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A vaccine that deals with such a situation should be designed to generate low-avidity T cells, since those might be more suitable to generate a pool of long-lasting effector T cells in a situation of chronic infection.
Sorry last bit was missing
now it works against the N because a natural infection picks it up
But ...................... where is the High Avidity this is the differential
https://www.hindawi.com/journals/jir/2012/153863/
Functional Avidity: A Measure to Predict the Efficacy of Effector T Cells? - Hindawi
The functional avidity is determined by exposing T-cell populations in vitro to different amounts of cognate antigen. T-cells with high functional avidity respond to low antigen doses. This in vitro measure is thought to correlate well with the in vivo effector capacity of T-cells. We here present the multifaceted factors determining and influencing the functional avidity of T-cells.
www.hindawi.com
9. Summary
Functional T-cell avidity is a critical attribute of antiviral and antitumoral immunity. The strength of interaction between the TCR and pMHC-molecule, expression levels of the coreceptors, as well as signaling particularities are pivotal in determining the functional avidity of a T-cell clone.
It is well established that T-cell populations can over the course of infection or upon multiple exposure to infections or infectious exacerbation undergo significant changes in the ability to recognize cognate antigen. The later is at a first glance somewhat surprising as T cells, unlike B cells, express a fixed TCR and cannot undergo somatic hypermutation. Predominantly, the clonal composition impacts the functional avidity of the T-cell population and avidity maturation. In addition to the reinforcement of the immunological synapses through the formation of TCR clusters, the optimization of the signal transduction machinery further contributes to avidity maturation. However, the understanding of mechanisms underlying this phenomenon is still limited, and further studies need to be undertaken to better understand how all these possible variations and likely many yet unknown ones impact the functional avidity of T cells when responding to different types of infections.
In the context of viral infections, functional avidity maturation allows faster virus clearance by recall T-cell responses. However, the role of high versus low functional avidity T cells in chronic viral infections such as HIV remains unclear. Here, it needs to be considered that high-avidity T cells exhibit greater T-cell exhaustion and lead to rapid emergence of escape variants suggesting a pivotal role of low-avidity T cells.
Studies to better delineate the factors influencing the functional avidity of T-cell responses are relevant in order to allow fine tuning of the profile of vaccine-induced T cells. We consider that the goal of vaccination or immunotherapy against acute infections and to induce pathogen clearance should be the induction of high-avidity T cells, since such cells most effectively eliminate infected cells. Conversely, when pathogen clearance cannot be achieved, then the ultimate goal is to provide durable control of a persistent pathogen. A vaccine that deals wit
Done a bit of digging into the competition ..
Immunity Bio ....... AD5 Vaccine against the "N" and the "S"
result in Cancer
n conclusion, the clinical data obtained using the Ad5 [E1-, E2b-]-CEA(6D) demonstrate that this product can be easily and safely administered to mCRC patients to induce CEA directed CMI responses. Although no objective antitumor responses were observed, there appeared to be favorable survival with an observed median overall survival of 11 months. A small number of patient PBMC samples were available for follow-up immune analyses and although the sample size was small, the results obtained indicate that the generated CEA directed CMI responses induced might require additional booster immunizations to maintain the induced immune response.
hTTps://www.clinicaltrialsarena.com/news/immunitybio-vaccine-preclinical-study/
hTTps://www.biorxiv.org/content/10.1101/2020.07.29.227595v1
hTTps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506904/
No evidence of High Avidity Potent T cells .....
SCIB1 was already in Trial .......
Immunology. 2012 Jan; 135(1): 19–26.
