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The CIMT Annual Meeting abstracts have now been published in full - just click the '2024 Meeting Abstracts' tab towards the top of the page in the link below.
https://www.meeting.cimt.eu/call-for-abstracts
Thanks Bermuda. When you have had time to rake through, it would be good to know . . . anything you find. Come on you Techies !
isolation and characterisation of tcrs that recognise citrullinated and ****citrullinated post translationally modified peptides
s. paston1 , r. choudhury2 , s. shah2 , g. cane1 , j. chadwick1 , r. metheringham2 , f. master1 , r. herbertson3 , l. durrant1,2
1 scancell ltd, oxford, united kingdom
2 scancell ltd, nottingham, united kingdom
3 brighton and sussex university hospitals, brighton, united kingdom
under conditions of cellular stress, proteins can be post translationally modified causing them to be recognised by the immune system. one such stress induced post translational modification (siptm) modification is citrullination, the conversion of arginine residues to citrulline by peptidylarginine deiminase (pad) enzymes. we have previously shown that targeting citrullination can induce cd4 responses that provides efficient tumour therapy in vivo in a process mediated by autophagy.
we are currently running a phase 1/2, multicentre, open-label study of modi-1 in patients with breast, head and neck, ovarian, or renal cancer (the modify study) study. the moditope® vaccine incorporates two citrullinated vimentin peptides (vim28cit and vim415cit), and a citrullinated a-enolase peptide (eno241cit), each conjugated to the toll-like receptor (tlr)1/2 ligand adjuvant amplivant®. sixty percent of patients receiving modi-1 monotherapy show stable disease and one patient showed a partial response. currently we are recruiting patients receiving modi-1 in combination with checkpoint inhibitors.
eighty three percent of patients make a t cell response to eno241cit, we have isolated a tcr from one of these patients. single-cell rna- & tcrseq was performed on sorted cd4+ ifnγ+. rnaseq analysis revealed these are cytotoxic cd4 t cells, using lentivirus-tcr transduced t cells we have successfully shown that two isolated tcrs react specifically to eno241cit peptide with little or no recognition of the wild type peptide. the epitope has been mapped and the presenting hla allele identified.
another post translational modification is the carbamylation of lysine to ****citrulline. this reaction occurs when isocyanic acid reacts with the amine (nh2) groups on lysine to yield ****citrulline. the carbamylation of amine groups leads to a change in molecular charge, which in turn alters antigenic properties and can lead to the generation of unique t cell and antibody epitopes. we have successfully isolated a cd8 tcr that specifically recognises a post translationally modified peptide from aldolase. the tcr recognises a 9mer peptide that has been modified with the conversion of lysine to ****citrulline at position 7 (vlaavy-hcit-al).
using lentivirus-tcr transduced t cells we have shown that the ****citrulline peptide is recognised and not wildtype, the epitope has been mapped and the hla restriction confirmed. t-cell based immunotherapy has achieved remarkable clinical responses in cancer patients. our own data in preclinical mouse models have sh
Four observations for me are as follows:
Author affiliations - none of the people listed seem to have links to BioNTech - does this mean that the 2018 collaboration to identify TCRs from moditope vaccinated people has gone quiet? Does this mean we're exploring these ourself - if so, this can be value add?
CD4+ T-cell confirmed and mapped - this demonstrates that the underlying mechanisms behind moditope are working - we are able to generate CD4+ T-cells against the moditope vaccine in patients. This evidence in addition to the resected patient information may prove beyond all doubt that moditope works and is capable of generating CD4+ responses in patients - this was something LD highlighted was high on the list that potential pharma companies would want to see. Furthermore, they stress that there is little or no-recognition to wild type - highlighting how specific this TCR is to the siPTM modified peptides.
CD8+ T-cell confirmed and mapped - this is curious to me, as LD has been keen to stress that moditope targets CD4 cells and not specifically CD8 cells. So the fact they have identified this TCR is also interesting.
Finally, from a IP perspective, I wonder what work is being done to secure this? Given that it is being presented, I'm a bit stumped as to what the IP position is on this.
Also to add 60% of patients showing stable disease with one patient showed (past tense) a partial response. That in itself is v.interesting addition. Curious how many people have been dosed so far and how many patients this 60% stable disease refers to.
Excellent technical summary Burble, thank you.
I asked about BionTech and the Moditope 'T' Cells back at the 2022 AGM. A that time LD was very positive that BionTech were still very much interested and those cells were being harvested at that time. So as you say its quite puzzling why we are going ahead with this research on our own.
Could it be that our price as gone to high !!
The bit that attracted my attention re poster 1 was a bit that was cut off the end of your copy, Burble: viz “…..complete regression of 70% of established tumours”
Also, no copy or comment re the 3rd poster on SCIB1? Or is there nothing new there?
Hi Burble,
Appreciate you taking the time to share your thoughts which have helped me focus on relevant points. So early data shows Moditope has demonstrated potential in humans. Not getting carried away but this is encouraging.
burble,
regarding your cd8+ /cd4+ t cell comment. scancell published some research back in september showing they had identified a cd8+ t cell response to some ****citrullinated peptides:-
'there is ample evidence suggesting an important role of cd8 t cells in eradicating tumor cells. here we present data for a novel class of antigens recognized in the tumor microenvironment by cd8 t cells. our previous studies have demonstrated that ptm specific cd4 t-cell responses provide survival benefits against aggressive tumor models in mice and suggest the presentation of modified epitopes in the tumor environment. in this study, we have shown the first evidence of cd8-mediated responses to hcit peptides and demonstrated that these are capable of selectively recognizing the modified but not the wt epitopes.'
https://jitc.bmj.com/content/11/10/e006966
Thanks Berm, that’s helpful to not take my inferences out of context. Both therefore also highlights that moditope is seen by both sides of the immune system which so good, especially if both can be harnessed.
Bojo,
I think the real excitement may come with the checkpoint inhibitor patients, if you look at things like Keytruda, it’s Ph1 trial wasn’t amazing but good enough to allow continuation of the trials. Larger cohorts then demonstrated clinical application and utility.
The fact modi is showing activity is good but I think the later cohorts will help demonstration further it’s clinical application.