Roundtable Discussion; The Future of Mineral Sands. Watch the video here.
Interesting to note - https://www.gov.uk/government/news/chancellor-unveils-a-budget-for-growth.
'The Medicines and Healthcare products Regulatory Agency (MHRA) will receive £10 million extra funding over two years to maximise its use of Brexit freedoms and accelerate patient access to treatments. This will allow, from 2024, the MHRA to introduce new, swift approvals systems, speeding up access to treatments already approved by trusted international partners and ground-breaking technologies such as cancer vaccines and AI therapeutics for mental health.'
The fact it's specifically noted cancer vaccines - suggests that we may continue to have favourable tail winds
The thing is with these events (be it AACR, or PEGS or any other of these huge conferences), is that it's the back room conversations which are why people go. They're not there to listen to academics or industry witter on ad nauseam, so much of this type of conference is about having the appetite whetted through rapid fire, short presentations and breakout sessions with posters, then most people are there for the networking events on the side and after the conference each day.
The full text of the Clinical Trial and Late-Breaking Abstracts will be posted to the AACR Online Itinerary Planner and the Meeting App no earlier than 12:00 p.m. U.S. ET on Friday, April 14, 2023, except those abstracts that are selected for inclusion in the official AACR press program. Abstracts that are featured in the official AACR press program will be made publicly available at the date and time of presentation, either at the meeting or an official AACR press conference.
In previous years, abstracts accepted for presentation at the AACR Annual Meeting were published in an online-only Proceedings supplement to the AACR journal Cancer Research after the conclusion of the meeting. Beginning in 2023, the Proceedings supplement will be published prior to the meeting in two parts. Part 1 of the online Proceedings (regular abstracts) will be published on Friday, March 31, and Part 2 (clinical trials and late-breaking abstracts) will be published on Friday, April 14.
Revised Proceedings supplements containing the full text of embargoed abstracts as well as any late change will be published in Cancer Research approximately one month after the meeting.
If you look at AIM RNS’s there seems a coordinated statement from many - same wording for all those not affected.
When you look down the list, there are a few which have exposure - some minor, others major. So I suspect it’s a requirement of the stock exchange to notify shareholders accordingly.
I feel for those other companies and shareholders who are exposed, sometimes by a considerable amount!
Yup it surprised me too - I blame my racing insomniac brain this morning for asking me that question. But I'm kind of glad I did because it further puts people's minds at ease that we're still early days. Especially if you then compare that to other immunotherapies which take a few months before they start showing promise. Next Modi-1 update should be interesting.
A further observation from me. I was thinking at what we already know about Modi-1 data in the public sphere.
AGM presentation - https://www.scancell.co.uk/Data/Sites/1/media/docspres/agm-presentationnovember-2022_final.pdf
Look at page 11 - there is a bulletpoint which states 'tumour regression seen within 4 days of Modi-1 vaccination'
If you think about mice models, it's generally suggested that 9 mouse days is the equivalent to a year as a human (https://www.sciencedirect.com/science/article/abs/pii/S0024320515300527?via%3Dihub). Or 1 mouse day is approximately 40 human days. I wonder whether many people following this share have conflated the two and thought that we would be seeing regression within 4 days. Yes in mouse models, but this is humans we are now talking about.
So based on the Scancell data if this translated directly into humans, we should be looking at starting to see regression of tumours from about 160 days i.e. nearly 6 (5.2) months into the trial.
Look at Figure 2Aii on the Modi-1 paper (https://jitc.bmj.com/content/jitc/8/1/e000560.full.pdf). The circles indicate the day of immunisation and X indicates day of tumour analysis. For some of these mice, you see an immediate regression of tumour bulk. But for some (blue, pink, orange) you see stabilisation of their tumour without regression over about a 10 day period (i.e. approximately a year in human time) before which animals were sacrificed and tumours analysed. In the control, you see continued tumour growth. This is then shown again in the 2Aiii figure waterfall plot. We don't know how long this stabilisation continues because the mice are sacrified early, but if that continued for longer, then you could be looking at a patient who has exhausted all current treatments, being given at least a year if not more to their lifespan even if Modi-1 doesn't remove tumour bulk.
In the rechallenge work that was done also in this paper, this was performed in mice at 58 days. So in humans that would suggest a rechallenge equivalent in humans of 6 years after the initial dosing of Modi-1.
Taking those together, what we saw in the mouse model data is being reflected in what we are seeing in the clinic.
You could also see it from the angle that getting this type of news out there earlier will drive recruitment of the trial and also drive site set-up. You don't want to be the single site that hasn't pulled its finger out and got the trial open before it finishes recruitment.
C7
As expected. I wasn't expecting major fireworks - we know of one patient who has had a prompt response, but as these things take time to show, I wasn't expecting more than that if I'm honest with you.
