this significance, would suggests synergy (i.e. Modi-1 not having as much of an effect), decreasing it would suggest that the Modi-1 combo is being driven more by the Modi-1 peptides rather than PD1 which could be seen as a benefit as a stand alone therapy. I guess this could be interpreted as a negative if SCLP were planning on licensing Modi-1 for use with PD1 combo therapy rather than outright sale. So depending on which direction the company want to take this in, depends I think on whether you want to have Modi-1 working better as a stand alone or a combo therapy.

Ivy, definitely. I think this is one of the selling points. Firstly we know that not all patients respond to PD1 therapeutics, secondly, we know that those who do response sometimes stop responding. So if you can add a second compound on which in itself as a stand along therapy is good in its own right is a promising step. I think the big thing with all of this though will be cost of manufacturing, cost of delivery. Obv. SCLP have been approved for clinical trial, so it doesn't seem to be too much of a problem at the small scale, but it would be interesting to see whether some of the hesitation comes from scaleability.

Immunobody on the other hand, as it's DNA based is relatively easy to scale. Peptides are costly to scale and have lower yields the longer they become and the more post-translational modifications you add. Hence, Moditope has some technical and manufacturing hurdles it needs to clear.

Bermuda

Not a problem in the slightest, was really interesting actually. I think the Amplivant stuff was also critical to the success of Modi-1, in so far as mg amounts of peptide were required for clinical action, however amplivant allowed this to be decreased 100-1000 times (so more then 1-10 ug amounts). What I didn't gather and I might follow up on this is whether that is ug total or ug/kg. If it's the latter then this possibly will be a hurdle to commercialisation as the cost of peptide synthesis is far higher than a small molecule compound or even a biologic.