Scancell Share Discussion Threads

[ruckrover] 08/3/2023 18:24

Still dropping - 15p "on the cards"?

[torquayfan] 08/3/2023 14:50

Step - Partygate is just a label but a fair one in the context of such happenings during those Covid times. 126 fines! But a Starmer conspiracy has been suggested LOL - pull the other one Guys! This stuff emanates from a 'Boris can do no wrong' position but he has no credibility left, at all. Not one iota!

[the real lozan] 07/3/2023 16:05

'Mr Step, a 'drink at your desk' doesn't normally ' result in police issuing 126 fines.... let alone leading to the removal of 2 ( or maybe more ) so called leaders of a countries rulers
,
Much more to come out... in due course..
.
One might ask -Would some folks opinions differ ,,, if views were not held by those who had/have a financial interest in the 'eventual outcome' of what has transpired ???

[ruckrover] 07/3/2023 15:21

Strange, but true!

[inanaco] 07/3/2023 14:58

strange post Ruck

[ruckrover] 07/3/2023 14:33

MT,Is there anything to suggest one of those small biotechs is Scancell?Or is Inan getting ahead of himself again?

[markingtime] 07/3/2023 13:26

Merck are evaluating the science in some smaller biotechs. They have said they intend to take some over (at the JPM conference, as reported on Bloomberg TV).

[markingtime] 07/3/2023 13:24

Breaking the swing was the Civil Service's doing...that was THEIR party whilst Johnson was at Chequers....

[stepone68] 07/3/2023 13:20

The point of my post was how the media refer to it as 'partygate' to make it sound worse than it was.

[inanaco] 07/3/2023 12:58

ask lindy ATB she has already mention BioNtech

[ruckrover] 07/3/2023 12:24

Inan,

You state:

"this is why Big Pharma is very keen on this data"

Do you know which pharmaceutical companies are "very keen"? Are they evaluating at the moment?

[inanaco] 07/3/2023 11:29

Discussion
ENO1 is a PDAC-associated antigen, capable of eliciting an anti-PDAC T cell response in situ, as demonstrated in a previous study, where we characterized the effector functions of ENO1-specific T-cells isolated from the tumor tissue of PDAC patients (24). We showed that ENO1-specific Th1/Th17 cells have a specific anticancer effector function, but they accumulate in the healthy tissue surrounding the cancer cells, where, conversely, there are elevated levels of ENO1-specific Tregs (24). Based on these observations, we hypothesize that the tumor microenvironment negatively influences the cytolytic activity of T lymphocytes by promoting the recruitment of specific Treg cells. To investigate this hypothesis, we characterized the ENO1-specific peripheral T cell response in the same previously-enrolled PDAC patients (24) to ascertain whether or not the T reg pool was still maintained.

Firstly, we showed that PBMCs from ten PDAC patients were able to proliferate in vitro in the presence of ENO1, while only three healthy controls reacted upon antigen stimulation. This indicates that most PDAC patients have ENO1-specific T cell precursors in their peripheral blood, which can be triggered by in vitro ENO1 re-stimulation. The presence of the anti ENO1-precursor appears to be PDAC-specific as very few healthy subjects displayed peripheral blood lymphocyte proliferation in response to ENO1 and also, a significantly lower index of proliferation.

To gain information on the functional status of anti-ENO1-specific peripheral T lymphocytes, we obtained ENO1-induced T cell lines and subsequently generated Tcc from all PDAC patients, with the exception of three patients (Pcp 3, 6 and 10). Notably, none of the PBMCs isolated from these three patients proliferated in the presence of ENO1, even though ENO1-specific Tcc were obtained from the tumor area in two (Pcp 3 and 10) out of the three patients (24). The lack of ENO1-specific T cells in the peripheral blood of these patients, is probably due to a difference in the migratory pattern of tumor-specific T cells (39), or to differences in the tumor microenvironment, in cytokine/chemokine secretion (40) or altered protein expression (such as integrins), which circumscribe the immune response in situ (41,42).

In addition, we did not analyze ENO1 expression in the tumor tissue of our patients, and we therefore cannot exclude the possibility that the absence of a T-cell response in one patient may result from reduced levels of ENO1 expression. We have shown, in fact, that the anti-ENO1 humoral and cellular responses are induced as a consequence of enhanced ENO1 expression in PDAC tissues (24).