To me the key take home was 'no dose limiting toxicities' and that it was 'safe and well tolerated'. These patients were the first to try a new class of medicines and tbh, there really is some heroism/altruism in making that decision - even given the circumstances that these patients find themselves in at that stage of their disease.
Early efficacy in Head and Neck, Ovarian and TNBC is also incredible - these are all hard to treat cancers which have limited treatment options available to them. If we take things in context, patients had progressive disease prior to enrolment. But 8 weeks later their disease is considered stable. That's good enough for me.
If you reflect on the Phase 1 trial of keytruda ($17.2bn in sales in 2021) - out of 30 patients treated (32 enrolled) (https://pubmed.ncbi.nlm.nih.gov/25977344/), 2 showed a complete response, 3 experienced partial response, 15 experienced stable disease, 1 died of a cryptococcal infection (considered drug related). 2 patients didn't recieved treatment due to rapid tumour progression and ongoing infection. In this trial in multiple tumour types it was noted 'patients with melanoma appeared to derive particular benefit, with 6 of 7 patients experiencing stable disease or better, including 3 confirmed partial responses and 1 complete response'.
So we may see that Modi-1 is better in some malignancies than others. Overall, my take-home is positive. Happy to leave my shares in the drawer, sit back and watch the excitement unfold over the coming months/years.
Yes is the answer - just checked the clinical trials page (https://clinicaltrials.gov/ct2/show/NCT05329532)
'Secondary Outcome Measures:
1 - Imaging Response using RECIST 1.1 and iRECIST to Modi-1 and Modi-1v in the non-neoadjuvant setting
Yes I would say yes they will be looking out for this. Especially as we have had clinician involvement from the beginning - these people will be well versed with immunotherapy response rates and progression of disease in patients treated with immunotherapies. I would therefore assume that the trial is using iRECIST (or better iRECIST1.1 criteria) to measure these patients with in a manner similar to other immunotherapy agents.
There is a range of different responses that can be observed - it should be highlighted that these differ from those observed with more traditional drugs such as chemotherapy or targeted agents such as mAbs etc.
Some patients only experience a response after disease progression - this is named pseudoprogression. As such, for many trials some of the response criteria for the trial may also include 'treatment allowed to continue after progression'. Though it should be noted that this is relatively rare and accounts for less than about 10% of patients treated with immunotherapies.
Some may experience hyperprogression - i.e. rapid progression of their disease. This can occur in anywhere upto about 30% of patients.
An important aspected for immunotherapy is that a repeat assessment should be conducted at least 4 weeks but not more than 8 weeks after the initial observation to give immunotherapy time to declare a response.
For many immunotherapy agents for example Keytruda, it can take 2-4 months after treatment is started before a measurable response is seen.
Reflections and comparisons of this work to Modi-1 data that we know so far.
1 - All patients dosed so far have had a response consistent with DTH. Will be interesting to see whether this does indeed translate to survival as this paper suggests.
2 - We know that LD and team are looking at inflammation. Inflammation at tumour sites = MHC-II expression = Modi-1 targets presented on cells.
3 - This is interesting, some patients had 100% lesion inflammation, others had 25-75%. What I would say is this work was done using an autologous whole cell-vaccine (i.e. cells taken from a patients own tumour). As such, you may find that if a patient’s disease is heterogeneous in nature (i.e. different metastasis may come from different lineages, therefore if you immunise using cells taken from metastasis A, you generate an immune response against A, but not against cells with lineage B,C,D. In a patient where all their metastasis are from the A lineage, they would have a higher % of lesions showing inflammation as the T-cells got to work because they recognise this. Modi-1 therefore may work within a patient on some tumours but not all - however, we are not immunising with patient derived autologous cells, we are immunising with epitopes which should be found in all stressed-cells…i.e. all cancer cells.
4 - LD is already on the case and stated at the AGM that they will be looking at tumour infiltration by T-cells in patients who are having surgery.
5 - another key difference. This paper found evidence of CD8 response, Modi-1 is going after a CD4 response (and in a patent protected way).
6 - Interferon gamma is a key part of modi-1 working.
7 - Stable disease…then complete tumour regression.
8 - In this patient stable disease, then tumour regression after 5 months but took 2 years to show complete tumour regression.
9 - The paper highlights a latency period of around 4 months and full after a year or so.
10 - DTH seems key.
