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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.

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

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). '
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