However, the most important result is that the peripheral anticancer response is a ‘mirror’ of the intratumoral PDAC-specific response, clearly demonstrated as the majority of patients displayed both immune responses with only two exceptions. Thus, analysis of the Tcc of the peripheral immune response in PDAC may be an adequate method to determine if a patient will have a cancer-specific immune response in situ.

The peripheral blood of PDAC patients has been shown to display serum anti-ENO1 IgG autoantibodies (26) and here, we provide the first evidence that, in PDAC patients, the overall percentage of peripheral ENO1-specific T cells, reaches one third of the total Tcc obtained.

With the exception of one patient (Pcp10), all patients had detectable serum anti-ENO1 IgG, and interestingly, those with higher titers had the highest percentage of ENO1-specific T clones, in particular patients 9 and 15.

Remarkably, out of the 54 ENO1-specific Tcc obtained, 51 were CD4+ and the vast majority of them (69%) displayed a Th1/Th17 profile, thus conferring to them a potential anti-cancer role (43–46). Of the remaining CD8+ Tcc, one displayed a Treg profile and two were Tc1.

Previously, we have confirmed the immune-suppressive role of the PDAC microenvironment, demonstrating that intratumoral ENO1-specific CD4+ T cells displayed an increased number of T null cells and a Treg phenotype (24). On the contrary, the present data demonstrate that, within the same patients, circulating ENO1-specific Tcc showed a different cytokine profile compared to Tcc isolated from the tumoral tissue, with an increased IFN-γ secretion and a decreased regulatory profile. In agreement with these findings, we have also demonstrated that the few Tc1 and all the ENO1-specific IFN-γ-producing CD4+ Tcc had cytotoxic activity and most of them induced apoptosis in target cells, showing an effective anticancer role.

Of particular relevance, the analysis of TCR rearrangements of some ENO1-specific peripheral and intratumoral Tcc from the same PDAC patient confirmed the ability of tumor-infiltrating lymphocytes to circulate. Therefore, cytotoxic ENO1-specific Tcc that reach the tumor could be subsequently modified and switched off by different immunosuppressive mechanisms including PD-1/PD-L1 (41,42).

""""However, because of the retained cytotoxic ability and potential antitumor function of peripheral ENO1-specific Tcc, they could be very important for the elimination of cancer-circulating cells and prevention of metastasis and disease relapse""""

[inanaco] 07/3/2023 11:14

Anti-tumour immune responses to modified self-epitopes
Patent number: 11382985
Abstract: The present invention relates to modified citrullinated enolase peptides that can be used as targets for cancer immunotherapy. These peptides can be used as vaccines or as targets for monoclonal antibody (mAb) therapy. Such vaccines cur mAbs may be used in the treatment of cancer.
Type: Grant
Filed: March 19, 2020
Date of Patent: July 12, 2022
Assignee: Scancell Limited
Inventors: Linda Gillian Durrant, Victoria Anne Brentville, Rachel Louise Metheringham

[inanaco] 07/3/2023 11:12

folks have no clue of the pent up value in Scancells target line up ... or just how easy it is to verify Scancells data

forget statistics ... read the evidence

ATB

[inanaco] 07/3/2023 11:10

ENO1 was proved to be involved in DNA replication, cell cycle, apoptosis, glycolysis process, and other processes. These findings indicate that ENO1 is a potential prognostic biomarker that correlates with cancer progression immune infiltration.