So general reflection. All patients dosed so far have a DTH response with no dose limiting toxicities. If the immune response seen in this paper is similar in the moditope trial, this looks especially promising. Furthermore, don’t be put off by the fact only a single patient has a confirmed partial response and seven have stable disease. As shown in this paper, it took unto 4 months before things started accelerating and nearly a year before things peaked. This is exciting, at the cutting edge of science and is in the words of LD ‘highly encouraging’
3/3/End
7 - ‘Patient #20063 (CR), a 28-yr-old man, developed multiple bilateral lung metastases shortly after tumor tissue had been obtained from a regional lymph node metastasis. These metastases increased in size and number just prior to the start of DNP-vaccine treatment. After a course of DNP vaccine administration, the appearance of the metastatic nodules was unchanged. However, 2 months later, the metastases had completely regressed’
8 - ‘Patient #20254 (CR), a 77-yr-old man, presented simultaneously with a regional lymph node metastasis in the neck and 2-cm diameter mass in the lung adjacent to the cardiac border that increased in size over 2 months of observation. At 5 months after beginning DNP-vaccine treatment, the same mass was thought to be slightly smaller. The mass continued to slowly regress and by the 2-year point it had regressed completely.’
9 - ‘These examples of regression of lung metastases are noteworthy because the regressions developed slowly and only after a latent period. Evidence of response required at least 4 months, and in two of these cases, maximum regression required at least 1 year’
10 - ‘Of 214 patients participating in the trials, 20 had in-transit metastases as well, and 40 had clinically evident metastases to two nodal sites. The 5-year overall survival rate of the 214 patients participating was 44%. As noted above, the development of a positive DTH response to autologous, unmodified melanoma cells was a highly significant determinant of overall survival, even in a multivariate analysis’??
2/3
This is a really interesting paper, especially when placed in the context of modi-1. https://www.tandfonline.com/doi/pdf/10.1080/21645515.2023.2172925. For clarity, this is written by David Berd - founder and chief medical officer for BioVaxys a company
The section on delayed type hypersensitivity response (page 4) is particularly interesting. I've copied some extracts.
1 - 'An important observation that has been sustained over the course of these studies is the association of a positive DTH response to unmodified, autologous melanoma cells with prolonged survival. Thus, in the measurable metastases group, the survival of patients who developed a positive DTH to unmodified tumor cells was significantly longer than the survival of those who did not: 16.5 months vs 8.4 months, respectively (p
= .023, log-rank test). In the post-surgical adjuvant group, the development of a positive response to unmodified tumor cells was associated with significantly greater 5-yr survival (p< .001, log-rank test)'
2 - 'A rather surprising observation was made early into the first clinical trials of DNP-modified autologous vaccine: the development of inflammatory responses at metastatic sites'
3 - 'The number of inflamed tumors on a single patient ranged from 1 to >100. In some patients who had multiple superficial metastases, the inflammatory response involved all of the observable lesions, whereas others had inflammation in 25–75% of their visible tumors.'
4 - 'Biopsy of superficial metastases excised following treatment with DNP-vaccine showed a striking histologic change: the tumors had become infiltrated with T lymphocytes.....The median number of T cells in 15 post vaccine tumors was 41%, with some tumors containing more than 50% T cells. In contrast, in subcutaneous metastases excised without prior immunotherapy, T cells were sp**** (median = 9%), and significantly less frequent than in post DNP-vaccine-treated tumors.'
5 - 'T cells were predominantly CD8(+); the mean CD8/CD4 ratio was 5.0 vs 1.0 in matched PBL.'
6 - 'The production of cytokines by lymphocytes infiltrating the metastases was studied by analyzing the tissues using a standard RT-PCR technique. Post-vaccine, inflamed biopsies contained messenger RNA for gamma interferon (five of eight), IL-4 (four of eight), or both (three of eight), and for tumor necrosis factor (TNF) (four of seven). In contrast, gamma interferon mRNA was detected in only 1 of 17 and TNF mRNA in 2 of 16 control specimens (pretreatment lymph node metastases or non inflamed subcutaneous metastases). '
1/3
What stands out for me is the following ‘ First clinical candidate from Moditope® platform well tolerated with no dose limiting toxicities’.
As a first in man and first in class therapeutic, I wonder whether the dose is currently on the cautious side. Similar to the original SCIB1 trial, I wonder whether we’ll see an amendment to increase the dose. Finding that sweet spot.
Will be interested to see the CPI combo arm in due course. Does anyone know when we may get early efficacy data from this arm?
Krafty,
I believe you may be slightly misunderstanding the role that Innovate plays. As the UK governments funding arm, they are not partners in this. They are merely a grant funding body and as such any reporting from Scancell will be basic quantitative metrics which are linked to the funding scheme that SCLP won, not anything more regarding trial results, etc. This is really is as far as involvement goes, there most likely won’t be any reporting further back into government other than top line ‘we funded X number of projects, and this the impact on the UK because of that funding was Y’.
IUK will run case studies but it’s not a pre-requisite of an organisation to participate and contribute to one.