doi: 10.1111/j.1365-2567.2011.03517.x
PMCID: PMC3246649
PMID: 22044118
T-cell-inducing vaccines – what's the future
Sarah C Gilbert
Antigen delivery for T-cell induction
What conclusions can we draw from the above to aid us in choosing the type of vaccine to use for induction of protective T-cell responses? DNA vaccines were at one time thought to be the ideal way to induce T-cell responses. After injection they express the encoded antigen inside the host cells resulting in both cellular and humoral immunity. They can be manipulated to express cytokines or other molecules intended to enhance the immune response, and are simple to produce.59 Unfortunately, the early successes in pre-clinical studies did not translate into clinical trials, and
""whereas DNA vaccines are safe to use and do induce T-cell responses in humans, they are of a very low magnitude.21 Efforts to increase immunogenicity by use of a ‘gene-gun’ resulted in more efficient delivery such that the dose could be considerably reduced, but the response was not increased, and although efforts to find an adjuvant to increase the immunogenicity of DNA vaccines in humans, success has so far been modest.60 The same is true of peptide vaccines.61,62 """"
Other research has concentrated on developing adjuvants to increase the immunogenicity of protein vaccines, reviewed in ref. 63, but again although responses can be induced in pre-clinical studies, they are not of high magnitude and in many cases have not yet been tested in clinical studies. Of all the replication-deficient viral vectors available, adenovirus is the most potent in priming T-cell responses to the recombinant antigen, and recent studies employing simian adenoviruses or rare human serotypes appear to hold the most promise. As extremely high T-cell responses can be primed with a single dose,38 the problem of anti-vector immunity is largely avoided.
Recombinant replication-deficient poxviruses have also been used with considerable success, and when used to boost an existing response rather than prime a novel one, the response becomes focused on the recombinant antigen rather than inducing significant anti-vector immunity.64 Replication-deficient viral vectors can be manufactured at large scale, thermostable formulations are available65 and the number of clinical trials now completed or underway is testament to the broad utility of these vectors.66
Complex therapeutic regimens requiring ex vivo treatment of patient's lymphocytes have been trialled for use against cancer, but there is no plausible reason why the most immunogenic vaccination regimens tested for infectious diseases should not also be highly effective at inducing T-cell responses against cancer antigens. Pre-clinical studies demonstrating that tolerance to self-antigens can be broken have been performed.67
i am happy to post, providing there are no personal attacks.
No opinions /facts are completely accurate Ruck, they are interpretations.
I am sure other are happy to read a decent post, and i,m not intending to proof read his post,as clearly as i do not have the understanding that he may have.
I cut and paste only what Inan requests from me.
If you have any observations , i would suggest that you direct then to him on the other boards
I am only the postman.
Scancell so far is the world leader and the only group to have developed a vaccine specific for CD4 T cells that are cytotoxic .
In this review you will see evidence of their existence
Don't forget these are "effector T cells" you will see this mentioned and the important role they play in controlling cancer
what's interesting here is our nemesis "suppressor CD4 T cells" and the possible ways they can be flipped to "Effector function" makes very interesting reading
Scancell has gone about this change using potent T cells and clonal expansion to flip the environment from Suppression to effector, but this article highlights the potential of Combinations that could assist Moditope in this critical path of clearance of Solid Tumor ... You have to shift the balance to the immune system
with Immunobody its the addition of Keytruda that gives the synergy to flip
Scancell is at the Start of this revolution in cancer treatments and holds the patents across all the targets in all cancers against the SIPTM's citrullinated and homo-citrullinated peptides and some enzymes conversions as well like Enolase
hTTps://www.nature.com/articles/s41417-020-0183-x
Review of CD4 T cells (moditope)
Conclusions and perspectives
In this review, we present recent literature showing that CD4+ T cells are a critical cornerstone of optimal anti-tumour immunity. Engagement of the CD4+ T cell compartment is associated with the generation of an effective anti-tumour response, even when CD4+ T cells themselves are not the primary immune cell subtype targeted by therapy. We highlight the emerging consensus that the majority of these tumour-specific CD4+ T cells are self-reactive, and juxtapose this against observations from preclinical studies that self-antigen-biased regulatory T cells can themselves mount anti-tumour responses when appropriately conditioned. These recent ongoing developments also present fascinating prospects for the engineering of CD4+ T cells for ACT. In conclusion, harnessing the full potential of the immune system for cancer immunotherapy will require a deeper understanding of, and rational targeting of self-reactive CD4+ T cells to sustain a durable, robust anti-tumour response towards clinical benefit while minimising autoimmunity.
hTTps://youtu.be/j80CDhunTAE
As I mentioned yesterday, regarding funding and Cepi, If you look at the slide on Covid vaccine "supported by Innovate Uk" Scancell used in the RNS
I know some have read into this statement as further funding would be needed for the phase 1 trial ""initiated phase 1 clinical Trial"" as from RNS
however if you look further down in the RNS
The Company's aim is to use this proven technology platform to produce a simple, safe, cost-effective and scalable vaccine that induces both durable T cell responses and virus neutralising antibodies (VNAbs) to provide long lasting immunity against COVID-19. With Scancell set to receive approximately £2m of the consortium awarded funding, """the Company expects it to cover the majority of the development and Phase 1 trial costs."""