Besides its major role in glycolysis, ENO1 is also considered as a multifunctional protein demonstrating various distinct activities (9). Previous studies found that the upregulation of ENO1 was positively correlated with progression and poor prognosis in breast cancer, prostate cancer, thyroid carcinoma, hepatocellular carcinoma, cholangiocarcinoma, neuroblastoma, neuroendocrine tumors, lung cancer, and pancreatic cancer (4, 9–13). Consistent to previous studies (2, 4, 14–23), more details are summarized in Supplementary Table 1 . Additionally, increased ENO1 expression has been observed in different types of drug-resistant cancer cells, suggesting the potential use of ENO1 as a biomarker for drug resistance and as a target for cancer therapy (5). ENO1 also involves in cell adhesion-mediated resistance in non-Hodgkin lymphoma and tamoxifen resistance in breast cancer (24). ENO1 has been shown to induce autoantibodies in patients with cholangiocarcinoma, breast cancer, head and neck cancer, leukemia, lung cancer, pancreatic cancer and melanoma (25–28). The correlation between tumor and autoimmunity may be due to the immunogenicity and proinflammatory stimulation produced by tumor cell death, as well as the activation of inflammatory process in tumor microenvironment, thus increasing the expression of autoantigen to the immune system (29). ENO1 is a major auto-antigen. ENO1 specific T cells from peripheral blood to tumor are inhibited by a number of immunosuppressive mechanisms (17). Their presence in the peripheral blood is associated with the prevention of metastasis by excision of cancer circulating cells (30, 31). One explanation may be that tumor cells physically absorb and neutralize ENO1 antibodies expressed and secreted on the surface to reduce circulating levels.

[inanaco] 07/3/2023 11:06

you may think that cancer stem cells are a tough cookie ....... they are but most express Alpha ENOLASE a peptide in the Modi1 vaccine

here is third party evidence including pancreatic cancer and lung cancer they can't all be wrong can they ....

this link if you scroll down gives you further example i have taken bits from those to

Alpha-enolase (ENO1) is a metabolic enzyme involved in the synthesis of pyruvate. It also acts as a plasminogen receptor and mediates the activation of plasmin and extracellular matrix degradation. In tumor cells, ENO1 is up-regulated and supports the Warburg effect; it is expressed at the cell surface, where it promotes cancer invasion, and is subjected to a specific array of post-translational modifications, namely acetylation, methylation and phosphorylation. ENO1 overexpression and post-translational modifications could be of diagnostic and prognostic value in many cancer types. Information on the biochemical, proteomics and immunological characterization of ENO1, and particularly its ability to trigger a strong specific humoral and cellular immune response, make this ubiquitous protein an interesting tumor target; DNA vaccination with ENO1 in preclinical models efficiently delays the development of very aggressive tumors such as pancreatic cancer. This review aims to analyze the main stages by which the tumor associated antigen (TAA) ENO1 has become a promising target that opens potential avenues for cancer immunotherapy.

Methods: Immunofluorescence was used for antigen localization. After targeted antigen purification by electrophoresis and immunoblot, the antigen was identified by LC-MALDI-TOF/TOF mass spectrometry, immunofluorescence, and immunoprecipitation. The overexpression or silence of ENO1 was induced by lentiviral transduction. Self-renewal, growth, and invasion of LCSCs were evaluated by sphere formation, colony formation, and invasion assay, respectively. High-throughput transcriptome sequencing (RNA-seq) and bioinformatics analysis were performed to analyze downstream targets and pathways of targeted antigen.

Results: Targeted antigen showed a surface antigen expression pattern, and the 43-55 kDa protein band was identified as α-enolase (ENO1). Self-renewal, growth, and invasion abilities of LCSCs were remarkably inhibited by ENO1 downregulation, while enhanced by ENO1 upregulation. RNA-seq and bioinformatics analysis eventually screened 4 self-renewal-related and 6 invasion-related differentially expressed genes. GSEA analysis and qRT-PCR verified that ENO1 regulated self-renewal, invasion-related genes, and pathways. KEGG pathway analysis and immunoblot demonstrated that ENO1 inactivated AMPK pathway and activated mTOR pathway in LCSCs.

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Conclusions: ENO1 is identified as a targeted antigen of mAb 12C7 and plays a pivotal role in facilitating self-renewal, growth, and invasion of LCSCs. These findings provide a potent therapeutic target for the stem cell therapy for lung cancer and have potential to improve the anti-tumor activity of 12C7.