So its my considered Opinion Scancell may apply for Funding From Cepi as a project going forward. However we might not hear anything until the phase 1 trials have given us blood work Data but with the knowledge that the cash flow allocated to the cancer programs will not be impacted.
What we do know Scancell cannot start cancer trials without ICU support so as soon as that pressure is off and the NHS stops for a cup of tea .. expect an RNS first patient treated on the SCIB1 trial ...
I would also expect an RNS soon regarding the Modi1 trial product has completed successfully the drug fill and finish operations. This really is the Crown jewels if it works ..
well worth listening again to this presentation from Lindy on moditope
hTTps://youtu.be/CXyPYib5JWc
On Moditope TCR ....... I know Lindy has not found yet what She considers the Ultimate little T cell to Clone However Like Lindy has pointed out Vaccinated Patients that have seen clinical evidence of cancer being destroyed by moditope is the best T cells to clone
Evidence of that is Here
"""In other words, our in vitro methods of TCR stimulation may lead to an underestimate of their efficacy in vivo."""
hTTps://link.springer.com/article/10.1007/s00262-019-02468-9
they have even cloned between T cells .... When we transduced our TCRs into NK92, which had been modified to overexpress human CD3, we observed that Radium-1 TCR was functional in this system, independently of the presence of CD8. Likewise, when we tested some of our CD4 T cell-derived TCRs to generate NK-TCR cells, we observed that these cells killed MHC class II+ antigen presenting tumour cells (Mensali, Inderberg and Wälchli et al., unpublished data). These data suggest that vaccinated patient-derived TCR can function without co-receptors.
its a field that is really moving on, but constantly they report "underestimating"
in vitro ....
so i do expect great things if we have patients that respond
...
Preview YouTube video Watch the Scancell Holdings webinar hosted by Vox Markets & Turner Pope Investments
Preview YouTube video
a reminder of .................. hTTps://pubmed.ncbi.nlm.nih.gov/31719197/
Moditope a Cytotoxic CD4 T cell ........
Supercentenarians, people who have reached 110 y of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Here we performed single-cell transcriptome analysis of 61,202 peripheral blood mononuclear cells (PBMCs), derived from 7 supercentenarians and 5 younger controls. We identified a marked increase of cytotoxic CD4 T cells (CD4 cytotoxic T lymphocytes [CTLs]) as a signature of supercentenarians. Furthermore, single-cell T cell receptor sequencing of 2 supercentenarians revealed that CD4 CTLs had accumulated through massive clonal expansion, with the most frequent clonotypes accounting for 15 to 35% of the entire CD4 T cell population. The CD4 CTLs exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of CD8 CTLs. This indicates that CD4 CTLs utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Indeed, CD4 CTLs extracted from supercentenarians produced IFN-? and TNF-a upon ex vivo stimulation. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases.
...
Just noticed something ... not picked up on it before, has anyone noticed a change in Modi3 ?
hTTps://www.scancell.co.uk/Data/Sites/1/media/docspres/scancell-agm-2020_final.pdf
""" Modi-3: potential to treat tumour recurrence """
its a follow on from this post
----------------------------------------------------------------------------------
hTTps://www.nottingham.ac.uk/news/cancer-survivor-funds-groundbreaking-study-to-find-out-why-cancer-returns-in-some-patients-and-not-others
Congratulations to Lindy Durrant and her Scancell team at the University of Nottingham for their incredible work on a potential mutation-resistant Covid 19 vaccine as featured on Sky News.
Professor Durrant is also part of our dedicated and valued Continuum Nottingham University team, researching our unique Continuum cohort of long term cancer survivors. """" We are expecting to announce exciting developments soon """"
So proud of you all.
hTTps://www.continuumlifesciences.com/lindy-durrant-and-her-team-developing-mutation-resistant-covid-19-vaccine/
"""" We are expecting to announce exciting developmen
hTTps://www.nottingham.ac.uk/news/cancer-survivor-funds-groundbreaking-study-to-find-out-why-cancer-returns-in-some-patients-and-not-others
Congratulations to Lindy Durrant and her Scancell team at the University of Nottingham for their incredible work on a potential mutation-resistant Covid 19 vaccine as featured on Sky News.
Professor Durrant is also part of our dedicated and valued Continuum Nottingham University team, researching our unique Continuum cohort of long term cancer survivors. """" We are expecting to announce exciting developments soon """"
So proud of you all.
hTTps://www.continuumlifesciences.com/lindy-durrant-and-her-team-developing-mutation-resistant-covid-19-vaccine/
"""" We are expecting to announce exciting developments soon """"
Ray/WTP
look at it like this .... Curevac/moderna/biontech are trying to build personal neoepitope cancer vaccines at speed all based around MRNA
the speed is because
1/ the cancer clock does not stop
2/ they are trying to get the vaccine itself easily approved so that they don'y have to run a trial for every personal vaccine its the principle of it, so they have had lots of trials in cancer but nothing approved because of the miss match between immune response and efficacy ... so they are forced to play with the check points and all sorts of combinations
Because they have now a proven Spike version of Covid and they can design simple single antigen at speed ... then that is the most effective way to get another shot to the market ....
trouble is that market will be swamped its already getting busy with other single Antigen Spike
so if you can achieve a Potent response using our proven T cells against the N you add a very broad response to an already vaccinated community thus its a one boost vaccine with the added advantage you stimulate another antibody response and the N covers a broad attack against all coronavirus with the same N as its conserved
but the bottle neck is speed of vaccination
you cannot keep a rolling vaccine program adding boosters to the entire population with the risk that every time you update you already maybe to late another variant appears
this is the niche ...... T cells against the N ..........
Scancell then has the upper hand .... its T cells are potent against Cancer
Scancell then adds Avidmab as an "extra boost"
that is a very serious vaccine to go head to head against ... a run of the mill Viral Vaccine
Challenge trials allow that .... Vaccine V vaccine .
"what becomes standard of care"
So much fuss on the LSE blaming Diggles for the Pull Back, a Non executive Director who would sit on infrequent Board Meetings who in reality has an Investment Company that is funded by its own investments !! Scancell does not pay a dividend so the odd capital sale is inevitable ...... they have all done it Calculus and the VCT funds
Reality ........ Market was prepared to pay 29p per share
Folks are selling at 24.5 ....
you maybe booking a profit but at a discount to what the market would actually pay
when it turns just watch how quick it motors
you have seen it from the 11p to 18p and back ... the up again
fun times if you catch it right .......... terrible if you miss it, as buying in on the ramp ups was/is so difficult
But when you look at the "Chance Cards" going forward .......
folks must be crazy to sell ..................
I am not telling any one How to invest ........... only read the long range weather forecast before you do ... it is known
The Potential deals ........ the ""Chance Cards""
Do,nt they say a watched kettle never brews..
Well in our case a watched bb..
Wonder what happened to Puritas all those years ago?
Could he still be in the share?
Think Bobbust yesterday wrote to CH and asked that question.I believe the reply was that they were exploring all options.
basically Sky is playing up the importance of MRNA as its linked to covid ..........
cancer is a far harder nut to crack .........
https://www.fiercebiotech.com/biotech/roche-biontech-post-low-response-rate-cancer-vaccine-trial
Message from Inanaco
Nothing to be concerned about with Chinese vaccine,
ow ! all systems go then ..........
Clear a phase 1/2 study potential straight to phase 3 challenge trials ... OMG
inanaco17 Feb '21 - 10:51 - 36849 of 36853
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I think folks maybe cannot understand the value of that ..........
a normal trial of 20,000 may only produce a 100 measurable infections on each arm
yet here we are getting 90 people infected = 20,000 patient trial
inanaco17 Feb '21 - 10:54 - 36850 of 36853
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think back to AZN approval in the over 65's with very little proof of efficacy which is why the Germans refused it
But the regulators approved it on "anticipated" based on immune response
we really are in the a Race now ........
its vaccine against vaccine ...........
WoW !