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The α-enolase (ENO1) plays pivotal roles in several types of cancer, but its clinical significance, functional role, and possible mechanism in colorectal cancer (CRC) have remained unclear. Expression level of ENO1 in CRC tissues was examined by qRT-PCR, Western blot, and immunohistochemistry. The effects of ENO1 on cell growth were investigated by MTT, colony formation, flow cytometry assays, and in vivo tumorigenic capacity analysis. The impacts of ENO1 on cell migration and invasion were also explored by scratch-healing, Transwell or Matrigel chamber assays, and in vivo metastatic capacity analysis. Our results showed that the expression level of ENO1 was significantly elevated in CRC tissues. High expression level of ENO1 was associated with disease progression in CRC patients. Overexpression of ENO1 in HCT116 cell line promoted cell proliferation, migration, and invasion in vitro as well as tumorigenesis and metastasis in vivo. In other hand, ablation of ENO1 in HCT116 cells led to totally reverse effects. Mechanistically, we revealed ENO1 could regulate AMPK/mTOR signaling pathway. AMPK pathway activation or mTOR pathway suppression blocked these ENO1 induced alterations. Together, our results demonstrated that ENO1 is a potent promoter of CRC genesis and metastasis at least in part though regulating AMPK/mTOR pathway. These findings also suggested that ENO1 may be a promising therapeutic target in CRC patients.

[inanaco] 07/3/2023 10:46

With all trials you are going up against standard of care ... so Chemo would be given and check points if approved etc ... and we pick up patients that have failed on these treatments as explained Chemo leaves "resistant" cancer Pd-1 patients have also gained further resistance that's before you try Modi1 ...



but the patients having surgery are not .... they are treatment naive giving scancell a chance to see what the cancer looks like with just Modi1 t cells and Modi1 t cells with checkpoint in patients that have ""not gained resistance"" from that, its possible to design further trials using Modi1 as a first line treatment from what they see, and if its as exciting as we suspect. Do we generate memory ? what we do not know if after resection the patient would go onto Chemo or would they consider time to give Modi1 memory t cells a chance to clear cancer stem cells

this is why Big Pharma is very keen on this data



SCCHN:

o Neoadjuvant expansion cohort only; patients who are treatment-naïve and are scheduled to have tumour resection surgery, in whom a period of 6 weeks of neoadjuvant immunotherapy can be administered. Patients will only be enrolled once the Modi-1 expansion doses and a lack of increased anti-CCP antibodies (with, and without, concomitant pembrolizumab) has been established.

[the real lozan] 07/3/2023 10:43

Step -
I might admit -"I must admit, the word 'partygate' annoys me."
In fact, I am glad 'partygate' annoys some...IT SHOULD
In expressing your opinion.I am sure you won't mind if others are FREE to express/HOLD the opposite view.

[markingtime] 07/3/2023 10:19

My point was simply that the comparison with/without checkpoint will be interesting. Possibly both contribute something - and analysis of tumours should give a good indication of what has worked to produce the shrinkage.

[inanaco] 07/3/2023 09:27

The analysis of resected tumours could be crucial? that bit is right ...

but previous treatment with checkpoint is not really relevant as that is more to do with supporting the patients own immune system to kick start, its actually makes scancell job harder as the cancer has halted that response and then continued to progress. Unlike a vaccine or a natural immune response you would not develop memory to the Check point MAB once they have been effectively used up by T cells your body would be clear of them within a few months ..every time a t cell expands it's progeny would require another MAB so you can see how you would lose its function over time

[stepone68] 07/3/2023 09:18

I must admit, the word 'partygate' annoys me. I don't think any of the events were what I would call a party. Most were just a drink at their desks after a long day of work, but the media persist with partygate because it makes it sound worse than it actually was.

[markingtime] 07/3/2023 08:32

Not at all, tf. I didn't vote for him or for his candidate. I'm simply pointing out that he continues to be stitched up by Starmer and Co who continue to peddle their lies and smears.Because of that - and only because of that - I would probably vote for him next time if the opportunity arises.Thanks for the trip wishes.... 24 hours of joy beckons....

[markingtime] 07/3/2023 01:59

Starmer is being deliberately evasive. There will be a reason for that.Same as with Durham, obfuscations and evasion pending investigation by the police.....whose chief got a big new long contract awarded (by Labour PCC) less than a week before he declared there was nothing to see.Starmer is the liar here.....he spent months smearing Johnson as personally participating in a series of parties - which he didn't - and has so far got away with it. For now. Meanwhile...last day of hols for me.....

[torquayfan] 07/3/2023 00:24

Inan - have you nothing else to do ? If not, that's sad. BFN